Protocol

Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004. DOI: 10.1056/NEJMoa1409077

Table of Contents

PDF page 2.

Original protocol dated 15-Sep-2009 (v. 01).

PDF page 95.

Amended protocol version v. 04 dated 7-Mar-2013, which includes amendments 1, 2, and 3. Summary of changes of all amendments can be found on p. 12 – 13 of amended protocol v. 04.

PDF page 196. PARADIGM-HF RAP module 3 – Detailed Statistical Methodology, also known as statistical analysis plan, v 1.0 dated 30-Sep-2012. PDF page 248. PARADIGM-HF RAP module 3 – Detailed Statistical Methodology v. 1.0 Amendment 1 dated 28-Apr-2014. Summary of changes included in Amendment 1 can be found on p. 5 of document.

Clinical Development & Medical Affairs

LCZ696B Clinical Study Protocol CLCZ696B2314

A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction

Authors:

Rizkala AR, Shi V, Chang WH, Chandra P, Lefkowitz M

Principal or Coordinating McMurray J and Packer M for the LCZ696 Executive Investigator Committee Document type:

Clinical Study Protocol

EUDRACT number:

2009-015834-31

Version number:

01

Development phase:

III

Release date:

10-Sep-2009 Template Version August 2007 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis

This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT

Novartis Clinical Study Protocol (Version No. 01)

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Page 2 Protocol No. CLCZ696B2314

Table of contents

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Table of contents .................................................................................................................2 List of tables ........................................................................................................................6 List of figures ......................................................................................................................6 List of abbreviations ............................................................................................................7 Glossary of terms...............................................................................................................10 Protocol synopsis...............................................................................................................11 Background........................................................................................................................21 Purpose and rationale ........................................................................................................24 Objectives ..........................................................................................................................24 3.1 Primary objective...................................................................................................24 3.2 Secondary objectives .............................................................................................24 3.3 Exploratory objectives ...........................................................................................25 Study design ......................................................................................................................25 4.1 Overview................................................................................................................25 4.2 Justification of key elements of the study design ..................................................26 4.2.1 Selection of the primary endpoint .........................................................26 4.2.2 Choice of enalapril as the comparator...................................................27 4.2.3 LCZ696 dose and dosing regimen ........................................................27 4.2.4 Single-blind active run-in period ..........................................................28 4.2.5 Duration of the study.............................................................................28 4.2.6 Early safety evaluation (seamless design).............................................29 4.3 Study visits.............................................................................................................29 4.3.1 Screening...............................................................................................29 4.3.2 Single-blind active run-in period ..........................................................29 4.3.3 Double-blind study treatment period ....................................................32 Population..........................................................................................................................34 5.1 Inclusion criteria ....................................................................................................34 5.2 Exclusion criteria ...................................................................................................35 Treatment...........................................................................................................................37 6.1 Investigational and control drugs...........................................................................37 6.2 Treatment arms ......................................................................................................39 6.3 Treatment assignment ............................................................................................39 6.4 Treatment blinding.................................................................................................40 6.5 Treating the patient ................................................................................................40 6.5.1 Patient numbering .................................................................................40



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6.5.2 Dispensing the study drug.....................................................................40 6.5.3 Study drug supply, storage and tracking ...............................................41 6.5.4 Instructions for prescribing and taking the study drug..........................41 6.5.5 Permitted study drug dose adjustments and interruptions.....................43 6.5.6 Rescue medication ................................................................................45 6.5.7 Other concomitant treatment.................................................................45 6.5.8 Study drug discontinuation and premature patient withdrawal.............46 6.5.9 Emergency unblinding of treatment assignment...................................47 6.5.10 Study completion and post-study treatment..........................................47 6.5.11 Early study termination .........................................................................47 Visit schedule and assessments .........................................................................................48 7.1 Information to be collected on screening failures..................................................52 7.2 Patient demographics/other baseline characteristics .............................................52 7.3 Treatment exposure and compliance .....................................................................52 7.4 Efficacy..................................................................................................................53 7.4.1 Primary and secondary efficacy endpoints ...........................................53 7.4.2 Endpoint Committee .............................................................................53 7.4.3 Estimated glomerular filtration rate (eGFR) .........................................54 7.4.4 Biomarkers ............................................................................................54 7.4.5 Urine albumin to creatinine ratio (UACR) and first morning void urine sampling.......................................................................................54 7.5 Safety .....................................................................................................................55 7.5.1 Physical examination ............................................................................55 7.5.2 Vital signs..............................................................................................55 7.5.3 Height, weight, and waist/hip circumference........................................55 7.5.4 Laboratory evaluations..........................................................................55 7.5.5 Electrocardiogram (ECG) .....................................................................58 7.5.6 Pregnancy and assessments of fertility .................................................58 7.5.7 Angioedema ..........................................................................................58 7.6 Other assessments ..................................................................................................59 7.6.1 Resource utilization...............................................................................59 7.6.2 Heart failure symptom reduction and reduction in physical limitation ...............................................................................................59 7.6.3 Clinical composite score .......................................................................60 7.6.4 EuroQol (EQ-5D)..................................................................................60 7.6.5 Pharmacokinetics ..................................................................................60 7.6.6 Pharmacogenetics/pharmacogenomics .................................................61



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7.6.7 Other biomarkers...................................................................................61 8 Safety monitoring ..............................................................................................................61 8.1 Adverse events.......................................................................................................61 8.2 Serious adverse event reporting.............................................................................62 8.3 Pregnancies ............................................................................................................63 8.4 Data Monitoring Committee..................................................................................63 8.5 Reporting angioedema-like events ........................................................................64 9 Data review and database management.............................................................................64 9.1 Site monitoring ......................................................................................................64 9.2 Data collection .......................................................................................................65 9.3 Database management and quality control ............................................................65 10 Data analysis......................................................................................................................66 10.1 Populations for analysis .........................................................................................66 10.2 Patient demographics/other baseline characteristics .............................................66 10.3 Treatments (study drug, rescue medication, other concomitant therapies, compliance)............................................................................................................67 10.4 Analysis of the primary objective..........................................................................67 10.4.1 Primary efficacy variable ......................................................................67 10.4.2 Statistical hypothesis, model, and method of analysis..........................67 10.4.3 Handling of missing values/censoring/discontinuations.......................67 10.4.4 Supportive analyses...............................................................................68 10.4.5 Subgroup Analyses................................................................................68 10.5 Analysis of secondary objectives...........................................................................69 10.5.1 Secondary efficacy variables.................................................................69 10.5.2 Analysis of secondary efficacy variables ..............................................69 10.6 Analysis of exploratory objectives ........................................................................71 10.7 Safety .....................................................................................................................72 10.8 Resource utilization ...............................................................................................73 10.9 Health-related quality of life..................................................................................73 10.10 Pharmacokinetics ...................................................................................................73 10.11 Pharmacogenetics/pharmacogenomics ..................................................................73 10.12 Biomarkers.............................................................................................................73 10.13 Pharmacodynamics ................................................................................................74 10.14 Sample size calculation..........................................................................................74 10.15 Power for analysis of critical secondary variables ................................................74 10.16 Interim analysis......................................................................................................75 10.17 End of the study .....................................................................................................76 This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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11 Ethical considerations........................................................................................................76 11.1 Regulatory and ethical compliance........................................................................76 11.2 Informed consent procedures.................................................................................76 11.3 Responsibilities of the investigator and IRB/IEC/REB.........................................77 11.4 Publication of study protocol and results...............................................................77 12 Protocol adherence ............................................................................................................77 12.1 Protocol Amendments ...........................................................................................77 13 References .........................................................................................................................77 14 Appendix 1: Clinically notable laboratory values and vital signs .....................................81 15 Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than or equal to 5.3 mmol/L).....................................................................................................81 16 Appendix 3: Guidelines for the management of blood pressure .......................................83 17 Appendix 4: Guidelines for the management of renal dysfunction...................................83 18 Appendix 5: Kansas City Cardiomyopathy Questionnaire ...............................................85 19 Appendix 6: EuroQoL (EQ-5D) ........................................................................................89



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List of tables Table 1 Table 4-1 Table 4-2 Table 6-1 Table 6-2 Table 7-1 Table 7-2

Criteria that must be met at screening, visit 3, and visit 5 ....................17 Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs ..................................................................................31 Safety monitoring criteria that must be met at Visit 1 (screening), Visit 3, and Visit 5 ................................................................................32 Study drug dispensed during the active run-in period by study visit....42 Study drug dispensed during the double-blind period ..........................42 Assessment schedule.............................................................................49 Routine laboratory examinations ..........................................................57

List of figures Figure 4-1 Figure 4-2 Figure 10-1

Timeframes between the visits of the active run-in period ...................30 Overall study design and timeframe between study visits occurring during the active run-in and double-blind periods ................................33 Illustration of weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary hypotheses............70



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List of abbreviations ACE

angiotensin converting enzyme

ACEI(s)

angiotensin converting enzyme inhibitor(s)

AE(s)

adverse event(s)

AF

atrial fibrillation

AHU377

pro-drug that is metabolized to the active moiety LBQ657

ALT

alanine aminotransferase

ANCOVA

analysis of covariance model

ANP

atrial natriuretic peptide

APP

aminopeptidase P

ARB(s)

angiotensin receptor blocker(s)

ARNi(s)

Angiotensin Receptor Neprilysin Inhibitor(s)

AST

aspartate aminotransferase

AT1

angiotensin type 1

AUC

area under the curve

bid

twice a day

BP

blood pressure

CHF

chronic heart failure

CPO

Country Pharma Organization

CRF

Case Report/Record Form

CRO

Contract Research Organization

CRTD

cardiac resynchronization therapy device

CSR

Clinical Study Report

CV

cardiovascular

DBP

diastolic blood pressure

DMC

Data Monitoring Committee

EC(s)

Ethics Committee(s)

ECG

electrocardiogram

eCRF

electronic case report form

eGFR

estimated glomerular filtration rate

EOS

end of study

EQ-5D

EuroQol



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ER

emergency room

ESRD

end stage renal disease

HF

heart failure

HTN

hypertension

IA

interim analysis(es)

ICH

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

ICU

intensive care unit

IEC

Independent Ethics Committee

IFCC

International Federation of Clinical Chemistry and Laboratory Medicine

IMS

Integrated Medical Safety

IRB(s)

Institutional Review Board(s)

i.v.

intravenous(ly)

IVRS

Interactive Voice Response System

KCCQ

Kansas City Cardiomyopathy Questionnaire

LCZ696

Novartis compound code

LVAD

left ventricular assistance device

LVEF

left ventricular ejection fraction

MDRD

Modification of Diet in Renal Disease

mg

milligram

MI

myocardial infarction

mmHg

millimeter mercury

MRI

magnetic resonance imaging

MUGA

multiple gate acquisition scan

NEP

neutral endopeptidase

NODM

new onset diabetes mellitus

NP(s)

natriuretic peptide(s)

NYHA

New York Heart Association

o.d.

once a day

PK

pharmacokinetic(s)

p.o.

oral(ly)

PCI

percutaneous coronary intervention



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PRA

plasma renin activity

RAAS

renin angiotensin aldosterone system

REB

Research Ethics Board

SAE(s)

serious adverse event(s)

SBP

systolic blood pressure

SHF

systolic heart failure

UACR

urinary albumin to creatinine ratio

ULN

upper limit of normal




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Glossary of terms Assessment

A procedure used to generate data required by the study

Control drug

A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. prior to starting any of the procedures described in the protocol)

Enrollment

Investigational drug

Medication number Patient number

Period

Premature patient withdrawal

Randomization number

The study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new drug.” A unique identifier on the label of each medication package in studies that dispense medication using an IVR system A number assigned to each patient who enrolls in the study. When combined with the center number, a unique identifier is created for each patient in the study. A major subdivision of the study timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc. Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are planned A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm assignment

Stop study participation

Point/time at which the patient came in for a final evaluation visit or when study drug was discontinued whichever is later

Study drug

Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs Point/time when patient permanently stops taking study drug for any reason; may or may not also be the point/time of premature patient withdrawal Information used in the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepoints

Study drug discontinuation

Variable



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Protocol synopsis Title of study: A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction. Purpose and rationale: A number of compensatory neurohormonal mechanisms are activated in heart failure (HF). While increases in the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activity are believed to be harmful in the long-term, the increase in natriuretic peptides (NPs) are thought to be a beneficial compensatory response, leading to vasodilation, natriuresis, and ameliorating many of the pathophysiological abnormalities of HF. Increasing the concentration of NPs by inhibiting neprilysin (neutral endopeptidase 24.11, NEP) represents a promising therapeutic approach which, so far, remains unexploited in clinical practice. Prior research has suggested that the potential clinical benefits from NEP inhibition can only be leveraged if the RAAS system is inhibited concomitantly. However, bradykinin, the putative mediator of angioedema, is broken down by angiotensin converting enzyme (ACE), and, to a modest degree, by NEP and concomitant ACE and NEP inhibition has been associated with an increased risk of angioedema. LCZ696, a dual-acting angiotensin receptor neprilysin inhibitor (ARNi), provides angiotensin receptor blockade via its valsartan moiety and NEP inhibition via the pro-drug AHU377 moiety. In contrast to ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs) have a lower risk of inducing angioedema, likely due to their neutral effect on the metallopeptidases involved in bradykinin breakdown. Therefore, LCZ696 is expected to deliver the benefits of combined RAAS and NEP inhibition without an increased risk of angioedema relative to ACEIs. ®

Prior studies have shown that LCZ696 200 mg provides valsartan exposure similar to Diovan 160 mg and results in approximately 90% NEP inhibition. In addition, a study in hypertensive patients showed the complementary effect of NEP inhibition to valsartan delivered by LCZ696 compared to valsartan alone. Therefore, the LCZ696 200 mg bid regimen delivers similar valsartan exposure as the ® evidence-based Diovan regimen approved for HF (160 mg bid), while potentially providing added benefits of NEP inhibition, i.e., antiproliferative/antihypertrophic effects, vasodilation, and natriuresis. The purpose of this study is to evaluate the effect of LCZ696 200 mg bid compared to enalapril 10 mg bid (the standard of care for RAAS blockade in patients with chronic heart failure [CHF]) in delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in patients with stable CHF New York Heart Association (NYHA) class II - IV and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) receiving conventional CHF treatment. Data from this study are intended to be used to support a worldwide registration submission of LCZ696 for treatment of patients with CHF and reduced ejection fraction. Objectives: The primary objective: • To test if LCZ696 is superior to enalapril in delaying time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization, in patients with CHF (NYHA class II – IV) and reduced ejection fraction. The secondary objectives: • To test whether LCZ696, compared to enalapril, improves the clinical summary score for HF symptoms and physical limitations (as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ]) at 8 months. •

To test whether LCZ696 is superior to enalapril in delaying the time to all-cause mortality.

•

To test whether LCZ696 is superior to enalapril in delaying the time to first occurrence of either (1) a 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, (2) >30 2 mL/min/1.73 m decline in eGFR relative to baseline, or (3) reaching end stage renal disease (ESRD).



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The exploratory objectives: • To compare the effects of LCZ696 and enalapril on delaying time to first occurrence of a composite of CV death, hospitalization for HF, non-fatal myocardial infarction (MI), non-fatal stroke or resuscitated sudden death. •

To compare the effects of LCZ696 and enalapril on reducing the number of patients hospitalized and number of hospital admissions (all-cause and cause-specific).

•

To compare the effects of LCZ696 and enalapril on increasing days alive out of the hospital at Month 12.

•

To test whether LCZ696 is superior to enalapril in slowing the rate of decline in eGFR (eGFR slope).

•

To compare the effects of LCZ696 and enalapril on delaying time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month.

•

To compare the effects of LCZ696 and enalapril on the clinical composite score (as assessed by NYHA classification and patient global assessment) at 8 months.

•

To compare the effects of LCZ696 and enalapril on delaying time to new onset of atrial fibrillation (AF).

•

To compare the effects of LCZ696 and enalapril on delaying time to new onset diabetes mellitus (NODM).

•

To compare the effects of LCZ696 and enalapril on improving health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and the EuroQol [EQ-5D]).

•

To compare the effects of LCZ696 and enalapril on reducing coronary revascularization procedures.

•

To compare the effects of LCZ696 and enalapril on pre-specified biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers) from baseline to predefined timepoints.

•

To compare the effects of LCZ696 and enalapril on reducing health resource utilization, i.e., number of days/stays in ICU and number of ER visits.

•

To characterize the pharmacokinetics (PK) of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or non-compartmental based methods.

Population: Patients with CHF (NYHA Class II-IV), aged 18 years or older with LVEF ≤ 40%. The target projected sample size is 7,980 patients (3,990 patients in each arm). It is estimated that approximately 16,000 patients will be screened at up to approximately 1,200 study sites because a screen failure rate of approximately 50% is anticipated based on previous experience. Key inclusion criteria: 1. Outpatients ≥ 18 years of age, male or female. 2. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction: •

LVEF ≤ 40% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI, or ventricular angiography is acceptable, provided no subsequent measurement above 40%)

•

BNP ≥ 150 pg/ml (NT-proBNP ≥ 600 pg/ml) at Visit 1 OR BNP ≥ 100 pg/mL (NT-proBNP ≥ 400 pg/ml) and a hospitalization for HF within the last 12 months 3. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1. •

For this protocol, doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d.



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•

For this protocol, doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 4. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication). Key exclusion criteria: 1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs. 2. Previous history of intolerance to recommended target doses of ACEIs or ARBs. 3. Known history of angioedema. 4. Requirement of treatment with both ACEIs and ARBs. 5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy). 6. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization). 2 7. Estimated GFR < 30 mL/min/1.73m as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 25% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5. 8. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (randomization). 9. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1. 10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1. 11. Implantation of a cardiac resynchronization therapy device (CRTD) within 3 months prior Visit 1 or intent to implant a CRTD. 12. History of heart transplant or on a transplant list or with left ventricular assistance device (LVAD). 13. History of severe pulmonary disease. 14. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1. 15. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1. 16. Symptomatic bradycardia or second or third degree heart block without a pacemaker. 17. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation. 18. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis. 19. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: •

History of active inflammatory bowel disease during the 12 months before Visit 1.

•

Active duodenal or gastric ulcers during the 3 months prior to Visit 1.

•

Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x upper limit of normal (ULN) at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt.



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• Current treatment with cholestyramine or colestipol resins. 20. Presence of any other disease with a life expectancy of < 5 years. Investigational and reference therapy: Active run-in All eligible patients will enter an active run-in period during which they will be exposed to enalapril 10 mg bid followed by LCZ696 (100 mg bid and then up titrated to 200 mg bid). The following study drugs will be provided: • Enalapril 5 mg tablets (enalapril dose level 2) •

Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2)

•

Enalapril 10 mg tablets (enalapril dose level 3)

•


•

LCZ696 100 mg film-coated tablets (LCZ696 dose level 2)

•

Placebo to match LCZ696 100 mg tablets (placebo matching LCZ696 dose level 2)

•


•


Patients will be required to take the single-blind enalapril or LCZ696 dose and placebo to match the opposite treatment at the corresponding dose level twice daily in addition to their conventional concomitant therapy (except for ACEI or ARB, which will be substituted with study drug). During the enalapril run-in period, the investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs (ACEI-naïve), or (2) currently treated with the lowest required doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, hyperkalemia). Double blind treatment All eligible patients will be randomized to receive either LCZ696 200 mg bid or enalapril 10 mg bid in addition to optimal CHF therapy, as considered appropriate by the investigator and in accordance with standard therapy guidelines, with the exception of an ACEI or an ARB as this will be replaced by the study drug. The following study drugs will be provided: • LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) •

Placebo to match LCZ696 50 mg film-coated tablets (placebo matching LCZ696 dose level 1)

•


•


•


•


•

Enalapril 2.5 mg film-coated tablets (enalapril dose level 1)

•

Placebo to match enalapril 2.5 mg film-coated tablets (placebo matching enalapril dose level 1)

•

Enalapril 5 mg film-coated tablets (enalapril dose level 2)

•

Placebo to match enalapril 5 mg film-coated tablets (placebo matching enalapril dose level 2)

•


•


Target doses: LCZ696 200 mg bid and enalapril 10 mg bid



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Patients not tolerating the target dose (LCZ696 200 mg bid or enalapril 10 mg bid) will be titrated down to the lower dose level, at the investigator’s discretion, based on the defined safety and tolerability criteria (Appendices 2, 3, and 4). All tablets (LCZ696 50 mg, LCZ696 100 mg, LCZ696 200 mg, enalapril 2.5 mg, enalapril 5 mg, enalapril 10 mg) have different shapes and colors. Therefore, the study will be designed as a doubleblind, double-dummy trial to ensure the blinding during the entire course of the study. To maintain the blinding, patients will be required to take their assigned active treatment tablet along with placebo matching the opposite treatment twice daily (morning and evening dose) in addition to their conventional concomitant therapy. The use of an ACEI or an ARB concomitantly with the study drug after randomization is strictly prohibited. Study design: This is a randomized, double-blind, parallel group, active-controlled study to evaluate the superiority of LCZ696 200 mg bid as compared to enalapril 10 mg bid, on morbidity and mortality reduction in patients with CHF (NYHA class II-IV) and reduced ejection fraction defined by a LVEF ≤40%. The trial consists of two main periods: (1) a single-blind run-in period, which will last ranging from 5 to 10 weeks, and (2) a double-blind randomized treatment period, which is projected to last up to 43 months. A subset of patients (approximately 400 worldwide of those participating in the biomarker sub-study) will participate in a population PK sub-study, which will be conducted at selected centers. Participating patients will provide four blood samples while at LCZ696 steady state at Visits 4 and 7 or 10 for analysis of valsartan, AHU377, and LBQ657 plasma levels. The trial will be event-driven and all randomized patients will remain in the trial until either the targeted number of patients with primary events has been reached or the trial is terminated prematurely at the recommendation of the Data Monitoring Committee (DMC) when pre-specified early-stopping criteria for efficacy (i.e., crossing pre-specified statistical limits for both the composite endpoint and the CV mortality component) or safety criteria are met. To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients who have reached 4 weeks of double-blind treatment is completed by an external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed. Since a total of 2,410 patients with primary events are targeted, it is anticipated that 7,980 patients will be required assuming the trial duration will be approximately 43 months, with a recruitment period of 22 months, and a mean follow up of approximately 30 to 32 months. The double-blind treatment stage will vary from 21 months to 43 months for each patient. Screening and the active run-in period At Visit 1 (screening), if the patient agrees to be in the study, he/she will be evaluated against the entry criteria and will be asked to sign an informed consent form prior to performing any study-related procedures. Visit 1 (Screening visit) At Visit 1, patient’s eligibility for entering the study will be assessed by the investigator by evaluating all inclusion/exclusion criteria. Any local measurement of LVEF made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography will be acceptable, provided no subsequent measurement above 40%. Screening BNP (and NT-proBNP) and potassium levels and eGFR will be assessed by sending blood samples to the central laboratory and only patients with the required values per the entry criteria will be eligible for entering the run-in period.



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At selected sites, if the patient has provided informed consent to participate in the biomarker substudy, the site should give the patient a urine collection container and instructions regarding collection of the first morning urine void before attending Visit 2. Visit 2 (enalapril run-in visit) At Visit 2, patients who meet all entry criteria, including the required clinical laboratory values, will be eligible to start the enalapril single-blind run-in period, during which patients will continue taking all other prescribed background treatments for CHF (except for ACEI or ARB). Patients will be started on enalapril 10 mg bid for 2 weeks. The investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). Patients tolerating enalapril 10 mg bid (enalapril target dose) will proceed to Visit 3, when they will start the LCZ696 single-blind run-in period. The site personnel should instruct the patient not to take their study medication (enalapril 10 mg bid) on the day of Visit 3. Visit 3 (LCZ696 run-in titration visit) At Visit 3, patients’ tolerability to enalapril 10 mg bid will be assessed. If the patients are found to tolerate enalapril 10 mg bid, they will enter the single-blind LCZ696 run-in period and begin taking LCZ696 100 mg bid starting the day after Visit 3. Patients should be maintained on this dose for 1 to 2 weeks at the investigator’s discretion. All patients tolerating LCZ696 100 mg bid will be scheduled for Visit 4 when the dose of LCZ696 will be up titrated to 200 mg bid (target dose). Visit 4 (LCZ696 up-titration visit) At Visit 4, patients’ tolerability to LCZ696 100 mg bid will be evaluated. If the patients are found to tolerate LCZ696 100 mg bid, patients will be up-titrated to LCZ696 200 mg bid (LCZ696 target dose) for 2 to 4 weeks at the investigator’s discretion. At the end of the active run-in period, only patients tolerating LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for at least 2 weeks will be randomized. At the investigator’s discretion, a patient receiving LCZ696 200 mg bid who experiences adverse effects, such as hyperkalemia, hypotension, or renal dysfunction, may be temporarily down-titrated to LCZ696 100 mg bid until such time that the investigator believes the patient may be able to tolerate up-titration back to LCZ696 200 mg bid. If subsequently the patient is unable to tolerate LCZ696 200 mg bid for at least two weeks despite the temporary down-titration to 100 mg bid, this patient will be considered a run-in failure and will be withdrawn from the study. Every attempt should be made to complete the run-in period within 10 weeks regardless of any downtitration that may occur There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning. Approximately 400 patients will participate in the PK substudy which will be conducted at select study sites. Participating subjects will provide a trough (Cmin) PK sample on the morning of Visit 4, prior to up-titration. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Safety and tolerability monitoring during the active run-in period Patients will be eligible for entering the enalapril run-in period at Visit 2, for entering the LCZ696 run-in period at Visit 3, and for randomization at Visit 5 if they meet all the inclusion criteria and none of the exclusion criteria, including the serum potassium, eGFR, blood pressure, and postural symptoms listed in Table 1. To ascertain patient’s eligibility for continuing in the study, Visit 3 (start of the LCZ696 run-in period) and Visit 5 (randomization) study drug should not be dispensed unless laboratory assessments of potassium and eGFR are available. This may require laboratory samples to be collected and analyzed up to 72 hours before these Visits. The reason for patient discontinuation during the active run-in period must be documented in detail in the appropriate electronic case report form(s) (eCRFs). Patients who experience angioedema during the run-in period will be withdrawn from the study.

Table 1

Criteria that must be met at screening, visit 3, and visit 5

Parameter

Visit 1 (screening)

Visit 3 (end of enalapril run-in) and Visit 5 (end of LCZ run-in and randomization)

Potassium level Kidney function

K ≤ 5.2 mmol/L

K ≤ 5.4 mmol/L

Blood pressure Adverse events (AEs) or conditions

No symptomatic hypotension and SBP ≥ 100 mmHg No postural symptoms or any conditions that preclude continuation according to the investigator’s judgment

eGFR ≥ 30 mL/min/1.73m

2

2

eGFR ≥ 30 mL/min/1.73m eGFR reduction ≤ 25% compared to Visit 1 No symptomatic hypotension and SBP ≥ 95 mmHg No postural symptoms or any AEs that preclude continuation according to the investigator’s judgment

Double-blind study treatment period Patients who have met all the entry criteria and tolerate enalapril 10 mg bid and LCZ696 200 mg bid by the end of the single-blind active run-in period will be randomized to either enalapril 10 mg bid or LCZ696 200 mg bid in a 1:1 ratio. Other conventional background HF medications should remain unchanged (particularly disease modifying treatments, such as β-blockers). All patients qualifying for randomization will have their LCZ696 active run-in medication stopped (not taken) starting on the day of Visit 5 (randomization) and will receive the first dose of double-blind randomization medication the morning after Visit 5. Patients will continue taking the target dose of the study drug and attending study visits every 2 to 8 weeks during the first 4 months of the double-blind period and every 4 months thereafter. In addition to the protocol-specified visits, patients may be seen at anytime throughout the study at the discretion of the investigator. All randomized patients, including any patient who has experience a health event, should continue to receive double-blind treatment until the trial is completed. The monitoring of safety and tolerability will include: (1) hyperkalemia; (2) symptomatic hypotension; (3) increase in serum creatinine; (4) angioedema; and (5) other AEs and serious AEs (SAEs). Patients who no longer tolerate the target dose at any time during the course of the double-blind period can be down-titrated to the lower dose at the investigator’s discretion. If, in the opinion of the investigator, the patient cannot tolerate the target dose of study drug, the investigator should consider whether non-life saving medication (e.g., calcium channel blockers [CCBs], nitrates, α-blockers) can be reduced to rectify the situation before considering reducing the dose of the study drug to the next lower dose level. The doses of background disease modifying drugs, such as β-blockers, should not be reduced to facilitate maintenance of study drug. Every attempt should be made to re-challenge the patients so This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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that they are kept on the maximal tolerated dose of study drug for as long a duration as possible throughout the trial. If the study drug is temporarily discontinued, it should be reintroduced as soon as medically justified in the opinion of the investigator. After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the study. On the contrary, even patients who have stopped taking study drug should be asked to attend all the protocol specified study visits to perform all assessments as stipulated in the visit schedule. Patients participating in the PK sub-study will provide three blood samples at Visit 7 or at Visit 10 for analysis of valsartan, AHU377, and LBQ657 plasma levels at predose, 0.5 to 2 hours, and 3 to 5 hours post-dose. It is not required that all samples are obtained during the same study visit. All randomized patients will remain in the trial until either (1) the projected number of primary endpoints (CV death or HF hospitalization) is reached, or (2) the trial is terminated prematurely at the recommendation of the DMC when pre-specified early-stopping criteria for efficacy or safety are met. Primary assessment: •

Time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization

Secondary assessments: • Improvement in clinical summary score for HF symptoms and physical limitations domains of the KCCQ at Month 8 •

All-cause mortality

•

Composite renal endpoint defined as (1) 50% decline in eGFR relative to baseline, (2) >30 2 mL/min/1.73m decline in eGFR relative to baseline, or (3) reaching ESRD

Exploratory assessments: • Composite CV mortality and morbidity (CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death) •

Non-fatal stroke

•

Non-fatal MI

•

Resuscitated sudden death

•

Days alive out of the hospital at 12 months

•

Decline in eGFR (eGFR slope)

•

Time to study treatment failure for HF

•

Change in clinical composite score (assessed by NYHA classification and patient global assessment) at 8 months

•

New onset of AF

•

New onset diabetes

•

Improvement in quality of life (KCCQ and EQ-5D)

•

Coronary revascularization procedures

•

BNP, NT-proBNP

•

Other predefined biomarkers

•

Days/stays in ICU

•

ER visits

•

Steady state plasma concentrations of valsartan, AHU377, and LBQ657 immediately before the study drug dose and at 0.5-2 hours and 3-5 hours after study drug dose

Safety assessments: This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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•

AEs and SAEs

•

Sitting systolic (SBP) and sitting diastolic BP (DBP)

•

Heart rate

•

Symptomatic hypotension

•

Angioedema

•

Laboratory values

•

Hyperkalemia

•

Renal dysfunction

•

ECG changes


Data analysis: The primary hypothesis to be tested is H10: λ2 ≥ λ1 versus H1a: λ2 < λ1, where λ1 and λ2 are hazards for enalapril and LCZ696 treatments, respectively. The primary efficacy variable is time to first occurrence of CV death or HF hospitalization. The primary efficacy variable will be analyzed using Cox proportional hazards model with treatment and region as two fixed-effect factors. The primary hypothesis will be tested at a one-sided significance level of 0.025 adjusted for interim analyses (IA). The Full Analysis Set (FAS) will be used for the primary analysis following the intent-to-treat principle. The PP (per-protocol population) will be used for supportive analyses. The hazards ratio and its associated two-sided confidence interval will be estimated from the Cox model. Kaplan-Meier curves will also be presented, by treatment group, to summarize the primary composite endpoint. Additionally, similar analyses will be performed for each of the components of the primary composite endpoint with all events for that component occurred during the double blind period of the study to quantify the strength of the effect for each component in the primary composite endpoint. The secondary hypotheses will be tested and statistical inference will be made only if the primary hypothesis is rejected. The three secondary efficacy variables will be tested for superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LZD696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. Quality of life, as assessed by KCCQ clinical summary score, will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit, and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance for each treatment group. The primary treatment comparison between LCZ696 and enalapril is to be made at Month 8. The analysis will be performed based on all available data in the FAS and based on likelihood method. The estimated treatment effect with the associated confidence interval at Month 8 will be provided. The time to all-cause mortality will be analyzed, similar to the primary efficacy variable, using Cox proportional hazards model with treatment and region as fixed-effect factors. Time to composite renal endpoint will be analyzed using Cox proportional hazards model with treatment and region as fixedeffect factors. Safety analysis will be performed primarily with summary on the frequency of AEs, SAEs, and notable laboratory abnormalities with the safety population. The number of patients with confirmed angioedema and renal dysfunction will be compared as well. No formal statistical inference analysis will be performed for the safety analysis. The sample size evaluation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the interim efficacy analyses. For the CV mortality component, with a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril using the log-rank test. Assuming an annual event rate of 7% in the enalapril group, an enrollment period of 22 months, and a minimum follow-up 21 months, a total sample size of 7,980 patients will be required to obtain the targeted 1,229 CV mortality events. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Assuming the same enrollment period and follow-up duration as above, a 15% reduction in hazard, and an annual event rate of 14.5% in the enalapril group, randomizing 7,980 patients will provide statistical power ≥ 97% for detecting a difference between the two treatment groups in the primary composite endpoint. This in turn will expect to have a total of 2,410 patients with primary events. The O’Brien-Fleming type of boundary with Lan-DeMets alpha spending function will be used for the interim efficacy analyses to assess superiority. As currently planned, two interim efficacy analyses are to be expected approximately at 1/3 and 2/3 of information time (i.e. approximately 803 and 1607 patients, respectively, with a primary events of CV mortality or HF hospitalization). The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (one-sided) at the first interim analysis and 0.00605 (one-sided) at the second interim analysis. The actual alpha to be spent for the interim efficacy analyses will be precisely determined based on the Lan-DeMets alpha spending function using the actual number of patients who have experienced a primary events at the interim efficacy analyses. Additionally, the CV death component will also be analyzed at each interim efficacy analysis. When 1/3 and 2/3 of the total number of patients with primary events occurred, approximately 409 and 819 CV deaths are to be expected, respectively. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the planned boundary are obtained for both primary composite endpoint and CV mortality component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment based on the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. Interim safety assessments are planned to be performed twice a year. In addition, to detect early safety signal, a blinded review of selected safety assessments will be performed when 200 patients have completed the first 4 weeks of randomized treatment. No further alpha adjustment will be made due to these interim safety assessments.



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Background

Chronic heart failure (CHF) is a major public health problem characterized by significant mortality, frequent hospitalization, and poor quality of life, with an overall prevalence that is increasing throughout the world. In the United State (US) alone, approximately 5 million patients have heart failure (HF) and there are over half a million newly diagnosed cases annually (Hunt et al 2009, ESC Guidelines 2008). In Europe, the prevalence of HF is between 2 and 3%, and that in the elderly is estimated between 10 to 20% (ESC Guidelines 2008). HF is responsible for more hospitalizations than all forms of cancer combined and is the leading cause of hospitalization in patients older than 65 years of age (Adams et al 2006, American Heart Association 2006). In-hospital mortality is excessive and readmission is distressingly common. Frequent hospitalizations, along with other direct and indirect costs, also place an enormous financial burden on healthcare systems; more is spent annually in the US for the treatment of HF by Medicare than on any other Medicare diagnosis (Adams et al 2006, American Heart Association 2006) and HF accounts for approximately 2% of the national expenditure on health in the United Kingdom (Stewart et al 2002). A complex clinical syndrome with varying pathophysiological and clinical manifestations, HF is exhibited in patients with reduced left ventricular ejection fraction (LVEF) as well as preserved LVEF. Therapies targeted at improving outcomes in HF with a low EF have been well studied over the past two decades, leading to an improvement in survival as well as a decrease in morbidity, mostly in the form of decrease in re-hospitalization for HF, with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), βblockers and mineralocorticoid antagonists (CONSENSUS Trial Study Group 1987, Cohn and Tagnoni 2001, SOLVD Investigators 1991, SOLVD Investigators 1992, RALES Investigators 1996, Pitt et al 1999, MERIT-HF Study group 1999, CIBIS II Investigators 1999, Packer et al 2002b, Pfeffer et al 2003, Flather et al 2005). However, despite advances in pharmacological (and device therapies), the outlook remains poor. Overall 50% of patients die within 4 years, and 40% of patients admitted to hospital with HF die or are readmitted within 1 year (ESC Guidelines 2008). Thus, HF still represents a major cause of cardiac mortality and morbidity with a clear need for better therapy. The neurohormonal response to cardiac injury is pivotal to the development and progression of heart failure. While increases in renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activity are believed to be harmful in the long-term, the increases in natriuretic peptides (NPs) are believed to be a beneficial compensatory response. As well as counteracting the effects of both RAAS and SNS, NPs have direct vasodilator and natriuretic actions, and exhibit antiproliferative and antihypertrophic effects, thereby, potentially, ameliorating many of the pathophysiological abnormalities in HF (Levin et al 1998, Gardner et al 2007, Pandey 2008). Therefore, therapy that increases circulating concentrations of NPs through inhibition of neprilysin (neutral endopeptidase 24.11, NEP), the enzyme responsible for breaking down NPs, is considered an attractive therapeutic approach for a number of cardiovascular (CV) diseases, such as hypertension (HTN) and HF. However, results from previous clinical studies indicated that the effects of NEP inhibition alone are not sustained in the longer term. For example, NEP inhibition alone failed to demonstrate clinically meaningful blood pressure This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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(BP) lowering despite significantly increasing atrial natriuretic peptide (ANP) concentrations (Bevan et al 1992). It has been hypothesized that the vasoconstriction induced by ancillary properties of NEP inhibitors on other physiological substrates (e.g., angiotensin II) and feedback mechanisms can offset the BP lowering effect of ANP (Richards et al 1993, Ferro et al 1998). Therefore, inhibition of NEP activity must be accompanied by inhibition of RAAS activity to achieve a beneficial effect. Vasopeptidase inhibitors constitute a class of drugs that simultaneously inhibit both NEP and ACE. Indeed, omapatrilat, the most extensively evaluated agent from this class, demonstrated greater BP lowering as compared to other therapeutic classes, including ACE inhibitors (ACEIs) and calcium channel blockers (CCBs) (Neutel et al 1999, Asmar et al 2000, Ruilope et al 2000). Additionally, omapatrilat also showed an encouraging trend toward reducing mortality and morbidity in patients with HF relative to enalapril (Packer et al 2002a). Unfortunately, omapatrilat treatment was associated with an increased incidence of angioedema compared with enalapril (2.17% vs. 0.68%) in hypertensive patients (Kostis et al 2004), though the increase in angioedema risk was less (0.8% and 0.5%, respectively) in HF patients (Packer et al 2002a). It was hypothesized that angioedema may have been a particular problem with omapatrilat because, in addition to inhibiting NEP and ACE, this compound also blocked a third key enzyme involved in bradykinin degradation, namely aminopeptidase P (APP) (Fryer et al 2008). Omapatrilat, thus, simultaneously blocked three key enzymes responsible for the breakdown of bradykinin, the putative mediator of angioedema (Fryer et al 2008, Sulpizio et al 2005). LCZ696, a dual acting RAAS and NEP inhibitor, is the most advanced dual angiotensin receptor neprilysin inhibitor (ARNi) compound in development. It delivers two moieties in a molar ratio of 1:1: a valsartan moiety, which is an orally active, potent, and specific competitive angiotensin type 1 (AT1) receptor antagonist, and an AHU377 moiety, which is a non-peptide, orally active pro-drug that is rapidly hydrolyzed to the active moiety LBQ657, a specific inhibitor of NEP. The molecular structure of LCZ696 conveys unique chemical and biological properties. LCZ696 has been shown to deliver 140-160% higher exposure of valsartan on an area-underthe-plasma-concentration-time-curve (AUC) basis than the Diovan® global formulation. Doses of LCZ696 (50 mg, 100 mg and 200 mg) deliver rates of valsartan exposures which are similar to those delivered from the Diovan® dose strengths (40 mg, 80 mg and 160 mg, respectively); for example, the exposure of valsartan following administration of LCZ696 200 mg (which contains 103 mg of valsartan) is similar on an AUC basis to that of the 160 mg Diovan® formulation. In addition, the half-life of valsartan following LCZ696 administration is comparable to that following Diovan® administration, suggesting that rate of elimination of valsartan for LCZ696 is similar to that for Diovan®. Biomarker analysis (i.e., increases in ANP and cGMP) indicates that LCZ696 at a dose of 200 mg dose delivers approximately 90% of its maximal NEP inhibition. The valsartan moiety delivered by LCZ696 has a peak plasma concentration (Tmax) of approximately 2 hours and a half-life (T½) of approximately 15 hours. Approximately 83% of an oral valsartan dose is recovered in feces, primarily as unchanged drug. Twenty percent of the dose is recovered as metabolites. Patients with mild to moderate hepatic insufficiency have an approximate 2-fold greater exposure (measured by AUC) compared to healthy This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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volunteers. LBQ657, the active NEPi moiety in LCZ696, has a Tmax of approximately 2 hours with a T½ of 12 - 16 hours. Approximately 50% of an oral dose is recovered as unchanged drug in urine. Patients with mild, moderate and severe renal insufficiency have an approximate 2.0, 2,4 and 2.7 fold greater exposure (measured by AUC), respectively, compared to healthy volunteers. No drug-drug interaction was observed between LCZ696 and warfarin (CYP2C9); LBQ657 showed little or no inhibition in in vitro assays against other human cyctochrome P450 (CYP) enzymes. To date, LCZ696 has been administered to a total of 255 subjects in completed short-term clinical pharmacology studies. LCZ696 was safe and well tolerated following administration of single doses up to 1200 mg and of daily doses of up to 900 mg in multiple doses (for 14 days) in healthy volunteers. Adverse events (AEs) were mostly mild, transient in nature and most were assessed as not suspected to be related to treatment. Most frequently reported AEs included postural orthostatic tachycardia, dizziness, headache, and orthostatic hypotension. No dose dependency of AEs was observed and there were no severe AEs or deaths reported. In a dose-ranging study (N=1328), a total of 497 hypertensive patients received LCZ696 (100 mg, 200 mg and 400 mg). This study showed that LCZ696 (400 mg/d and 200 mg/d) lowered BP to a greater extent than corresponding doses of valsartan 320 mg/d and 160 mg/d. Discontinuation rate due to AEs was similar to placebo. No dose related trends were observed for any specific AEs. The most frequent AE was headache, which was more frequent in the placebo group compared to any other group. A total of 2 SAEs occurred with LCZ696 treatment (road accident/limb fracture; back pain/dyspnea) with none suspected to be related to study drug. The incidence of hypotension and dizziness was low (< 1%) and there were no reported cases of angioedema over the 9-week duration of the study. The pharmacokinetics and tolerability/safety of LCZ696 were recently evaluated in 30 CHF patients with reduced ejection fraction (LVEF 5.5 mmol/L). Two patients experienced brief episodes of syncope, one due to hypoglycemia and the second due to a vasovagal reaction following blood drawing. There were no serious adverse events or angioedema reported in this study. Although the risk of angioedema due to NEP inhibition by LCZ696 is not fully characterized due to the availability of limited clinical data, NEP represents a relatively minor metabolic pathway of bradykinin breakdown (Fryer et al 2008). Furthermore, LBQ657, the active metabolite of the NEP inhibitor moiety in LCZ696, is a poor inhibitor of ACE and APP in vitro, which represent major degradation pathways for bradykinin. ARBs have a low risk of inducing angioedema likely due to their neutral effect on the metallopeptidases involved in bradykinin breakdown (Cicardi et al 2004). Therefore, LCZ696 may deliver the benefits of combined RAAS and NEP inhibition without an increase in the risk of angioedema. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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As a dual-acting ARB-NEP inhibitor, LCZ696 offers the therapeutic advantage of concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (i.e., blockade of RAAS via the ARB component), while stimulating an anti-fibrotic/anti-hypertrophic mechanism (i.e., increasing NP levels via the NEP inhibitor component) (Perlini 2005, Pu et al 2005). Therefore, it is anticipated that LCZ696 will confer a superior/additional cardio-renal protection than ARB therapy alone. Due to this unique mechanism of action, LCZ696 may fulfill the promise of providing a novel, more effective therapy for patients with CHF where vasoconstriction, volume expansion, as well as hypertrophy and fibrosis play key roles in the pathophysiology of disease development and progression. Study CLCZ696B2314 is a multicenter, randomized, double-blind, parallel group activecontrolled study to evaluate the efficacy of LCZ696 on morbidity and mortality compared to enalapril, the current gold standard for RAAS blockade in HF treatment, in patients with CHF and reduced ejection fraction. This study is outcome-driven and is designed to test the primary hypothesis that, compared to enalapril, simultaneous angiotensin receptor blockade and NEP inhibition with LCZ696 delays the time to first occurrence of either CV death or HF hospitalization. Secondary endpoints are change in the clinical summary score, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), time to all-cause mortality, and time to composite renal endpoint defined as (1) 50% decline in eGFR compared to baseline, (2) > 30 ml/min/1.73m2 decline in eGFR compared to baseline, or (3) reaching end stage renal disease (ESRD).

2

Purpose and rationale

The purpose of this study is to evaluate the effect of LCZ696 200 mg bid compared to enalapril 10 mg bid, in addition to conventional HF treatment, in delaying time to first occurrence of either CV death or HF hospitalization events in patients with stable CHF NYHA classes II-IV and reduced ejection fraction (LVEF ≤ 40%). Data from this study are intended to be used to support a worldwide registration submission of LCZ696 for treatment of patients with CHF and reduced ejection fraction.

3

Objectives

3.1

Primary objective

The primary objective of this study is to test if LCZ696 is superior to enalapril in delaying time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization, in patients with CHF (NYHA class II – IV) and reduced ejection fraction (LVEF ≤ 40%).

3.2 • •

Secondary objectives

To test whether LCZ696, compared to enalapril, improves the clinical summary score for HF symptoms and physical limitations (as assessed by KCCQ) at 8 months. To test whether LCZ696 is superior to enalapril in delaying the time to all-cause mortality.



•

• • • •

• • • •

• •

• •


To test whether LCZ696 is superior to enalapril in delaying the time to first occurrence of either (1) a 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, (2) >30 mL/min/1.73 m2 decline in eGFR relative to baseline, or (3) reaching ESRD.

3.3 •

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Exploratory objectives

To compare the effects of LCZ696 and enalapril on delaying time to first occurrence of a composite of CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death. To compare the effects of LCZ696 and enalapril on reducing the number of patients hospitalized and number of hospital admissions (all-cause and cause-specific). To compare the effects of LCZ696 and enalapril on increasing days alive out of the hospital at Month 12. To test whether LCZ696 is superior to enalapril in slowing the rate of decline in eGFR (eGFR slope). To compare the effects of LCZ696 and enalapril on delaying time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month. To compare the effects of LCZ696 and enalapril on the clinical composite score (assessed by NYHA classification and patient global assessment) at 8 months. To compare the effects of LCZ696 and enalapril on delaying time to new onset of AF. To compare the effects of LCZ696 and enalapril on delaying time to new onset diabetes mellitus (NODM). To compare the effects of LCZ696 and enalapril on improving health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and the EQ-5D). To compare the effects of LCZ696 and enalapril on reducing the incidence of coronary revascularization procedures. To compare the effects of LCZ696 and enalapril on the profile of pre-specified biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers) from baseline to predefined timepoints. To compare the effects of LCZ696 and enalapril on reducing health resource utilization, i.e., number of days/stays in ICU and number of ER visits. To characterize the PK of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or non-compartmental based methods.

4

Study design

4.1

Overview

This study is a randomized, double-blind, double-dummy, parallel-group, active-controlled, two-arm, long-term trial to compare LCZ696 200 mg bid to enalapril 10 mg bid in CV This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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mortality and morbidity reduction in patients with stable CHF and reduced ejection fraction. Patients will enter a single-blind active run-in period ranging from 5 to 10 weeks in which they will receive enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid. Patients who tolerate the target dose of enalapril (10 mg bid) and the target dose of LCZ696 (200 mg bid) for at least 2 weeks will then be randomized in equal allocation to receive LCZ696 200 mg bid or enalapril 10 mg bid during the double-blind period. The investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). A subset of patients (approximately 400 worldwide of those participating in the biomarker substudy) will participate in a population PK substudy, which will be conducted at selected centers (Section 7.6.5). Participating patients will provide 4 blood samples in total, while at LCZ696 steady state at Visits 4 and Visits 7 (or Visit 10 if not taken at Visit 7) for analysis of valsartan, AHU377, and LBQ657 plasma levels. This study will be event-driven in which patients will remain in the study (regardless of whether receiving study medications) until the projected number of patients with primary events (2,410 events) has been reached or early termination of the study when a pre-specified efficacy or safety criterion is met. To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients to complete 4 weeks of double-blind treatment is completed by the external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed. Two interim efficacy analyses are planned when approximately 1/3 and 2/3 of the projected primary events occur. Interim safety assessments will be performed twice a year. It is planned that the total trial duration will be approximately 43 months, with a projected recruitment period of 22 months and a follow-up period of 21 months after the enrollment of the last patient into the trial. It is expected that the average follow-up time will be approximately 32 months.

4.2

Justification of key elements of the study design

4.2.1

Selection of the primary endpoint

Apart from improving symptoms, there is general agreement that the major goal of treating HF with a reduced LVEF is to reduce the major fatal and non-fatal consequences of this illness, i.e., CV death and hospitalization for worsening HF. CV death accounts for approximately 80% of all deaths in HF patients and most CV deaths are due to either sudden (presumed arrhythmic) death or death due to worsening heart (i.e., pump) failure. Only a small proportion of CV deaths is due to other CV events. Hospitalization for worsening HF is the single most common cause of hospital admission in this patient population and is an ominous development in that it portends high subsequent risk – both of readmission and of This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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death. HF hospitalization is also the main driver of the huge economic burden of this syndrome. As CV death and HF hospitalization both reflect disease-specific endpoints related to progressive worsening of the HF syndrome, they should both be modifiable by treatments improving this condition, which has generally proved to be the case with both drugs (ACEIs, aldosterone antagonists, and β-blockers) and devices (cardiac resynchronization therapy). This understanding of HF and its treatment has led to the disease-specific composite outcome of CV death or HF hospitalization becoming the most commonly used primary endpoint in current HF outcomes trials. Importantly, this study is sized sufficiently to detect a reduction in cardiovascular mortality. 4.2.2

Choice of enalapril as the comparator

Major clinical trials have established ACEI treatment as the standard of care for RAAS blockade and are recommended by treatment guidelines as the treatment of choice for all patients with CHF and reduced LVEF, unless ACEI-intolerant. Since the ultimate goal of the LCZ696 development program is to replace ACEIs as the guideline-recommended RAASbased agent in HF with reduced LVEF, an ACEI has been selected as the control in this study. As a well-studied ACEI in HF, enalapril is used as the comparator in this study. Enalapril was studied in a number of previous large, outcome-driven studies, such as OVERTURE (Packer 2002a), CONSENSUS (CONSENSUS Trial Group 1987), SOLVD-Treatment (SOLVD Investigators 1991), and SOLVD-Prevention (SOLVD Investigators 1992). Enalapril dose of 10 mg bid has been selected as the comparator target dose for this study based on its ability to reduce the risk of death or hospitalization as demonstrated in the SOLVD-Treatment study (SOLVD Investigators 1991). 4.2.3

LCZ696 dose and dosing regimen

A strong rationale exists for the selection of LCZ696 200 mg bid as the target dose. Importantly, a dose of LCZ696 200 mg bid delivers similar exposures of valsartan (assessed by AUC) as Diovan® 160 mg bid, the maximal approved Diovan® dose for HF and the dose recommended in international guidelines for the treatment of HF. In addition, biomarker analysis (increase in ANP and cGMP) indicates that this dose delivers approximately 90% of its maximal NEP inhibition. The biomarker data are also consistent with results obtained in a dose ranging study in HTN, which demonstrated additive effects of the ARB moiety and the NEPi moiety with LCZ696 400 mg and 200 mg once daily, with a minimal incremental BP reduction from LCZ696 200 mg/d to LCZ696 400 mg/d. LCZ696 400 mg/d and 200 mg/d were well tolerated in this study. Rather than 400 mg once daily dosing of LCZ696 that was used in the HTN study, this dose will be split and LCZ696 will be dosed at 200 mg twice daily in the current study. This will ensure sustained NEP inhibition over 24 hours, which is thought to be critical for patients with HF. Furthermore, twice daily dosing will also mitigate the likelihood of hypotension, particularly in those with more severe HF impairment (NYHA III-IV).



4.2.4

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Single-blind active run-in period

The single-blind active run-in period consists of enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a duration of 5 to 10 weeks. During the run-in period, patients will continue their background HF medications. Patients unable to tolerate enalapril 10 mg bid and LCZ696 200 mg bid during the run-in will not be eligible for randomization, and will be discontinued from the study. This design will allow a careful assessment of the patients’ tolerability to the target doses of enalapril (10 mg bid) and LCZ696 (200 mg bid) prior to randomization. Importantly, this study design maximizes the number of randomized patients able to tolerate the target dose of either LCZ696 (200 mg bid) or enalapril (10 mg bid) during the long-term follow-up period. Thus, the study is comparing patients who are both ACEI and LCZ696 tolerant. Down titration from LCZ696 200 mg bid to LCZ696 100 mg bid will be allowed during the single-blind active run-in period. As a result of including the active run-in period in the current study design, it is anticipated that the average dose of enalapril achieved in the proposed study will be similar to, or will exceed, that achieved in the SOLVD-Treatment study (16.6 mg/d) (SOLVD Investigators 1991). There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning. On the other hand, the risk of HF deterioration associated with stopping concomitant ACEIs or ARBs for 36 hours, the duration of the ACEI/ARB-free period, will be minimal, especially since all patients will be allowed to continue receiving their background HF and CV medications. 4.2.5

Duration of the study

This study is an event driven, outcomes trial. The end of the study will occur when the prespecified number of patients achieves the primary composite endpoint of CV deaths or hospitalizations for heart failure (2,410 patients), unless the study is terminated early because of a statistically significant results in the efficacy interim analyses or because of a critical safety concern that arises at any of the safety interim analyses. In the event of an early trial termination, the secondary endpoints would be analyzed exactly as they would be if the study had not been stopped early. As an event driven trial, the actual length of the trial will depend on the observed event rates, the patient accrual rate, and length of the accrual period. As planned, it is expected to be up to 43 months: a recruitment period of approximately 22 months and a minimal follow-up of 21 months. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


4.2.6

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Early safety evaluation (seamless design)

To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients who have reached 4 weeks of doubleblind treatment is completed by an external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed.

4.3

Study visits

4.3.1

Screening

Visit 1 (Screening Visit) All patients must provide informed consent before any study-specific procedure is performed. At Visit 1, patients’ eligibility for entering the active run-in period, including the required minimum daily doses of pre-study ACEI or ARB (Table 4-1), will be assessed by the investigator. LVEF measurements required for eligibility will be based on locally obtained echocardiograms, MUGA scans, CT scans, MRIs, or ventricular angiographies performed within the last 6 months provided that no subsequent measurements were above 40%. Screening BNP (or NT-proBNP) and potassium levels and eGFR will be assessed by sending blood samples to the central laboratory and only patients with the required values per the entry criteria will be eligible for entering the run-in period, which will begin at Visit 2. A patient may qualify for inclusion into the study based either on a BNP value or a NT-proBNP value according to the inclusion criteria mentioned in Section 5.1. Since it may take up to 72 hours to obtain the results of the clinical laboratory assessments to evaluate the patient’s eligibility for the study, it is recommended that at Visit 1 the site schedules Visit 2 approximately one week after Visit 1. At select sites, if the patient has provided informed consent to participate in the biomarker sub-study, the site should give the patient a urine collection container and instructions on how to collect the first morning urine void, which should be performed before returning to the site for Visit 2. 4.3.2


Patients who are successfully screened into the study at Visit 1 will enter the single-blind active run-in period, which includes an enalapril run-in followed by an LCZ696 run-in. Since this period will be a single-blind period, the site staff working with patients should exercise caution when discussing the study procedures and the study drug with patients to keep the patient blinded to the identity of the study drug. Figure 4-1 is a schematic that illustrates the timeframe between the run-in period visits.



Figure 4-1

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Timeframes between the visits of the active run-in period

Every attempt should be made to complete the run-in period within 10 weeks regardless of any down-titration that may occur. Please refer to Section 6.5.5 for guidance on dose titration during the run-in period. Please refer to Table 7-1 for a detailed list of study procedures and assessment to be performed at each run-in period visit. Visit 2 (Enalapril run-in visit) Once patients’ eligibility has been ascertained, they will attend Visit 2 approximately one week after Visit 1 to start enalapril 10 mg bid for 2 weeks. Patients should continue to take their background medications for CHF, with the exception of ACEI or ARBs which must be discontinued. All patients tolerating enalapril 10 mg bid will be scheduled for Visit 3 when they will start the single-blind LCZ696 run–in period. Patients will continue to take all other prescribed background treatments for CHF and other CV conditions. The investigator may consider initiating treatment with enalapril 5 mg bid for 1 to 2 weeks in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). Visit 3 should be scheduled 2 weeks after Visit 2. The site personnel should instruct the patient not to take either the enalapril run-in medication (enalapril 10 mg bid) or the LCZ696 run-in medication on the day of Visit 3.



Table 4-1

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Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs

ACEIs

Minimum dose

ARBs

Minimum dose

Enalapril Captopril Cilazapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril Zofenopril

10 mg 100 mg 2.5 mg 20 mg 10 mg 7.5 mg 4 mg 20 mg 5 mg 2 mg 30 mg

Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan

16 mg 400 mg 150 mg 50 mg 10 mg 40 mg 160 mg

Visit 3 (LCZ696 run-in titration visit) Patients’ tolerability to enalapril 10 mg bid will be assessed at this visit. The site staff should instruct the patients to refrain from taking the enalapril 10 mg bid run-in medication on the day of Visit 3. The site staff will document the date and time of the last dose of the enalapril single-blind run-in medication. If appropriate, patients will start to take the LCZ696 100 mg bid run-in medication the day after Visit 3. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril 10 mg bid run-in medication after Tuesday evening. The patient will then start taking the first dose of LCZ696 100 mg bid runin medication on Thursday morning. Patients must be stabilized on this dose of LCZ696 (100 mg bid) for 1 to 2 weeks, at the investigator’s discretion. Visit 4 (LCZ696 up-titration visit) Patients’ tolerability to LCZ696 100 mg bid (LCZ696 dose level 2) will be assessed at this visit. Patients will be up-titrated from LCZ696 100 mg bid to LCZ696 200 mg bid (dose level 3) for 2 to 4 weeks at the investigator’s discretion. Patients participating in the population PK substudy will provide a trough (Cmin) blood sample on the morning of Visit 4 prior to up-titration. At the end of the single-blind active run-in period, only patients who tolerate LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for 2 to 4 weeks will be eligible for randomization. Safety and tolerability monitoring during the active run-in period Patients will be eligible for entering the enalapril run-in period at Visit 2, for entering the LCZ696 run-in period at Visit 3, and for randomization at Visit 5 if they meet all the inclusion criteria and none of the exclusion criteria, including the serum potassium, eGFR, blood pressure, and postural symptoms listed in Table 4-2.



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To ascertain patient’s eligibility for continuing in the study, Visit 3 (start of the LCZ696 runin period) and Visit 5 (randomization) study drug should not be dispensed unless laboratory assessments of potassium and eGFR are available. This may require laboratory samples to be collected and analyzed up to 72 hours before these Visits. The reason for patient discontinuation during the active run-in period must be carefully documented in the appropriate eCRFs. Patients who experience angioedema at any time during the run-in period must be withdrawn from the study. Table 4-2

Safety monitoring criteria that must be met at Visit 1 (screening), Visit 3, and Visit 5

Parameter

Visit 1 (screening)

Visit 3 (end of enalapril run-in) and Visit 5 (end of LCZ696 run-in and randomization)


K ≤ 5.2 mmol/L

K ≤ 5.4 mmol/L



4.3.3


2

2


Double-blind study treatment period

Please refer to Table 7-1 for a detailed list of study procedures and assessment to be performed at each double-blind period visit. The double-blind treatment period will begin at Visit 5. Only patients who tolerate LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for at least 2 weeks will be eligible for randomization. The study medication will be added to the prescribed background HF therapy, and as considered appropriate by the investigator. Concomitant administration of ACEIs or ARBs with the study medication is strictly prohibited. Please refer to Section 6.5.7 for more information on co-administration of other medications. Reported trial outcome endpoint events and other pre-specified endpoint events of intent will be collected as they occur throughout the double-blind period. All laboratory evaluations for planned visits after randomization will be performed through the central laboratory. Unscheduled laboratory assessments can be performed locally as necessary. Visit 5 will be considered the reference visit for all study visits during the double-blind period. Regardless of the occurrence of any unscheduled visits, scheduled visits must occur within the timeframe in relation to Visit 5 as outlined in Table 7-1. Figure 4-2 provides a schematic of the timeframe between study visits occurring during the double-blind period.



Figure 4-2

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Overall study design and timeframe between study visits occurring during the active run-in and double-blind periods

w = week; m = month a. Projected duration of the trial. Actual duration of the trial is event-driven.

Visit 5 (Randomization Visit) Patients who have met all the inclusion criteria and none of the exclusion criteria at the end of the active run-in period will be randomized to either enalapril 10 mg bid or LCZ696 200 mg bid in a 1:1 ratio. Site personnel should instruct the patient to refrain from taking their run-in medication on the day of Visit 5. Site personnel will document the date and time of the last dose of the LCZ696 run-in medication. This is necessary to minimize the potential risk of occurrence of angioedema. If appropriate, the patient will start to take the double-blind study medication (enalapril 10 mg bid or LCZ696 200 mg bid) the day after Visit 5. For example, if a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 200 mg bid run-in medication after Tuesday evening. The patient will then start taking the first dose of the double-blind study medication on Thursday morning. Table 7-1 lists all procedures to be performed at Visit 5. Visits 6 up to end of study (EOS) visit In the first 4 months of the double-blind treatment period, patients will return to the site for study visits every two to eight weeks. Visits after the first four months of the double-blind period will be scheduled for every four months. In addition to the protocol-required visits, patients may be seen at anytime throughout the study at the discretion of the investigator to investigate or follow any new lab abnormalities or AEs. All randomized patients, including any patient who has experienced a health event, should continue to receive double-blind treatment until the trial is completed. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Monitoring of safety and tolerability will include: (1) hyperkalemia; (2) symptomatic hypotension; (3) increase in serum creatinine; (d) angioedema; and (e) AEs and SAEs. If, in the opinion of the investigator, the patient cannot tolerate the target dose of study drug, the investigator should consider whether non-life saving medication (e.g., CCBs, nitrates, αblockers) can be reduced to rectify the situation before considering reducing the dose of the study drug to the lower dose level. The dose of background disease modifying drugs, such as β-blockers and mineralocorticoid receptor antagonists, should not be reduced to facilitate maintenance of study drug. If the situation is not rectified despite adjusting/discontinuing nonlife-saving medications or if adjusting non-life-saving concomitant medications is not possible, patients who no longer tolerate the target dose at any time during the course of the trial can be down-titrated to the lower dose level at the investigator’s discretion (please refer to Table 6-2 for dose levels available for titration). However, every attempt should be made to re-challenge the patients so that they are kept on the maximal tolerated dose of study drug for as long a duration as possible throughout the double blind period of the trial. Please refer to Section 6.5.5 for a guidance on study drug dose adjustment. If the study drug is temporarily discontinued, it should be reintroduced as soon as medically justified in the opinion of the investigator. After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the study. On the contrary, even patients who have stopped taking study drug should be asked to attend all the protocol specified study visits and perform all measurements as stipulated in the visit schedule. At Visit 7 or at Visit 10, blood samples will be obtained from patients participating in the PK substudy for analysis of valsartan, AHU377, and LBQ657 at steady state. Three samples will be obtained at either of those visits: pre-dose and at 0.5 to 2 hours and 3 to 5 hours post-dose. All randomized patients will remain in the trial until either (1) the projected number of primary endpoint (CV death or HF hospitalization) is reached, or (2) the trial is terminated prematurely at the recommendation of the DMC when pre-specified early-stopping criteria for efficacy and/or safety criteria are met. Table 7-1 lists all procedures to be performed at Visit 6 and all the remaining visits in the study.

5

Population

The study population will consist of patients with CHF (NYHA class II - IV), aged 18 years or older with LVEF ≤ 40%. Eligible patients should also be on a stable dose of an ACEI or an ARB for at least 4 weeks before entering into the study. The required minimum doses of prestudy ACEIs and ARBs are listed in Table 4-1. Patients from up to approximately 1,200 research sites worldwide will be randomized in a 1:1 ratio to either LCZ696 200 mg bid or enalapril 10 mg bid. In order to randomize 7,980 patients (3,990 patients in each arm) it is estimated that approximately 16,000 patients will have to be screened as the screen failure rate is anticipated to be approximately 50%.

5.1

Inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria: This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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1. Patients must give written informed consent before any assessment is performed. 2. Outpatients ≥ 18 years of age, male or female. 3. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction: o LVEF ≤ 40% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is acceptable, provided no subsequent measurement above 40%) o BNP ≥ 150 pg/ml (NT-proBNP ≥ 600 pg/ml) at Visit 1 OR BNP ≥ 100 pg/mL (NTproBNP ≥ 400 pg/ml) and a hospitalization for HF within the last 12 months 4. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1 o For this protocol doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d. o For this protocol doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 5. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication).

5.2 1. 2.

3. 4. 5. 6. 7. 8.

9.

Exclusion criteria Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives of enrollment, whichever is longer History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs Previous history of intolerance to recommended target doses of ACEIs or ARBs Known history of angioedema Requirement of treatment with both ACEIs and ARBs Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization) Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 25% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5 Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (randomization)



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10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1 11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1 12. Implantation of a cardiac resynchronization therapy device (CRTD) within 3 months prior Visit 1 or intent to implant a CRTD 13. History of heart transplant or on a transplant list or with left ventricular assistance device (LVAD) 14. History of severe pulmonary disease 15. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1 16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1 17. Symptomatic bradycardia or second or third degree heart block without a pacemaker 18. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation 19. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis 20. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: o History of active inflammatory bowel disease during the 12 months before Visit 1. o Current duodenal or gastric ulcers during the 3 months prior to Visit 1 o Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt o Active treatment with cholestyramine or colestipol resins 21. Presence of any other disease with a life expectancy of < 5 years 22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL) 23. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method (if accepted by the local regulatory authority and ethics committee) or a barrier method plus a hormonal method o Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progesterone agent. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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o Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. o Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

6

Treatment

6.1

Investigational and control drugs

Active run-in All eligible patients will enter an active run-in period during which they will be exposed to an enalapril run-in period, followed by an LCZ696 run-in period. The following study drugs will be provided: • Enalapril 5 mg tablets (enalapril dose level 2) • Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2) • Enalapril 10 mg tablets (enalapril dose level 3) • Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3) • LCZ696 100 mg film-coated tablets (LCZ696 dose level 2) • Placebo to match LCZ696 100 mg tablets (placebo matching LCZ696 dose level 2) • LCZ696 200 mg film-coated tablets (LCZ696 dose level 3) • Placebo to match LCZ696 200 mg tablets (placebo matching LCZ696 dose level 3) Dose level 1 for enalapril (2.5 mg bid) and LCZ696 (50 mg bid) will only be available in the double-blind period. Patients will be required to take the single-blind enalapril or LCZ696 dose and placebo to match the opposite treatment at the corresponding dose level twice daily in addition to their conventional concomitant therapy (except for ACEI or ARB, which will be substituted with study drug). Double blind treatment All eligible patients will be randomized to receive either LCZ696 or enalapril in addition to optimal CHF therapy, as considered appropriate by the investigator and in accordance with standard therapy guidelines, but with the exception of an ACEI or ARB as this will be This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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replaced by study drug. The use of an ACEI or an ARB in addition to study drug after randomization is strictly prohibited. The following study drugs will be provided: • LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) • Placebo to match LCZ696 50 mg film-coated tablets (placebo matching LCZ696 dose level 1) • LCZ696 100 mg film-coated tablets (LCZ696 dose level 2) • Placebo to match LCZ696 100 mg film-coated tablets (placebo matching LCZ696 dose level 2) • LCZ696 200 mg film-coated tablets (LCZ696 dose level 3) • Placebo to match LCZ696 200 mg film-coated tablets (placebo matching LCZ696 dose level 3) • Enalapril 2.5 mg film-coated tablets (enalapril dose level 1) • Placebo to match enalapril 2.5 mg film-coated tablets (placebo matching enalapril dose level 1) • Enalapril 5 mg film-coated tablets (enalapril dose level 2) • Placebo to match enalapril 5 mg film-coated tablets (placebo matching enalapril dose level 2) • Enalapril 10 mg film-coated tablets (enalapril dose level 3) • Placebo to match enalapril 10 mg film-coated tablets (placebo matching enalapril dose level 3) Target doses: LCZ696 200 mg bid and enalapril 10 mg bid Patients not tolerating the target dose (LCZ696 200 mg bid or enalapril 10 mg bid) will be titrated down to the lower dose level twice a day, at the investigator’s discretion, based on the defined safety and tolerability criteria (Appendices 2, 3, and 4). All tablets (LCZ696 50 mg, LCZ696 100 mg, LCZ696 200 mg, enalapril 2.5 mg, enalapril 5 mg, enalapril 10 mg) have different shapes and colors. Therefore, the study will be designed as a double- blind, double-dummy trial to ensure the blinding during the entire course of the study. To maintain the blinding, patients will be required to take their assigned active treatment tablet along with placebo matching the opposite treatment twice daily (morning and evening dose) in addition to their conventional concomitant therapy. LCZ696 and its matching placebo will be provided in HDPE bottles. Enalapril 2.5 mg and its matching placebo will be provided in HDPE bottles, while enalapril 5 mg and 10 mg and its matching placebo will be provided in blister packs. LCZ696 and enalapril will be packaged separately to limit the number of pack types which will allow more flexibility in the drug supply process to cover all the different treatment possibilities (treatment arm and medication level) (Section 6.5.4).



6.2

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Treatment arms

Patients who are eligible for randomization at Visit 5 will be assigned to one of the following two treatment arms in a 1:1 ratio: • LCZ696 200 mg bid • Enalapril 10 mg bid

6.3

Treatment assignment

At Visit 5, the investigator or his/her delegate will call the interactive voice response system (IVRS), enter the patient’s patient number, and confirm that the patient qualifies for randomization. The IVRS will assign a randomization number to the patient, which will be used to link the patient to a treatment arm and will specify unique medication numbers for the packages of the first supply of the study drugs to be dispensed to the patient. The IVRS will provide unique medication numbers for both the LCZ696 or its matching placebo and enalapril or its matching placebo. Subsequent supplies of study drug will be assigned in the following manner. The investigator or his/her delegate will call the IVRS and provide the patient’s number. The IVRS will ask the caller whether there is a change in the dose level of the study drug. If the caller indicates that there is no change in the dose level, IVRS will provide the unique medication numbers of study drug with the same dose level that was dispensed at the previous dispensing. If the caller indicates that the dose level has changed since the last dispensing, IVRS will ask the caller which dose level should be dispensed. The caller will enter the dose level to dispense, i.e., level 1 (LCZ696 50 mg or enalapril 2.5 mg bid), level 2 (LCZ696 100 mg or enalapril 5 mg bid), or level 3 (LCZ696 200 mg or enalapril 10 mg bid), or whether no study drug needs to be dispensed (in case of study drug withdrawal). If applicable, the IVRS will provide the unique medication numbers for the packages of the study drug supplies that should be dispensed at the new dose level. Randomization numbers will be generated using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. A patient randomization list will be produced by the IVRS provider using a validated system that automates the random assignment of patient numbers to randomization numbers. These randomization numbers are linked to the different treatment arms, which in turn will be linked to medication numbers. A separate medication randomization list will be produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs. The randomization scheme for patients will be reviewed and approved by a member of the Biostatistics Quality Assurance Group. In addition to the IVRS, a web-based system will also be available and will have the same functionalities as the IVRS.



6.4

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Treatment blinding

Single-blind enalapril or LCZ696 will be dispensed to patients during the active run-in period. During the active run-in period, patients will receive LCZ696 or enalapril and placebo matching the appearance of the opposite treatment. The identity of the treatments will be concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, and odor to the supplies that will be used in the double-blind treatment period. Patients, investigator staff, persons performing the assessments, and data analysts will remain blind to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) Randomization data are kept strictly confidential until the time of unblinding, and will not be accessible by anyone else involved in the study with the exception of the members of the DMC (Section 8.4) and the independent biostatistician who will perform the IA, and (2) the identity of the treatments will be concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, and odor. Unblinding will only occur in the case of patient emergencies (Section 6.5.9), at the time of the IA (Section 10.16), and at the conclusion of the study.

6.5

Treating the patient

6.5.1

Patient numbering

Each patient is uniquely identified in the study by a combination of his/her site number and patient number. The site number is assigned by Novartis to the investigative site and consists of 4 digits (e.g., 1234). After the patient has signed the informed consent form, the investigator or his/her staff will telephone the IVRS and provide the requested identifying information for the patient. The IVRS will then assign the patient number, which is a 5-digit sequential number that begins with “00” (e.g., 00001, 00002, 00003, etc.). Only the assigned patient number should be entered in the field labeled “Patient” on the EDC data entry screen. Once assigned to a patient, the patient number will not be reused. If the patient fails to be randomized, the IVRS must be notified regarding the patient’s screen-failure or run-in failure and the appropriate eCRFs should be completed within 3 days. In addition, the screening log should be completed for all patients. 6.5.2

Dispensing the study drug

Each study site will be supplied by Novartis with study drug in identically-appearing packaging for each medication (LCZ696 or enalapril). The study medication packaging has a 2-part label. A unique randomization medication number is printed on each part of this label, which corresponds to one of the two treatment arms and a dose level. Investigator staff will identify the study drug package to dispense to the patient by calling the IVRS and obtaining the study drugs medication numbers as described in Section 6.3. Immediately before dispensing the packages to the patient, investigator staff will detach the outer part of the label from the packaging and affix it to the source document (Drug Label Form) for that patient’s unique patient number.



6.5.3

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Study drug supply, storage and tracking

Study drugs must be received by a designated person at the study site, handled, and stored safely and properly, and kept in a secured location to which only the investigator and designated assistants have access. Upon receipt, all study drugs should be stored according to the instructions specified on the drug labels. Clinical supplies are to be dispensed only in accordance with the protocol. Medication labels will be in the local language and comply with the legal requirements of each country. They will include storage conditions for the drug, but no information about the patient, except for the medication number. The investigator must maintain an accurate record of the shipment and dispensing of study drug in a drug accountability ledger. Monitoring of drug accountability will be performed by the field monitor during site visits and at the completion of the trial. Patients will be asked to return all unused study drug and packaging at each visit, at the time of study drug discontinuation, and at the end of the study. At the conclusion of the study, and as appropriate during the course of the study, the investigator will return all unused study drug, including opened and unopened packaging, drug labels, and a copy of the completed drug accountability ledger to Novartis according to the instructions provided by Novartis or its agents. 6.5.4

Instructions for prescribing and taking the study drug

Novartis will supply the investigators with all medications sufficient for the course of the study. Patients will be provided with medication packs containing study drug corresponding to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. In order to adequately blind the study, patients will be required to take a total of two tablets (one tablet from the LCZ696/LCZ696 matching placebo pack and one tablet from the enalapril/enalapril matching placebo pack) twice a day for the duration of the study. Table 6-1 summarizes the study drug that will be taken during the active run-in period by visit and Table 6-2 summarizes the study drug that will be taken during the double-blind period.



Table 6-1 Study visit

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Study drug dispensed during the active run-in period by study visit Dose level

LCZ696

Visit 2A

2

Placebo matching 100 mg bid

Enalapril 5 mg bid

Visit 2

3


Enalapril 10 mg bid

Visit 3

2

100 mg bid


3

200 mg bid


a

b, c

Visit 4

Enalapril

a. Investigators may consider initiating treatment on enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACE inhibitors (see Table 41) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated. b. During the run-in period, patients may be temporarily down-titrated from LCZ696 200 mg bid to LCZ696 100 mg bid with subsequent re-challenge to ensure that they tolerate LCZ696 200 mg bid for at least 2 weeks. The run-in period should be completed within 10 weeks regardless of any down-titration that may have occurred. c. Patients unable to tolerate LCZ696 200 mg bid after re-challenge will be withdrawn from the study and will not be randomized.


Study drug dispensed during the double-blind period Dose level

LCZ696

Enalapril

a

Visit 5 and all 3 200 mg or matching placebo bid 10 mg or matching placebo bid subsequent visits b Available for any 2 100 mg or matching placebo bid 5 mg or matching placebo bid visit after Visit 5 c Available for any 1 50 mg or matching placebo bid 2.5 mg or matching placebo bid visit after Visit 5 a. This dose level must be maintained for as long a duration as possible. If down-titration is necessary due to side effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgment. b. Only if dose level 3 is not tolerated despite modification of other non-life-saving HF medications. c. Only if dose levels 2 and 3 are not tolerated despite modification of other non-life-saving HF medications.

Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 AM) and their evening study drug doses at approximately 19:00 (7 PM). The study medications should be taken with a glass of water with or without food. If the patient misses taking any study drug dose, he/she should take it as soon as possible, unless if it is almost time for the following scheduled dose. In this case, the patient should skip the missed dose and return back to his/her regular study drug administration schedule. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded in the IVRS and on the Dosage Administration Record eCRF. The investigator should promote compliance by instructing the patient to take the study drug exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the validity of the study. The patient should be instructed to contact the investigator if he/she is unable to take the study drug as prescribed for any reason.



6.5.5

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Permitted study drug dose adjustments and interruptions

Every attempt should be made to maintain patients on the target study drug dose level for as long a duration as possible throughout the trial. If, however, in the opinion of the investigator, the patient does not tolerate the target dose of study drug (dose level 3), the investigator should consider whether non-life saving medication (e.g., CCBs, nitrates, α-blockers) can be reduced to rectify the situation, before considering to reduce the dose of the study drug to the next lower dose level. If adjustment/elimination of other non-life-saving HF medications is not possible or does not alleviate the side effects of concern, the investigator may down-titrate the dose of the study drug to the next lower level up to complete withdrawal of the study drug. The patient should be re-challenged with the higher dose when the investigator feels it is appropriate to do so per the directions provided below in this section. If needed, the study drug may be stopped completely, but the patient should continue to attend the study visits and be followed until the completion of the study. Ultimately the goal is to keep the patient on the highest study drug dose possible for as long as possible and to follow the patient in the study as long as possible. Study drug dose level adjustments should mainly be based on overall safety and tolerability with special focus on a) hyperkalemia; b) symptomatic hypotension; and c) clinically significant decrease in eGFR/increase in serum creatinine (see Appendices 2, 3 and 4 for treatment guidelines for hyperkalemia, management of BP, and renal dysfunction, respectively). Adjustment of study drug dose level Study drug dose adjustments during the single-blind run-in period – At the investigator’s discretion, LCZ696 200 mg bid can be down-titrated to LCZ696 100 mg bid until such time that investigator believes the patient may be able to tolerate titration back up to LCZ696 200 mg bid. If the investigator does not feel that the patient will ultimately be able to tolerate this dose, he/she may withdraw the patient from the study without re-challenge. Every attempt should be made to complete the run-in period within 10 weeks regardless of any downtitration that may occur. Study drug dose adjustments during the double-blind treatment period – During the double-blind treatment period down-titration of the study drug at any time will be allowed based on the safety and tolerability criteria defined in Appendices 2, 3, and 4. If downtitration is necessary, the patient should be down-titrated to the next lower dose level (Table 6-2). The patient may continue receiving the lower dose level for a recommended period of 1 to 4 weeks before re-challenging the patient with the next higher dose level. For example, a patient who encounters tolerability problems at the target dose level (dose level 3), should receive the study drug at dose level 2 for 1 to 4 weeks. Then, he/she should be re-challenged with up-titration back to dose level 3. If the tolerability issues are not alleviated despite down-titration by one dose level, the investigator may lower the study drug dose further to the next lower level for 1 to 4 weeks, up to temporary withdrawal of the study drug. Again, once stable, the patient should be rechallenged with up-titration to the next higher dose level every 1 to 4 weeks in an attempt to bring back the patient gradually to the target study drug dose level (dose level 3). The investigator may choose the next dose level for down- or up-titration according to his or her This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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judgment (Table 6-2). As discussed in Section 6.3, the IVRS should be contacted to register any changes in the patient’s study drug dose level, including in cases of temporary and permanent withdrawal of the study drug, and to obtain the medication numbers of the study drug supplies required for the new study drug dose level. In some instances, according to the safety and tolerability criteria and the investigator’s judgment, dose level 1 or 2 could be maintained if he/she considers that the patient’s condition would not allow any further up-titration to the target dose of study medication (level 3). In this case it would be acceptable to maintain the patient at dose level 1 or level 2, whichever is the higher and tolerated dose level by the patient. Study drug restart after temporary treatment interruption Study drug should be reintroduced in those who temporarily discontinue it as soon as medically justified in the opinion of the investigator. Once the investigator considers the patient’s condition appropriate for receiving the study drug, the investigator should re-start the patient on the study drug at the most appropriate and allowable dose level (Table 6-2) per his/her medical judgment. If tolerated based on the safety and tolerability criteria in Appendices 2, 3, and 4, the patient should be up-titrated up to dose level 3 every 1 to 4 weeks, as per the investigator’s judgment. Patients re-started on the study drug will retain their original randomization and study identification numbers. Should the patient not tolerate the re-start study drug dose level, he/she may be down-titrated again (if appropriate) or discontinue the study medication again and a new attempt to up-titrate or reintroduce the study drug could be considered by the investigator as soon as medically justified in his/her medical judgment. Study visits should occur as close as possible to the time points indicated in Table 7-1. The timeframe between the regular visits should be maintained as scheduled, irrespective of the number of unscheduled visits that may be performed in between, according to the visit and time schedule described in Table 7-1. For example, if the patient’s treatment needs to be adjusted between Visit 9 and Visit 10, Visit 10 will still be planned 4 months after Visit 9, irrespective of the number of unscheduled visits that may have occurred between these two visits or the additional period that the medication pack dispensed could have covered. Any changes in the study drug dose level, including temporary/permanent withdrawal or restart of the study drug, must be recorded on the Dosage Administration Record eCRF and registered in the IVRS. In case of pregnancy discovered during the run-in period, the patient will be withdrawn from the study immediately. In case of pregnancy discovered during the double-blind treatment period, the patient should be instructed to stop taking the study drug immediately. Study drug intake should be resumed as soon as possible after the completion of the pregnancy and lactation period. Meanwhile, the patient should continue to attend scheduled study visits. See Section 8.3 for further details on pregnancies and reporting guidelines.



6.5.6

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Rescue medication

Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to investigators in Appendices 2, 3, and 4, respectively. Patients may receive open-label ACEIs and/or ARBs during the study ONLY if the study medication has been discontinued either temporarily or permanently. 6.5.7

Other concomitant treatment

The investigator should instruct the patient to notify the study site staff of any changes in concomitant medications (new medications or changes in dose regimens of existing medications). All concomitant medications and significant non-drug therapies (including physical therapy and blood transfusions) administered after the patient starts treatment with the study medication must be listed on the Concomitant Medications/Significant Non-Drug Therapies eCRF. ACEIs and ARBs Patients’ pre-study ACEIs/ARBs will be replaced with the study medications. The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient is receiving study medication, regardless of study period (active run-in period or double-blind period). If the investigator believes that addition of an ACEI or ARB is necessary, then study drug must be discontinued. Study medication should be stopped the day prior to addition of open-label ACEI and/or ARB. If not already treated with an aldosterone antagonist, consideration should be given to adding this therapy rather than an ACEI or ARB. Similarly, if study medication is to be restarted, the open-label ACEI and/or ARB should be discontinued the day prior to resuming study medication. Heart failure medications and other cardiovascular medications The patient should be on an optimal medical regimen of background HF medications. This must include an individually optimized dose of a β-blocker (i.e., maximally tolerated dose) at a stable dose for at least 4 weeks prior to study entry, unless contraindicated or not tolerated. Use of an aldosterone antagonist is encouraged in more advanced HF as indicated by local guidelines and as tolerated. In self-identified black patients, the use of isosorbide dinitrate/hydralazine hydrochloride (e.g., BiDil®) should be considered. Every effort should be made to keep the dose level of these background, life-saving HF medications stable throughout the entire study. However, if the patient’s condition warrants a change in any of these medications, it is allowed at the discretion of the study investigator. Diuretics may be used and may be adjusted throughout the length of the study at the discretion of the investigator. If a patient experiences any AEs that may be contributed to the study drug, other HF medications, or other CV medications, the investigator should adjust non-life saving medications (e.g., CCBs, nitrates, a-blockers, and diuretics) first in an attempt to alleviate the AEs. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Medications known to raise potassium levels Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, renin inhibitors, and any other medications known to raise potassium levels should be used with caution while the patient is receiving the study medication due to the increased possibility of occurrence of hyperkalemia. The investigator is encouraged to assess patients’ potassium levels regularly, especially in those who are receiving these medications. 6.5.8

Study drug discontinuation and premature patient withdrawal

After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the entire study. On the contrary, even patients who have stopped taking study drug should be asked to attend all the protocol specified study visits and perform all measurements as stipulated in the visit schedule (Table 7-1). If the patient does not attend the study visits, follow-up should continue according to the specified schedule by telephone to determine if any of the health events/endpoint prespecified in the protocol has occurred, except in the case that the patient specifically refuses such follow-up and withdraws his/her consent. The emergence of the following circumstances will require study drug discontinuation: • Withdrawal of informed consent • Pregnancy (Section 8.3) • Investigator thinks that continuation would be detrimental to the patient’s well-being • Suspected occurrence of angioedema during the run-in period Study medication may be discontinued at the investigator’s discretion if any of the following occurs: • Any severe suspected drug related AE • Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically significant angioedema should be thoroughly evaluated by the investigator and constitute a reason for interruption of study medication. • Depending on the serum potassium, blood pressure, or eGFR, patients may need to have their study drug dose or the dose of another concomitant medication reduced or discontinued, or, if appropriate, have potentially contributing agents adjusted. Please refer to Appendices 2, 3, and 4 for treatment guidelines for hyperkalemia, hypotension, or renal dysfunction, respectively. In the case of study drug discontinuation, the patient should continue to complete all scheduled study visits and procedures. If the patient refuses, he/she should be contacted by telephone in place of protocol-specified visits unless the patient expressly refuses such contacts. The investigator must also notify the IVRS of the study drug discontinuation and record it on the drug administration form of the eCRF.



6.5.9

Confidential


Emergency unblinding of treatment assignment

Emergency unblinding should only be undertaken when it is essential for effective treatment of the patient. Most often, study drug discontinuation and knowledge of the possible treatment assignments are sufficient to treat a study patient who presents with an emergency condition. Emergency code breaks are performed using the IVRS. When the investigator telephones the system to unblind a patient, he/she must provide the requested patient identifying information and the date, time, and reason for unblinding. The investigator will then receive details of the drug treatment for the specified patient and a fax confirming this information. The system will automatically inform the Novartis site monitor and the Clinical Trial Head that the code has been broken. It is the investigator’s responsibility to ensure that there is a procedure in place to allow access to the IVRS in case of emergency. The investigator will inform the patient how to contact his/her backup in cases of emergency when he/she is unavailable. The protocol number, study drug name if available, patient number, and instructions for contacting the local Novartis Country Pharma Organization (CPO) (or any entity to which it has delegated responsibility for emergency code breaks) will be provided to the patient in case emergency unblinding is required at a time when the investigator and backup are unavailable. Study drug must be discontinued after emergency unblinding. Study drug also must be discontinued for any patient whose treatment code has been broken inadvertently or for any non-emergency reason. 6.5.10

Study completion and post-study treatment

At the EOS visit (Visit 778) patients will be asked to return the remaining study drug. There is no extension study planned after all assessments of the end-of-study visit are completed. Patients who do not fulfill the eligibility criteria during the run-in period should be discontinued from the study and the appropriate eCRF should be completed accordingly (e.g., run-in completion page, see Section 7.1). The investigator also must provide follow-up medical care for all patients who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care. When the patient has completed all scheduled study assessments, the investigator must call the IVRS within 3 days to record the patient completion in the IVRS. 6.5.11

Early study termination

The study can be terminated at any time for any reason by Novartis Pharmaceuticals. Should this be necessary, the patient should be seen as soon as possible and an EOS visit (Visit 778) must be conducted as described in Section 7. The investigator may be informed of additional procedures to be followed in order to assure that adequate consideration is given to the protection of the patient’s interests. The investigator will be responsible for informing institutional review boards (IRBs) and/or ethics committees (ECs) of the early termination of the trial.



7

Confidential


Visit schedule and assessments

All patients, including those who discontinue the study medication before completing the study, should continue attending the scheduled visits as outlined in Table 7-1 until the study ends. At that point all patients will return to the study sites as soon as possible to undergo the EOS visit (Visit 778) assessments. If any patient refuses to return for these assessments or is unable to do so, every effort should be made to contact him/her or a knowledgeable informant by telephone to ask if any of the primary, secondary, or other endpoints (see Section 3.1 and Section 3.2) have occurred at the foreseen visit dates for the remaining duration of the study. Documentation of attempts to contact the patient should be recorded in the patient’s record. All data obtained from the assessments listed in Table 7-1 and described in detail in the subsections below must be supported in the patient’s source documentation (e.g., medical charts or patient notes). Table 7-1 indicates which data remain in source documents only (S), or may be entered directly into the database (D; i.e., these data are considered source documentation and do not require separate source documentation), or are entered into the database from separate source documents (DS). Assessments that generate data for database entry and are recorded on eCRFs are listed using the eCRF name. Assessments that are transferred to the database electronically (e.g., laboratory data) are listed by test name. With regards to timing of study visits of patients who participate in the population PK substudy, the timing of study drug administration should be taken into account when scheduling study visits when blood samples will be obtained. Please refer to Section 7.6.5 for more information on scheduling the PK sampling. If one visit is postponed or brought forward, it should not result in the next visit being postponed or brought forward. The next visit, if at all possible, should adhere to the original time schedule. Patients will also be instructed to take study drug, as usual, on the morning of their site visits (except for Visits 3 and 5), with or without food. If a patient did not take his/her study drug on the morning of his/her scheduled visit, the study visit could nevertheless be conducted. The only exception to this rule is for visits when population PK substudy patients are to provide the pre-study drug dose blood sample. In this case, the patient should not take the study drug before attending the study visit, but the study visit should be scheduled so that the PK blood sample is obtained immediately before the time when the patient usually takes his/her study medication. There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of the single-blind LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


Table 7-1


Assessment schedule

Phase

Screening

Visit

D/S*

Weeks (w) / Months (m)

1

Single-blind active run-in Enalapril run-in 14

2A

2

15

Double blind treatment**

LCZ696 run-in 3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

999° 778°°

-11 to -7w -10 to -6w -8 to -5w -6 to -3w -4 to -2w 0 2w 4w 8w 4m 8m 12m 16m 20m 24m 28m 32m 36m 40m 44m Uns

Informed consent form Call to IVRS

Confidential

1 2

S

x

S

x

x

x

x

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Inclusion/Exclusion criteria

DS

Demography/Medical history (including alcohol and smoking history)

DS

x

Heart Failure History

DS

x

Cardiovascular disease History

DS

x

S

x

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Height (H) / Weight (W)

DS

H/W

W

W

W

W

W W W W W W

W

W

W

W

W

W

W

W

W

W

W

Vital signs

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Waist/hip circumference

DS

NYHA Classification (HF signs and symptoms)

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Heart Failure and CV Medications

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Concomitant Medications

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Endpoint information

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

AEs / SAEs

DS

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

Physical Exam

3

Pregnancy tests

4

x

x

2

EOS

x

x

x

x

x

x

x

DS

x

x

Plasma BNP and NT-proBNP DS

x

x

x

x

x

x

x

Plasma/serum biomarkers (other than BNP & NT5 proBNP) and biobanking

DS

x

x

x


x

x

Novartis Clinical Study Protocol (Version No. 01) Phase

Screening

Visit

D/S*

Weeks (w) / Months (m) st

1 Urine morning void

DS 7


2A

2

15


LCZ696 run-in 3

x

4

5

6

Complete laboratory assessments

DS 9

(x)

DS

Screening log

DS

x

x

x

7

8

9

10

(x)

x

11

12

13

14

15

16

17

18

19

999° 778°°

x

x

16

x x

x

x

x

x

x x

x

x

x x

x

x

x x

x

x

(x) (x)

x

x

x (x) x

x

x

DS DS

Randomization

DS

x

Double blind medication dispense

DS

x x

x

x

x

(x)

x

x

x

Drug accountability

Patient Global Assessment

x

EOS

(x)

x

Run-in medication dispense

S

x

x

x

13

DS

11

x

x

DS

12-lead ECG evaluation 10

x x

DS

Abbreviated chemistry panel

x

DS

Local laboratory 8 assessments

Urinalysis (local dipstick)



6

Pharmacokinetic sampling

Run-in completion log

1

Confidential

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

x

x

(x)

x

x

x

x

x

x

x

DS

x

x

x

x

x

x

x

EuroQol (EQ-5D)

DS

x

x

x

x

x

x

x

End of study information

DS

KCCQ

12

DS

x


x

Novartis Clinical Study Protocol (Version No. 01) Phase Visit Weeks (w) / Months (m)

Screening D/S*

1

Confidential



2A

2

15


LCZ696 run-in 3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

999° 778°°


EOS

* D: to be documented in the clinical database, S: in the source data and DS: in the database from separate source documentation ** If the trial is extended, Visits 20, 21, 22 and so forth to be performed at the same intervals and with same measurements as at visits 17, 18, 19 and so forth. ° Visit 999 = Unscheduled visit. Assessments marked with (x) are optional procedures that may be performed at the investigator’s discretion. °° 778 (final visit: End Of Study [EOS]) scheduled upon the decision to close the study. 1 Phone calls to IVRS have to be performed at all visits (including unscheduled visits) and when the patient is on study drug interruption. 2 During the single-blind active run-in at Visits 2 (if Visit 2A is conducted), 3, 4 and 5, patient safety will be monitored to ensure eligibility to continue to the next phase until randomization at Visit 5. Reason for not qualifying for randomization must be documented in detail in the eCRFs. 3 Complete physical examination required at Visits 1 and 11 and yearly thereafter up until Visit 778 (end-of-study visit). Short physical exam at interim visits. 4 Women of childbearing potential only. At Visit 1 and in case of a positive urine pregnancy result, a confirmatory serum pregnancy test has to be performed at the central laboratory. A Urine pregnancy test will be performed locally at Visit 5, and yearly thereafter up until Visit 778. 5 Plasma/serum biomarkers, biobanking, and first morning urine void samples will be taken in a subset of patients. These samples should be collected at Visit 2 (or Visit 2A if applicable). If samples are collected at Visit 2A, they should not be collected at Visit 2. 6 Sites will give the urine collection containers and instructions at Visits 1, 4, 6, and 9. If first morning urine void is collected for Visit 2A, it should not be collected at Visit 2. 7 Patients participating in the PK substudy must also be participating in the biomarker substudy. Pre-dose (trough) samples will be collected at Visits 4 and 7. PK samples will also be collected at pre-dose (trough) and at 0.5 to 2 hours and 3 to 5 hours post-dose at Visit 7. 8 Serum potassium and eGFR. 9 Abbreviated chemistry panel including potassium, BUN, and serum creatinine will be measured at interim visits at the central laboratory. 10 Run-in completion page to be completed for all patients who entered into the run-in period. This may occur at Visit 2 (only if V2A is conducted), 3, 4, or 5. 11 Dipstick urinalysis will be conducted at Visits 1, 5, and yearly thereafter until visit 778. If dipstick is positive, a qualitative microscopic determination, including white blood cells high power field (WBCs/HPF) and red blood cells high power field (RBCs/HPF) will be performed. 12 KCCQ = Kansas City Cardiomyopathy Questionnaire. 13 Screening ECG performed within the 6 months before Visit 1 is accepted. 14 Visit 2A is an optional visit that will be performed only if the investigator elects to start the patient on single-blind enalapril 5 mg bid instead of directly on single-blind enalapril 10 mg bid. 15 Assessments marked with (x) will only be performed if a patient starts the active run-in period at Visit 2A. 16 PK sampling at pre-dose and at 0.5 to 2 hours and 3 to 5 hours post-dose will be performed at Visit 10 only if not already done at Visit 7.



7.1

Confidential


Information to be collected on screening failures

Patients may discontinue from the study prior to randomization from Visit 1 through Visit 5, prior to any double-blind medication being administered. Patients discontinuing at: • Visit 1 (never received active run-in study drug) are considered screening failures • Visit 2A, Visit 2, Visit 3, Visit 4, or Visit 5 after entering into the run-in and prior to randomization, are considered run-in failures. If a patient discontinues before entering in the run-in treatment period, only the demographic information and Screening Log entry with the reason for discontinuation should be completed on the eCRF. It is not necessary to complete all the required evaluations at the time of discontinuation unless medically indicated. All required evaluations must be performed and clearly documented in the appropriate eCRFs of patients who entered the run-in period and received study medication. This information must include demographics, reason for discontinuation, and AEs and safety data (e.g., hyperkalemia, hypotension, renal dysfunction, and other AEs). Re-screening If a patient is not eligible to enter into the run-in period and screen-fails, the investigator may consider re-screening the patient at a later time if he/she believes that the patient’s condition has changed and may potentially be eligible. In this case, a completely new patient number will be allocated to the subject and he/she will need to re-perform all Visit 1 assessments. A patient who is successfully screened and enters into the active run-in period but is later found not to be eligible for randomization due to intolerance to target doses of enalapril or LCZ696 may be re-screened at a future time if the investigator feels that the circumstances that may have contributed to the patient’s intolerance are no longer present. In this case, a completely new patient number is to be allocated to the subject and he/she will need to reperform all Visit 1 assessments.

7.2

Patient demographics/other baseline characteristics

Patient demographic and baseline characteristic data to be collected on all patients include: date of birth, age, sex, race, ethnicity and source of patient referral. Relevant medical history/current medical condition data includes data until the start of study drug. Where possible, diagnoses and not symptoms will be recorded. HF medications and other CV medications will be recorded in eCRFs separately from other medications. Likewise, detailed HF history and other relevant CV medical history will be recorded on eCRFs separately from other medical history.

7.3

Treatment exposure and compliance

Compliance will be assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the care giver. This information should be captured in the source document at each visit. Patient compliance should be at least 80% during the doubleThis document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


Confidential


blind treatment period. The investigator and/or study personnel will counsel the patient if compliance is below 80%. Study drug accountability will also be determined by the site monitor while performing routine site visits and at the completion of the study. Duration of double-blind study drug exposure will be calculated based upon the start and stop dates recorded in the eCRF.

7.4

Efficacy

7.4.1

Primary and secondary efficacy endpoints

The primary composite endpoint consists of the following components: • CV death • HF hospitalization The target number of primary composite endpoint events is 2,410. The secondary endpoints are: • HF symptoms and physical limitation clinical summary score of the KCCQ (Appendix 5) • All-cause mortality • Composite renal endpoint defined as (1) 50% decline in eGFR compared to baseline, (2) >30 mL/min/1.73m2 decline in eGFR relative to baseline, or (3) reaching ESRD. 7.4.2

Endpoint Committee

All of the following events, which could potentially fulfill the criteria for the primary, secondary, or other endpoints will be assessed during the study, including the active run-in period, and reported to the Endpoint Adjudication Committee for adjudication or assessment: • All death events • Unplanned hospitalization for HF • Non-fatal MI • Non-fatal stroke • Resuscitated sudden death (successful resuscitation following cardiac arrest) • Renal dysfunction • Others The Endpoint Adjudication Committee will be responsible for classifying all death events and for determining whether pre-specified endpoint criteria were met for the non-fatal events. Sites are instructed to take a conservative approach when reporting endpoints; if the investigator suspects an endpoint may have occurred, it is best to report the event to the Endpoint Adjudication Committee for the final determination. Novartis’ reporting guidelines for AE and SAE as outlined in Section 8.1 and Section 8.2 must be followed, independent from the circumstance that an event is also reported as a suspected study endpoint.



7.4.3

Confidential


Estimated glomerular filtration rate (eGFR)

The eGFR to determine eligibility of the patient for screening into the trial will be calculated at Visit 1 from the serum creatinine concentration which will be measured centrally. The eGFR will be further measured at each visit during the run-in period to guide the investigator to take any appropriate action as necessary (e.g., removing the patient from the trial) in case of eGFR decrease (according to the criteria defined in Table 4-2). Estimated GFR will only be calculated using the following formula (Stevens et al 2006): Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if female) × (1.212 if black), where SCr is the standardized serum creatinine value

7.4.4

Biomarkers

BNP and NT-proBNP will be obtained in all patients by using the central laboratory at Visit 1 to determine eligibility for screening into the trial. In addition, biomarker measurements will be obtained from serum, plasma, and first morning void (FMV) urine samples in a subset of patients at selected sites at Visits 2, 5, 7, and 10 to determine effects of treatments on biomarkers of CV, CHF, or renal risk. The selected biomarkers studied will be ones believed to be relevant to the pathophysiology of the disease processes of CHF, HTN, and/or renal dysfunction. Biomarkers studied may include, but are not limited to: • neurohormones, such as BNP and NT-proBNP, • RAAS biomarkers, such as plasma and urinary aldosterone and plasma renin activity (PRA; only at Visit 5), • renal biomarkers, such as cystatin-C and eGFR (enzymatic creatinine assay), and • the second messenger cGMP (measured both in plasma and FMV urine) To allow indexing of urinary biomarkers, creatinine in FMV urine will also be measured. The list may be changed or expanded further, as it is recognized that new, relevant (nongenomic) biomarkers may be discovered during the process of this study and after its completion. As such, plasma, serum and FMV urine will be biobanked for analysis of yet to be identified diagnostic biomarkers. Details on sample collection, handling and shipment of biomarker samples will be provided to investigators in the laboratory manual. 7.4.5

Urine albumin to creatinine ratio (UACR) and first morning void urine sampling

First morning void urine samples will be collected from the biomarker substudy patients at Visits 2, 5, 7, and 10 for analysis of renal biomarkers and/or electrolytes, such as urinary albumin to creatinine ratio (measured as UACR). The list of biomarkers may be changed or expanded further if new or more relevant (non-genomic) biomarkers are discovered during the process of this study. Details on sample collection, handling and shipment of biomarker samples will be provided to investigators in the laboratory manual.



7.5 7.5.1

Confidential


Safety Physical examination

A complete physical examination will be performed at Visits 1 and 11 and then at yearly intervals thereafter until the EOS visit. It will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. A short physical exam will include the examination of general appearance and vital signs (BP and pulse). A short physical exam will be at all visits starting from Visit 2, except where a complete physical exam is required (see above). Information about the all physical examinations must be present in the source documentation at the study site. Significant findings that are present prior to the start of study drug must be included in the Relevant Medical History/Current Medical Conditions screen on the patient’s eCRF. Significant findings made after the start of study drug which meet the definition of an AE must be recorded on the AE screen of the patient’s eCRF. 7.5.2

Vital signs

Vital signs will be assessed at every visit. This will include BP and pulse measurements. BP will be measured by using a standard sphygmomanometer with an appropriate size cuff and the non-dominant arm in the sitting position after 5 minutes of rest. 7.5.3

Height, weight, and waist/hip circumference

Height in centimeters (cm) will be measured at Visit 1. Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing without shoes) will be measured at all visits, until the EOS visit. Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured at Visit 5 and at the EOS visit. 7.5.4

Laboratory evaluations

A central laboratory will be used for analysis of all collected specimens. Details on the collections, shipment of samples and reporting of results by the central laboratory will be provided to investigators in the laboratory manual. Clinically notable laboratory findings are defined in Appendix 1. Complete laboratory evaluations (hematology, blood chemistry, and urine; Table 7-2) for the assessment of safety in this study will be performed at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit). Yearly laboratory evaluations should be performed in a fasting state. Electrolyte laboratory evaluations will be included in the abbreviated laboratory assessments at Visits 3 and 4, and at the interim visits starting at Visit 6. Local laboratory may be used for the assessment of potassium values and eGFR during the active run-in period up to the randomization visit (Visit 2, Visit 3, Visit 4, and Visit 5). In This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


Confidential


addition, local laboratory assessments may be performed on an as-needed basis for unscheduled visits. Categorical renal endpoints (i.e., ≥ 50% decline in eGFR compared to baseline, decline in eGFR by ≥ 30 mL/min/1.73m2 compared to baseline, and ESRD) have to be calculated and confirmed by two standardized serum creatinine measurements at least one month apart and analyzed by the central laboratory. For this purpose, patients may need to attend an unscheduled visit one month after the study visit. For visits other than the run-in period visits, study procedures may be performed without restriction while the laboratory results are pending. In these cases, the investigator or his/her designee should review the central laboratory results as soon as they become available to decide on whether any adjustments in the patient’s study drug or non-study drug regimen are needed. All central laboratory results will be communicated to the investigators and the sponsor, with the exception of plasma/serum and urinary biomarkers, of which only the Visit 1 BNP and NT-proBNP will be reported to the investigator and the sponsor. Details on the collection, shipment of samples and reporting of results by the central laboratory will be provided to investigators in the laboratory manual. Laboratory values that exceed the boundaries of a notable laboratory abnormality must be commented on by the investigator in the Comments screen of the patient's eCRF and additional laboratory evaluations should be performed, as judged appropriate by the investigator. If the laboratory abnormality induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or medical condition must be entered on the AEs screen of the patient's eCRF. If the laboratory abnormality is the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification of SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation from the study drug (temporarily or permanently), the patient must be followed until the abnormality resolves or until it is judged to be permanent.



Table 7-2

Confidential


Routine laboratory examinations

Hematology*

Biochemistry*

Urine measurements

Red Blood Cells count White Blood Cells count Platelet Count Hemoglobin Hematocrit WBC Differential

Sodium Potassium ** Chloride Calcium Blood urea nitrogen (BUN) ** Creatinine ** Total Bilirubin Aspartate amino-transferase (AST) Alanine amino-transferase (ALT) Alkaline phosphatase Total protein Albumin Uric Acid a Serum Pregnancy Test Lipid profile (total cholesterol, LDL, HDL, and triglycerides) Hemoglobin A1C

UACR (to calculate urinary albumin/creatinine ratio) Urinalysis

b

* List of laboratory assessments performed at Visits 1, 5, 11 and yearly thereafter until EOS. ** Laboratory assessments for the abbreviated biochemistry test performed at visits where the complete laboratory test is not performed. a. At Visit 1 and in case of positive urine pregnancy test only. b. In a subset of patients only.

7.5.4.1

Hematology

Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count will be measured at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit) (Table 7-2). 7.5.4.2

Clinical chemistry

Blood urea nitrogen (BUN), creatinine, total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, total protein, albumin, uric acid, and lipid profile will be measured at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit). BUN, serum potassium, and serum creatinine value for eGFR calculation will be obtained from patients at Visit 2 (only if Visit 2A is performed), Visit 3, Visit 4 and at every visit when a complete laboratory test is not done (i.e., Visits 6-10, 12, 13, 15, 16, 18, and 19). 7.5.4.3

Potassium and eGFR assessments by local laboratory

In addition to the central laboratory assessments, potassium and eGFR, may be measured locally during the active run-in period (Visit 2, Visit 3, Visit 4), up to the randomization visit (Visit 5) to determine eligibility of the patient into the trial. Local potassium and eGFR This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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measurements may also be performed during the double-blind treatment period, mainly at the unscheduled visits, to monitor the tolerability to study medication dose administered and adjust medication dose if needed. The results of the local laboratory during the active run-in period will not be reconciled with the central laboratory measurements. 7.5.4.4

Urinalysis

Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, ketones, and leukocytes will be measured at Visits 1, 5, 11 and then at yearly intervals until EOS. If dipstick is positive, a qualitative microscopic determination, including white blood cells high power field (WBCs/HPF) and red blood cells high power field (RBCs/HPF) will be performed. 7.5.5

Electrocardiogram (ECG)

A standard 12-lead ECG will be performed at screening (Visit 1, unless an ECG performed within the last 6 months is available), randomization (Visit 5), Visit 11, and at yearly intervals thereafter until the end of the study up till Visit 778 (EOS visit). Interpretation of the tracing must be made by a qualified physician and documented on the ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient initials, patient number, and date and kept in the source documents at the study site. Only clinically significant abnormalities should be reported on this page. Clinically significant abnormalities should also be recorded on the relevant medical history/current medical conditions or AE eCRF page. 7.5.6

Pregnancy and assessments of fertility

All female patients of childbearing potential will have a serum pregnancy test performed at Visit 1 (central laboratory). Additionally, these patients will have urine pregnancy tests performed at the investigational sites at Visit 5 and yearly thereafter until Visit 778. In case of a positive urine pregnancy result a confirmatory serum pregnancy test will be performed at the central laboratory. See Section 6.5.5 and Section 8.3 for details on pregnancies. 7.5.7

Angioedema

Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genetalia and intestines. Severe cases may be associated with airway compromise. Although, the mechanism is not fully understood, bradykinin has been implicated as the putative mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may result in this potentially dangerous side effect. Simultaneous inhibition of multiple breakdown pathways of bradykinin is thought to significantly increase the risk of occurrence of angioedema (Sulpizio et al 2004). Section 4.3.1 details how to avoid the simultaneous inhibition of the ACE and NEP pathways by overlapping exposure to LCZ696 and enalapril at Visit 3 (start of LCZ696 run-in) and at Visit 5 (randomization). The method outlined in Section 4.3.1 is expected to provide at least 36 hours free of significant simultaneous inhibition of NEP and ACE, thereby minimizing the This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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potential risk of occurrence of angioedema. This 36-hour washout period is expected to present minimal risk to patients, especially since all patients will continue using their other background HF medications during this period. The procedure for reporting angioedema-like events is outlined in Section 8.5.

7.6

Other assessments

7.6.1

Resource utilization

Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare resource utilization (RU) parameters. At Visit 1 (screening), prior hospitalizations for CV-related complications, relevant medical conditions and therapies, and prior procedures will be collected. At Visit 6 and each subsequent scheduled visit, the level of health care resource utilization will be assessed through procedures rendered during hospital stays. The frequency and duration of any inpatient hospitalization will be recorded along with the primary reason for the hospital admission and discharge. All attempts will be made to collect RU variables in all patients throughout the duration of the study in order to avoid selection bias. There may also be circumstances when the collection of such data after completion of the study may be warranted. 7.6.2

Heart failure symptom reduction and reduction in physical limitation

The KCCQ is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and patient global reports of change. The KCCQ is a valid, reliable and responsive health status measure for patients with CHF and may serve as a clinically meaningful outcome in CV clinical research, patient management and quality assessment (Green et al 2000). The HF symptoms and physical limitation domains scores show the best the correlation for improvements following a CHF exacerbation (Green et al 2000). Thus, one of the secondary endpoints is a clinical summary score based on the HF symptom reduction and physical limitation domains scores of the KCCQ at 8 months. All other domains will be analyzed as exploratory endpoints, as the instruments will be administered as a whole. The questionnaire will be completed at Visits 5, 9, 10, 11, 14, 17, and 778 (EOS). The KCCQ is available in a number of validated translations. However, patients in whose language a validated translation of the KCCQ is not available will be exempt from completing this instrument.



7.6.3

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Clinical composite score

The clinical composite score is one of the exploratory endpoints of this study. It is derived from two instruments: the patient global assessment and the NYHA functional classification. The global patient assessment is a seven-point patient self-evaluation scale. At Visit 5 (randomization), the investigator should call the patient’s attention to how he/she feels at that time and to explain that periodically the patient will be asked to rate how he/she feels compared to at this point in the study. Subsequently, patients will be asked to rate how well they feel compared to Visit 5 (randomization/baseline) (COPERNICUS Investigators 2002). This evaluation is combined with the NYHA functional class, one of the most reliable instruments for rating HF patients’ functionality, to arrive at an overall evaluation of whether a patient is considered to have improved, worsened, or unchanged after a pre-specified period of time (Packer 2001). The patient global assessment will be conducted at Visits 9, 10, 11, 14, 17, and 778 (EOS). HF signs and symptoms/NYHA classification will be conducted at all visits. 7.6.4

EuroQol (EQ-5D)

The EuroQol (EQ-5D) (Appendix 6) is an instrument used to assess the current health status of patients. It consists of five domains and one visual analogue scale. This instrument assesses morbidity, self-care, usual activity, pain, and anxiety and depression of patients. The EQ-5D will be completed at Visits 5, 9, 10, 11, 14, 17, and 778 (EOS). The EQ-5D is available in a number of validated translations. However, patients in whose language a validated translation of the EQ-5D is not available will be exempt from completing this instrument. 7.6.5

Pharmacokinetics

Approximately 400 of the patients participating in the biomarker substudy will also participate in the population PK substudy during the run-in and double-blind treatment periods at select study centers. Plasma levels of valsartan, AHU377, and LBQ657 will be determined from these patients. During the run-in period, participating patients will provide a trough (Cmin) PK sample on the morning of Visit 4 prior to up-titration. During the double-blind treatment period, a total of 3 samples will be collected either at one visit or at multiple visits depending on the availability of the patient and site staff. The samples will be collected at the following intervals at Visit 7: • Sample #1: pre-dose trough (immediately before the administration of study drug) • Sample #2: 0.5 to 2 hours post-dose • Sample #3: 3 to 5 hours post-dose If the PK samples are not taken at Visit 7, then they will be taken at Visit 10. Site should make every effort to collect sample as close to the interval periods as possible. The exact time of the treatment administration, dose of LCZ696, sample number, and time of sample collection will be recorded for each sample collected on the Pharmacokinetic Sample eCRF.



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Patients participating in the PK substudy are not required to provide all three required blood samples during the same study visit. However, samples should always be taken when the patient is expected to be at steady state, i.e., has been receiving the study drug regularly on the same dose level as prescribed for at least 1 week. Special instructions on preparation, labeling, storage, and shipment of PK samples will be provided to the sites in a separate document. 7.6.6

Pharmacogenetics/pharmacogenomics

No pharmacogenetics/pharmacogenomics assessments will be made in this study. 7.6.7

Other biomarkers

New, relevant, biomarkers that may be discovered during the process of this study and after its completion may be analyzed in addition to those already defined in Sections 7.4.4 and 7.4.5.

8

Safety monitoring

8.1

Adverse events

An AE is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. Study drug includes the investigational drug under evaluation and the comparator drug or placebo that is given during any phase of the study. Medical conditions/diseases present before starting study drug are only considered AEs if they worsen after starting study drug. Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy. The occurrence of AEs should be sought by non-directive questioning of the patient at each visit during the study. AEs also may be detected when they are volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. All AEs must be recorded on the Adverse Events CRF with the following information: 1. the severity grade [mild, moderate, severe] 2. its relationship to the study drug(s) (suspected/not suspected) 3. its duration (start and end dates or if continuing at final exam) 4. whether it constitutes a serious adverse event (SAE) An SAE is defined as an event which: •

is fatal or life-threatening

•

results in persistent or significant disability/incapacity

•

constitutes a congenital anomaly/birth defect



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requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: • routine treatment or monitoring of the studied indication, not associated with any deterioration in condition • elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since the start of study drug • treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission • social reasons and respite care in the absence of any deterioration in the patient’s general condition

•

is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above

Unlike routine safety assessments, SAEs are monitored continuously and have special reporting requirements; see Section 8.2. All AEs should be treated appropriately. Treatment may include one or more of the following: no action taken (i.e. further observation only); study drug dosage adjusted/temporarily interrupted; study drug permanently discontinued due to this AE; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The action taken to treat the AE should be recorded on the Adverse Event CRF. Once an AE is detected, it should be followed until its resolution or until it is judged to be permanent, and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the outcome. Information about common side effects already known about the investigational drug can be found in the Investigator Brochure (IB) or will be communicated between IB updates in the form of Investigator Notifications. This information will be included in the patient informed consent and should be discussed with the patient during the study as needed.

8.2

Serious adverse event reporting

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided informed consent and until 30 days after the patient has stopped study participation must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 30 day period should only be reported to Novartis if the investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode, regardless of when the event occurs. This report must be submitted within 24 hours of the investigator receiving the follow-up information. An SAE that is considered completely unrelated to a previously reported one should be reported separately as a new event. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form. The investigator must assess the relationship to study drug, complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the local Novartis Integrated Medical Safety (IMS) Department. The telephone and telecopy number of the contact persons in the local department of Integrated Medical Safety, specific to the site, are listed in the investigator folder provided to each site. The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same person to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation. If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new occurrence) and is thought to be related to the Novartis study drug, a Integrated Medical Safety Department associate may urgently require further information from the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all investigators involved in any study with the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries.

8.3

Pregnancies

In case a patient becomes pregnant, or plans to become pregnant, the study drug must be interrupted before contraception is discontinued (or, from the date the pregnancy becomes known) for the entire duration of the pregnancy and lactation period (or, for the entire duration that contraception is discontinued). To ensure patient safety, each pregnancy in a patient on study drug must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the local Novartis IMS Department. Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form.

8.4


An external data monitoring committee (DMC) independent of Novartis will be appointed to monitor the study conduct and to review the results of the IA from the study and to determine if it is safe to continue the study according to the protocol. If applicable, the recommendation may include any new relevant safety issues(s) identified by the DMC during the evaluation or recommendation to stop for early proof of efficacy. Any major recommendation from the This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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DMC will be communicated to the Executive Committee and must be reviewed and ratified by the Executive Committee prior to its enactment. The membership of the DMC and the responsibilities of the DMC and Novartis will be defined in a separate document entitled the ”Data Monitoring Committee Charter.” The DMC Charter will include information about data flow, purpose and timing of DMC meetings, guidance in the decision making process, communication strategy, procedures for ensuring confidentiality, procedures to address conflicts of interest and statistical monitoring guidelines.

8.5

Reporting angioedema-like events

It is important that the investigator pays special attention to any swelling or edema that may resemble angioedema or angioedema-like events that may be reported by patients. If such an event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate outcome and communicate this report to Novartis as soon as possible. Followup reports must be communicated to Novartis as soon as new information regarding the event becomes available. All hospital records related to the event must be communicated to Novartis. Occasionally, the investigator may be contacted by the Novartis regarding AEs that were reported on behalf of patients that may resemble an angioedema-like event. The investigator or his/her delegated staff must complete the required report forms and supply the required medical records for such events, regardless of whether the investigator views the event in question as angioedema or not. All angioedema reports will be forwarded to an angioedema adjudication committee by Novartis for assessment. Submission of an angioedema report is not a substitution for the submission of a SAE report. If an angioedema-like event satisfies the definition of a SAE, the investigator must submit a SAE report (as described in Section 8.2) in addition to the Adjudication Questionnaire for an Angioedema-like Event.

9

Data review and database management

9.1

Site monitoring

Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis representative will review the protocol and eCRFs with the investigators and their staff. During the study, the field monitor will visit the site regularly to check the completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being stored, dispensed, and accounted for according to specifications. Key study personnel must be available to assist the field monitor during these visits. The investigator must maintain source documents for each patient in the study, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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information, laboratory data, electrocardiograms, and the results of any other tests or assessments. All information on eCRFs must be traceable to these source documents in the patient's file. Data not requiring a separate written record will be defined before study start and will be recorded directly on the CRFs. The investigator must also keep the original informed consent form signed by the patient (a signed copy is given to the patient). The investigator must give the monitor access to all relevant source documents to confirm their consistency with the eCRF entries. Novartis monitoring standards require full verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be used for all primary and safety variables. Additional checks of the consistency of the source data with the eCRFs are performed according to the study-specific monitoring plan. No information in source documents about the identity of the patients will be disclosed.

9.2

Data collection

Designated investigator staff will enter the data required by the protocol into the Electronic Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. Designated investigator site staff will not be given access to the EDC system until they have been trained. Automatic validation programs check for data discrepancies and, by generating appropriate error messages, allow the data to be confirmed or corrected before transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify that the data entered into the Electronic Case Report Forms are complete and accurate. After database lock, the investigator will receive a CD-ROM or paper copies of the patient data for archiving at the investigational site.

9.3

Database management and quality control

Novartis staff, or CRO staff working on behalf of Novartis, review the data entered into the eCRFs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Obvious errors are corrected by Novartis personnel or CRO staff working on behalf of Novartis. Queries are sent to the investigational site using an electronic data query. Designated investigator site staff is required to respond to the query and confirm or correct the data. If the electronic query system is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff who will make the correction to the database. The signed copy of the Data Query Form is kept at the investigator site. Concomitant medications entered into the database will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. Medical history/current medical conditions and AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Laboratory samples will be processed centrally and the results will be sent electronically to Novartis (or a designated CRO). Randomization codes and data about all study drug dispensed to the patient and all dosage changes will be tracked using an Interactive Voice Response System. The system will be This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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supplied by a vendor, who will also manage the database. The database will be sent electronically to Novartis (or a designated CRO). At the conclusion of the study, the occurrence of any emergency code breaks will be determined after return of all code break reports and unused drug supplies to Novartis. The occurrence of any protocol deviations will be determined. After these actions have been completed and the database has been declared to be complete and accurate, it will be locked and the treatment codes will be unblinded and made available for data analysis. Any changes to the database after that time can only be made by joint written agreement between the Global Head of Biostatistics and Statistical Reporting and the Global Therapeutic Area Head.

10

Data analysis

10.1

Populations for analysis

The following populations will be used for the statistical analyses: The full analysis set (FAS) will consist of all randomized patients. Following the intent-totreat principle, patients will be analyzed according to the treatment to which they were assigned at randomization. Efficacy variables will be analyzed based on the FAS as the primary population. The Safety Population (SAF) will consist of all randomized patients who received at least one dose of study drug. Patients will be analyzed according to the treatment actually received. The safety population will be used for the analyses of safety variables. The Per-protocol (PP) population will be a subset of the FAS which will consist of the patients who do not have major deviations from the protocol procedures in the double-blind study stage. Major protocol deviations will be pre-specified prior to unblinding treatment codes for analyses. This supplemental efficacy population will be used to support the primary analysis results.

10.2


Baseline value is defined as the last non-missing assessment prior to the first dose of randomized study medication unless specified otherwise. Summary statistics will be provided by treatment group for demographics and baseline characteristics, including age, age group ( median) AF at baseline (yes/no) Hypertension at baseline (yes/no) Prior RAAS drug at screening (ACEI/ARB) Use of β-blocker at baseline (yes/no) Use of aldosterone antagonists at baseline (yes/no) Previous hospitalization for HF (yes/no) Time since diagnosis of HF (three groups: ≤1 year; 1 to 5 years; >5 years)

10.5

Analysis of secondary objectives

10.5.1

Secondary efficacy variables

Please refer to Section 3.2 for the secondary efficacy objectives. The corresponding secondary efficacy variables are listed below: • Change from baseline to month 8 in clinical summary score for HF symptoms and physical limitations assessed by KCCQ • Time to all-cause mortality • Time to the first occurrence of (1) a 50% decline in eGFR relative to baseline, (2) >30 mL/min/1.73 m2 decline in eGFR relative to baseline, or (3) reaching ESRD. 10.5.2

Analysis of secondary efficacy variables

The secondary hypotheses will be tested and statistical inferences will be made only if the primary hypothesis is rejected. The three secondary efficacy variables will be tested for superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LCZ696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. As indicated in Figure 10-1, after rejection of the primary null hypothesis (H10), the sequentially rejective multiple test procedure for the secondary variables is illustrated below: • The initial allocation of significance levels are 0.2α, 0.8α, and 0 for the comparisons of KCCQ clinical summary score (noted as H210), all-cause mortality (noted as H220), and the composite renal endpoint (noted as H230), respectively. • If both of the hypotheses H210 and H220 are rejected at the initially assigned alpha levels, then the composite renal endpoint will be tested at the level of alpha. • If the hypothesis H220 is rejected and H210 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.8α. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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If the hypothesis H210 is rejected and H220 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.2α. o If H230 is rejected at this 0.2α level, then 0.2α will be added to 0.8α and H220 will be further tested at a level of alpha. o If H230 is not rejected at this 0.2α level, then no further hypothesis will be tested for influence

Figure 10-1

Illustration of weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary hypotheses

H210 denotes the null hypothesis for the comparison of KCCQ clinical summary score. H220 denotes the null hypothesis for the comparison of all-cause mortality. H230 denotes the null hypothesis for the composite renal endpoint.

For publications, these secondary variables may be further assessed using full level of alpha without consideration of multiplicity adjustment. Analysis of KCCQ clinical summary score as continuous variable The KCCQ instrument includes several domains. Only the domains that address HF symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is computed as the mean of the following available domain scores: • Physical limitation score • Total HF symptom score The clinical summary score of KCCQ will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit, and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance for each treatment group. The primary treatment comparison between LCZ696 and enalapril is to be made at Month 8. The analysis will be performed based on all available data in the FAS and based on likelihood method. The estimated treatment effect with the associated confidence interval at Month 8 will be provided.



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Analysis of time to all-cause mortality The time to all-cause mortality will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided confidence interval will be provided in the FAS. The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of all-cause mortality will be provided by treatment group. Analysis of time to composite renal endpoint The time to composite renal endpoint will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided confidence interval will be provided in the FAS. The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of composite renal endpoint will be provided by treatment group.

10.6

Analysis of exploratory objectives

10.6.1.1 Analyses of exploratory variables The variables planned to be analyzed are provided in the exploratory objectives in Section 3.3. In general, exploratory variables (Section 3.3) will be analyzed in the FAS unless specified otherwise. Statistical tests will be performed at the two-sided significance level of 0.05. To better satisfy the normality assumption, the log-transformation will be taken on each biomarker prior to statistical analysis. There will be no multiplicity adjustment for analysis of exploratory variables. Analysis of time-to-events Time-to-event variables will be analyzed using the Cox proportional hazard model with treatment and region as fixed effect factors. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided. Analysis of continuous variables Continuous variable will be analyzed using ANCOVA model with treatment and region as fixed effect factors. Additionally, the baseline value of the corresponding variable may be included as a covariate if appropriate. The estimated treatment effect and the corresponding two-sided 95% confidence interval will be provided. The last-observation-carried-forward (LOCF) technique will be used to impute the missing value if the last observation is assessed at post-randomization. Analysis of ordinal variables Binary variables will be analyzed using logistic regression with treatment and region as fixedeffect factors and baseline value as a covariate, if appropriate.



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Other ordinal variables will be analyzed using Cochran-Mantel-Haenszel (CMH) test for different row (treatment) means, adjusted for region, based on modified ridit scores which are also referred to as standardized midranks. The LOCF technique will be used to impute the missing value if the last observation is assessed at post-randomization. Analysis of eGFR slope For each patient, the eGFR slope will be calculated by fitting the patient’s eGFR assessments into a linear regression model with time as the independent variable. The derived eGFR slope will be analyzed using an ANCOVA model with baseline eGFR as the covariate and treatment and region as fixed-effect factors. The estimated treatment effect and the associated confidence interval for the eGFR slope will be provided. Days alive out of the hospital during the first 12 months The duration in days of hospital-free survival at Month 12 will be summarized by treatment group, and descriptive statistics (n, mean, standard deviation, median, max, and min) will be provided. Death within the first 12 months will be treated as zero-duration of hospital-free survival, regardless of how many days the patient was alive and out of the hospital prior to month 12. The mean difference between treatment groups will be compared using t-test and 95% confidence interval will be provided.

10.7

Safety

The safety and tolerability assessments are listed below: • AEs and SAEs • Sitting systolic, diastolic BP, and pulse pressure • Heart rate • Symptomatic hypotension • Angioedema • Laboratory values • Hyperkalemia • Renal dysfunction • ECG changes The assessment of safety will be based primarily on the frequency of adverse events, SAEs, and laboratory abnormalities. Other safety data will be summarized as appropriate. The incidence of treatment-emergent adverse events (new or worsened) will be summarized by primary system organ class, preferred term, severity, and relationship to study drug. In addition, the incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately by primary system organ class and preferred term. Laboratory data will be summarized by presenting shift tables using extended normal ranges (baseline to most extreme post-baseline value), by presenting summary statistics of raw data This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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and change from baseline values (mean, medians, standard deviations, ranges) and by the flagging of notable values in data listings. Data from other tests (e.g., ECG or vital signs) will be listed, notable values will be flagged, and any other information collected will be listed as appropriate. Safety analyses will be performed based on the safety population. There will be no formal statistical inference analysis. In addition to the above safety analyses for the randomized double-blinded treatment period, the AEs, SAEs, and reasons for active run-in failures will be summarized for the active run-in period. A frequency table will be provided by dose and reason for those patients who are unable to tolerate LCZ696 during the active run-in period.

10.8


Data relating to resource utilization will be used to describe medical resources used by the study participants. Only descriptive statistics of resources utilization data will be provided by treatment group.

10.9

Health-related quality of life

The reduction in combination of HF symptoms and physical limitation scores assessed by the clinical summary score of the KCCQ is one of the secondary efficacy endpoints. Please refer to Section 7.6.2 for more details. As discussed in Section 10.5.2, the clinical summary score will be analyzed using ANCOVA. All other domains will be analyzed similarly as exploratory endpoints, as the instruments will be administered as a whole.

10.10

Pharmacokinetics

Steady-state PK time profile of valsartan, AHU377, and LBQ657 will be analyzed by graphical methods to determine the appropriate structural PK model to fit the data. Following this, a population PK model will be developed using the plasma time profile patient-level data from this study and/or in combination with PK data from other studies with LCZ696 to quantify the PK of valsartan, AHU377, and LBQ657 and test for significant covariates that influence their PK.

10.11


Not applicable.

10.12

Biomarkers

Biological markers will be collected in a subset of patients (see Sections 7.4.4 and 7.4.5). Visit 1 will be considered baseline for BNP and NT-proBNP, while Visit 2 will be considered baseline for all other biomarkers. For the FAS, summary statistics by treatment group will be performed for the baseline values, the post-baseline values, and the change from baseline and from Visit 5 (randomization visit) to Visit 6 (2 weeks) and Visit 10 (8 months). This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


10.13

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Pharmacodynamics

Not applicable.

10.14

Sample size calculation

The sample size estimation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the efficacy interim analyses currently planned (Section 10.16). The targeted sample size mainly is driven by the CV mortality component of the primary composite endpoint. With a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril for CV mortality, using the log-rank test. Assuming an annual CV death rate of 7% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months, a total sample size of 7,980 patients will be required to obtain 1,229 CV deaths. By randomizing 7,980 patients in the study, assuming the same enrollment period, follow-up duration same as above, 15% reduction in hazard, and an annual primary event rate of 14.5% in the enalapril group, it is expected to attain greater than 97% power to detect a difference between treatments for the primary composite endpoint. This, in turn, corresponds to a total number of at least 2,410 patients with primary events during the course of the trial. The assumption of 14.5% annual event rate for the primary composite endpoint is based on the CHARM-Added trial (CHARM Investigators and Committees 2003). In that study the reported annual event rate was 14.1% in the candesartan group and 16.6% in the placebo group. In CHARM-Added all patients received ACEIs, such as enalapril, as background therapy, although the ACEIs may not have been administered at their top doses. Hence, an estimate of the annual primary event rate between the candesartan and placebo group in CHARM-Added would provide a reasonable estimate for event rate for the active comparator enalapril in the current study. Assuming further improvement in underlying HF therapy within the past 5 years since CHARM-Added was conducted, a more conservative annual rate of 14.5% was chosen for sample size calculation. The 7% CV mortality annual event rate is estimated from the CHARM-Added trial in a similar manner.

10.15

Power for analysis of critical secondary variables

The tests of secondary variables are part of the global testing strategy. For the change from baseline to Month 8 in clinical summary score assessed by KCCQ, the above sample size will provide 96~99% individual power to detect a treatment difference of 2 points at the one-sided significance level of 0.00463 (i.e., 0.02314 × 0.2), assuming a standard deviation between 15 and 20. A standard deviation of 15 was observed in the published literature (Flynn et al 2009). For time to all-cause mortality, the above sample size will provide approximately 87% individual power to detect a 15% reduction in hazard at one-sided significance level of 0.0185 (i.e. 0.02314 × 0.8). Assuming an annual event of 9% in the enalapril group, an enrollment This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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period of 18 to 22 months and a minimum follow-up of 21 months. The numbers in the assumption are estimated based on the CHARM-low LVEF trial (Young et al 2004). For time to composite renal endpoint, the above sample size will provide about 80% power to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.02314 and 0.004628 (i.e., 0.02314 × 0.2), respectively. It is assumed for the annual rate to be 0.021 based on the CHARM trials and AASK trial (Wright, Jr 2002).

10.16

Interim analysis

The O’Brien-Fleming type of boundary with Lan-DeMets alpha spending function will be used for the interim efficacy analyses to assess superiority. As currently planned, two interim efficacy analyses are to be expected approximately at 1/3 and 2/3 of information time (i.e., approximately 803 and 1607 patients, respectively, with a primary events of CV mortality or HF hospitalization). The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (one-sided) at the first interim analysis and 0.00605 (one-sided) at the second interim analysis. The actual alpha to be spent for the interim efficacy analyses will be precisely determined based on the Lan-DeMets alpha spending function using the actual number of patients who have experienced a primary events at the interim efficacy analyses. The spending function can be expressed as f (t ) = min 2 − 2 ⋅ Φ zα 2 t , α , t is the information included in percentage at the interim efficacy analysis (Lan and DeMets 1983). Additionally, the CV death component will also be analyzed at each interim efficacy analysis. When 1/3 and 2/3 of the total number of patients with primary events occurred, approximately 409 and 819 CV deaths are to be expected, respectively. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the planned boundary are obtained for both primary composite endpoint and CV mortality component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment based on the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. The details of the futility boundary will be described in the DMC Charter

{

(

) }

If the study is stopped early for claiming superiority efficacy due to statistically significant results for both primary endpoint and the CV death component at an interim analysis, the secondary endpoints will be tested using the same testing procedure as described in Section 10.5.2 for the final analysis at the overall alpha level equal to the one used for the interim analysis of the primary endpoint. Interim safety assessments are planned to be performed twice a year. As discussed in Section 4.2.6, in order to identify potential safety signals earlier, a review of selected safety assessments is planned to be performed when 200 patients have completed the first 4 weeks of double-blind randomized treatment. Additionally, reviews of selected safety assessments are planned when the first 100, 300, and 600 patients completing the run-in period. Summary of the selected safety assessments during the run-in period will be provided for enalapril and LCZ696 separately. No further alpha adjustment will be made due to these interim safety assessments.



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Interim analyses will be performed by an independent statistician who will not be involved in the trial conduct. The results will be reviewed by the independent DMC. Investigators, Novartis employees, and others who are involved in the conduct of the trial will remain blinded to the treatment codes and IA results until all monitoring decisions have been made and the database has been locked for final analysis.

10.17

End of the study

This trial is planned as a maximum information trial. The end of the study will be concluded at the time when the pre-specified number (2410) of patients achieves the primary composite endpoint of CV deaths or hospitalizations due to heart failure unless the study is terminated early because of a statistically significant interim analysis or a critical safety concern. As a maximum information trial, the actual length of the trial will depend on the observed event rates, the patient accrual rate, and length of the accrual period. As planned, it is expected to be about 43 months: a recruitment period of 22 months and a minimal follow up of 21 months.

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Ethical considerations

11.1

Regulatory and ethical compliance

This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of Helsinki.

11.2

Informed consent procedures

Eligible patients may only be included in the study after providing written (witnessed, where required by law or regulation), IRB/IEC/REB-approved informed consent. Informed consent must be obtained before conducting any study-specific procedures (i.e. all of the procedures described in the protocol). The process of obtaining informed consent should be documented in the patient source documents. Novartis will provide to investigators in a separate document a proposed informed consent form that complies with the ICH GCP guideline and regulatory requirements and is considered appropriate for this study. Any changes to the proposed consent form suggested by the investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. Women of child bearing potential should be informed that taking the study medication may involve unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to participate in the study they must adhere to the contraception requirement for the duration of the study. If there is any question that the patient will not reliably comply, they should not be entered in the study. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


11.3

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Responsibilities of the investigator and IRB/IEC/REB

The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted Institutional Review Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB must be given to Novartis before study initiation. Prior to study start, the investigator is required to sign a protocol signature page confirming his/her agreement to conduct the study in accordance with these documents and all of the instructions and procedures found in this protocol and to give access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs, and regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator must inform Novartis immediately that this request has been made.

11.4

Publication of study protocol and results

Novartis assures that the key design elements of this protocol will be posted in a publicly accessible database such as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the results of this trial will be either submitted for publication and/or posted in a publicly accessible database of clinical trial results.

12

Protocol adherence

Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial to request approval of a protocol deviation, as no authorized deviations are permitted. If the investigator feels a protocol deviation would improve the conduct of the study this must be considered a protocol amendment, and unless such an amendment is agreed upon by Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded and reported in the CSR.

12.1

Protocol Amendments

Any change or addition to the protocol can only be made in a written protocol amendment that must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only amendments that are required for patient safety may be implemented prior to IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol amendments, the investigator is expected to take any immediate action required for the safety of any patient included in this study, even if this action represents a deviation from the protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the study site should be informed within 10 working days.

13

References

Available upon request.



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Adams KF, Lindenfeld J, Arndol JMO, et al (2006) Executive Summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Cardiac Fail; 12: 10-38. American Heart Association (2006) Heart disease and stroke statistics – 2006 update. Dallas, Texas: American Heart Association. Asmar R, Fredebohm W. Senftlebr I, et al (2000) Omapatrilat compared with lisinopril in treatment of hypertension as assessed by ambulatory blood pressure monitoring. Am J Hypertens; 13: 143A. Abstract A 085. Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially rejective multiple test procedures. Statist Med; 28:586-604. CHARM Investigators and Committees (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin convertingenzyme inhibitors: the CHARM-Added trial. Lancet; 362: 767-771. CIBIS II Investigators (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet; 353: 9-13. Cicardi M, Zingale LC, Bergamaschini L, Agostoni A (2004) Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment. Arch Intern Med; 164:910-3. Cohn JN and Tognoni G (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med; 345:1667-1675. CONSENSUS Trial Study Group (1987) Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med; 316:1429-1435. ESC Guidelines (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008. Eur Heart J; 29:2388–2442. Ferro CJ, Spratt JC, Haynes WG, Webb DJ (1998) Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation; 97:2323-30. Flather MD, Shibata MC, Coats AJ, et al (2005) Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J; 26:215-25. Flynn KE, Pina IL, Whellan DJ, et al (2009) Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA; 301: 1451-1459. Fryer RM, Segreti J, Banfor PN, et al (2008) Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. Br J Pharmacol; 153:947-955. Gardner DG, Chen S, Glenn DJ, et al (2007) Molecular biology of natriuretic peptide system: implications for physiology and hypertension. Hypertension; 49:419-426.



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Green C, Porter C, Bresnahan D and Spertus J (2000) Development and Evaluation of the Kansas City Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. JACC; 35(5):1245-1255. Hunt SA, Abraham WT, Chin MH, et al (2009) Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation;119:e391– e479. Kostis JB, Packer M, Black HR, et al (2004) Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens; 17:103-11. Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika; 70: 659-663. Levin ER, Gardner DG, Samson WK (1998) Natriuretic peptides. N Engl J Med; 339:321-8. MERIT-HF Study group (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet; 353:2001-7. Neutel J, Shepherd A, Pool J, et al for the Omapatrilat Investigators (1999) Antihypertensive efficacy of Omapatrilat, a vasopeptidase inhibitor, compared with lisinopril. J Hypertens.; 17(suppl 3); S67. Abstract P1.167. Packer M (2001) Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Cardiac Fail; 7: 176-182. Packer M, Califf RM, Konstam MA, et al (2002a) Comparison of Omapatrilat and Enalapril in Patients with Chronic Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation; 106;920-926. Packer M, Fowler MB, Roecker EB, et al for the COPERNICUS Study Group (2002b) Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation; 106:2194-2199. Pandey KN (2008) Emerging roles of natriuretic peptides and their receptors in pathophysiology of hypertension and cardiovascular regulation. J Am Soc Hypertens; 2:210226. Perlini S (2005) The potential advantage of omapatrilat: dual anti-fibrotic and antiinflammatory effects in one single molecule. J Hypertens; 23:273-275. Pfeffer MA, Swedberg K, Granger CB, et al for the CHARM Investigators and Committees (2003) Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet; 362: 759-766. Prasad PP, Yeh CM, Gurrieri P, Glazer R, McLeod J (2002) Pharmacokinetics of multiple doses of valsartan in patients with heart failure. J Cardiovasc Pharmacol; 40:801-807. This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Pitt B, Zannad F, Remme WJ, et al (1999) The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med; 341:709-17. Pu Q, Amiri F, Gannon P, Schiffrin EL (2005) Dual angiotensin-converting enzyme/neutral endopeptidase inhibition on cardiac and renal fibrosis and inflammation in DOCA-salt hypertensive rats. J Hypertens; 23:401-9. RALES Investigators (1996) Effectiveness of spironolactone added to an angiotensinconverting enzyme inhibitor and loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol; 78:902-7. Richards AM, Wittert GA, Crozier IG, et al (1993) Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II. J Hypertens; 11:407-16. Ruilope LM, Plantini P, and Grossman E, et al (2000) Randomized, double-blind comparison of omapatrilat with amlodipine in mild-to-moderate hypertension. Am J Hypertens; 13 (pt 2), p. 134A. SOLVD Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med; 325:293-302. SOLVD Investigators (1992) Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med; 327:685-691. Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med; 354:2473-2483. Stewart S, Jenkin A, Buchan S, et al (2002) The current cost of heart failure to the National Health Service in the UK. Eur J Heart Fail; 4:361-71. Sulpizio AC, Pullen MA, Edwards RM, Brooks DP (2005) The effect of acute angiotensinconverting enzyme and neutral endopeptidase 24.11 inhibition on plasma extravasation in the rat. J Pharmacol Exp Ther; 309:1141-1147. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology (2008) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J; 29:2388-2442. Wright, Jr JT, Bakris G, Greene T, et al (2002) Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA; 288:2421-2431. Young JB, Dunlap ME, Pfeffer MA, et al (2004) Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction, results of the CHARM low-left ventricular ejection fraction trials. Circulation; 110:26182626.



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Appendix 1: Clinically notable laboratory values and vital signs

Clinically notable laboratory abnormalities for selected tests based on a percent change from baseline: Hematology RBC count

>50% increase, >20% decrease

Hemoglobin


Hematocrit


WBC count


Platelet count


Blood Chemistry ALT (SGPT)

>150% increase

AST (SGOT)

>150% increase

BUN

>50% increase

Creatinine

>50% increase

Total bilirubin

>100% increase

CPK

>300% increase

Alkaline phosphatase >100% increase Potassium


Chloride


Calcium


Uric acid

>50% increase

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Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than or equal to 5.3 mmol/L)

General principles Elevation of potassium levels above the predefined values should be repeated and confirmed before any action is taken. Any patient who experiences a potassium level ≥ 5.5 mmol/L confirmed by repeated testing during the run-in period should be withdrawn from the study. Any patient with a serum potassium > 5.3 mmol/L after randomization requires regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) until it is clear that the potassium concentration is stable and not rising into the range of concern (≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L). This document (090095af81be45ab in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 9/15/2009 10:43:18 AM, signing status at this time: Completed (3 of 3 signatures) Approved for report publication by Rizkala Adel in East Hanover at Tue, 15 Sep 2009 09:42:53 AM EDT Approved for report publication by Shi Victor in East Hanover at Tue, 15 Sep 2009 10:13:13 AM EDT Approved for report publication by Gong Jianjian in East Hanover at Tue, 15 Sep 2009 10:40:37 AM EDT


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Investigators should not randomize a patient with a serum potassium ≥ 5.5 mmol/L during the run-in period. Patients with elevated potassium value will be managed according to the corrective actions outlined below. Corrective action for management of hyperkalemia Serum potassium > 5.3 and less than or equal to 5.5 mmol/L • • •

• • •

Confirm potassium concentration in a non-hemolyzed sample Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. orange juice, melon, bananas, low-salt substitutes etc.) Review medical regimen (including dietary supplements and over-the-counter medications) for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of these agents: • Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination products with thiazide or loop diuretics • Potassium supplements, e.g., potassium chloride • Salt substitutes • Non-steroidal anti-inflammatory drugs (NSAIDs) • Cyclo-oxygenase-2 (COX-2) inhibitors • Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and Septra® (trimethoprim/sulfamethoxazole fixed combination) • Herbal Supplements: • For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian ginseng, hawthorn berries Repeat serum potassium measurement within 3 to 5 days If serum potassium remains > 5.3 and ≤ 5.5 mmol/L, regularly monitor serum potassium levels to ensure stability (suggested once monthly) Consider down-titration of study medication, according to investigator’s medical judgment.

Serum potassium > 5.5 and < 6.0 mmol/L • • • • •

Confirm potassium concentration in a non-hemolyzed sample Consider down-titration or temporarily discontinue study drug according to investigator medical judgment. Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L Repeat serum potassium measurement after 2-3 days If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with repeat potassium within 5 days



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Serum potassium greater than or equal to 6.0 mmol/L • • • •

Immediately discontinue study drug Confirm potassium concentration in a non-hemolyzed sample Urgently evaluate patient and treat hyperkalemia as clinically indicated Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L

No resumption of study drug without individualized case discussion with and permission from Novartis medical monitor or his/her designee.

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Appendix 3: Guidelines for the management of blood pressure

Guidelines 1. Investigator should monitor blood pressure closely 2. If symptomatic hypotension occurs: a. Correct any treatable cause, e.g. hypovolemia b. If hypotension persists, any antihypertensive drug and non-life saving drugs should be down-titrated or stopped first before down-titration of the study drug is considered c. If hypotension persists, the study drug should be down-titrated or even temporarily withdrawn. The dose re-challenge and medications adjust guidelines described in Section 6.5.5 should be adhered to as much as possible.

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Appendix 4: Guidelines for the management of renal dysfunction

General principles: Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a stimulation of angiotensin II and could be affected by either study medication. Moreover, renal dysfunction may develop or may deteriorate in some patients after study drug administration. These recommendations have been developed to guide the investigators in managing patients with renal dysfunction after randomization. During the run-in period any patient who experiences a decline in eGFR > 25% from Visit 1 or an eGFR < 30 mL/min/1.73m2 will be considered a run-in failure and withdrawn from the study.



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Two types of response to serum creatinine increase are described: Surveillance situation If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 5) (or if serum creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will check for potentially reversible cases of renal dysfunction such as: • Non-steroidal anti-Inflammatory drug intake, antibiotics, or other treatments known to affect creatininemia • Volume decrease • Urinary infection • Urinary tract obstruction • Study medication Action situation If a patient eGFR decreases by ≥ 40% from baseline (Visit 5) (or if serum creatinine concentration rises above 3 mg/dL (265 µmol/L), the investigator will check for potentially reversible causes of renal dysfunction (see above). If the investigator judges that study medication has to be stopped, he/she will have to contact the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments will have to be repeated at least each week until levels return to acceptable values. If study medication was stopped, every effort will be done to restart it again, according to clinical conditions.



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Appendix 5: Kansas City Cardiomyopathy Questionnaire



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Appendix 6: EuroQoL (EQ-5D)



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Clinical Development & Medical Affairs

LCZ696B Clinical Study Protocol CLCZ696B2314


Authors:

Rizkala Adel R, Shi Victor, Gong Jim, Chandra Priya, Lefkowitz Martin

Principal or Coordinating McMurray J and Packer M for the LCZ696 Executive Investigator Committee Document type:

Amended Protocol Version

EUDRACT number:

2009-015834-31

Version number:

v04 Clean

Development phase:

III

Release date:

7-March-2013 Template Version August 2007 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis

This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST

Novartis Amended Protocol Version v04 Clean

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Page 2 CLCZ696B2314

Table of contents Table of contents ................................................................................................................. 2 List of tables ........................................................................................................................ 6 List of figures ...................................................................................................................... 7 List of abbreviations ............................................................................................................ 8 Glossary of terms ............................................................................................................... 11 Amendment 3 ........................................................................................................................... 12 Protocol synopsis ............................................................................................................... 14 1 Background........................................................................................................................ 24 2 Purpose and rationale ........................................................................................................ 27 3 Objectives .......................................................................................................................... 27 3.1 Primary objective ................................................................................................... 27 3.2 Secondary objectives ............................................................................................. 27 3.3 Exploratory objectives ........................................................................................... 28 4 Study design ...................................................................................................................... 28 4.1 Overview................................................................................................................ 28 4.2 Justification of key elements of the study design .................................................. 29 4.2.1 Selection of the primary endpoint ......................................................... 29 4.2.2 Choice of enalapril as the comparator ................................................... 30 4.2.3 LCZ696 dose and dosing regimen ........................................................ 30 4.2.4 Single-blind active run-in period .......................................................... 31 4.2.5 Duration of the study............................................................................. 31 4.2.6 Early safety evaluation (seamless design)............................................. 32 4.3 Study visits............................................................................................................. 32 4.3.1 Screening ............................................................................................... 32 4.3.2 Single-blind active run-in period .......................................................... 32 4.3.3 Double-blind study treatment period .................................................... 35 5 Population .......................................................................................................................... 38 5.1 Inclusion criteria .................................................................................................... 38 5.2 Exclusion criteria ................................................................................................... 39 6 Treatment ........................................................................................................................... 41 6.1 Investigational and control drugs........................................................................... 41 6.2 Treatment arms ...................................................................................................... 42 6.3 Treatment assignment ............................................................................................ 43 6.4 Treatment blinding................................................................................................. 43 6.5 Treating the patient ................................................................................................ 44 This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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6.5.1 Patient numbering ................................................................................. 44 6.5.2 Dispensing the study drug ..................................................................... 44 6.5.3 Study drug supply, storage and tracking ............................................... 44 6.5.4 Instructions for prescribing and taking the study drug.......................... 45 6.5.5 Permitted study drug dose adjustments and interruptions..................... 47 6.5.6 Rescue medication ................................................................................ 49 6.5.7 Other concomitant treatment ................................................................. 49 6.5.8 Study drug discontinuation and premature patient withdrawal............. 50 6.5.9 Emergency unblinding of treatment assignment ................................... 51 6.5.10 Study completion and post-study treatment .......................................... 51 6.5.11 Early study termination ......................................................................... 52 Visit schedule and assessments ......................................................................................... 52 7.1 Information to be collected on screening failures.................................................. 57 7.2 Patient demographics/other baseline characteristics ............................................. 57 7.3 Treatment exposure and compliance ..................................................................... 58 7.4 Efficacy .................................................................................................................. 58 7.4.1 Primary and secondary efficacy endpoints ........................................... 58 7.4.2 Endpoint Committee ............................................................................. 58 7.4.3 Estimated glomerular filtration rate (eGFR) ......................................... 59 7.4.4 Biomarkers ............................................................................................ 59 7.4.5 Urine albumin to creatinine ratio (UACR) and first morning void urine sampling ....................................................................................... 60 7.5 Safety ..................................................................................................................... 60 7.5.1 Physical examination ............................................................................ 60 7.5.2 Vital signs.............................................................................................. 60 7.5.3 Height, weight, and waist/hip circumference ........................................ 60 7.5.4 Laboratory evaluations .......................................................................... 60 7.5.5 Electrocardiogram (ECG) ..................................................................... 63 7.5.6 Pregnancy and assessments of fertility ................................................. 63 7.5.7 Angioedema .......................................................................................... 63 7.6 Other assessments .................................................................................................. 64 7.6.1 Resource utilization ............................................................................... 64 7.6.2 Heart failure symptoms reduction and reduction in physical limitation ............................................................................................... 64 7.6.3 Clinical composite score ....................................................................... 65 7.6.4 EuroQol (EQ-5D) .................................................................................. 65 7.6.5 Pharmacokinetics .................................................................................. 65



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7.6.6 Pharmacogenetics/pharmacogenomics ................................................. 66 7.6.7 Other biomarkers ................................................................................... 67 8 Safety monitoring .............................................................................................................. 67 8.1 Adverse events ....................................................................................................... 67 8.2 Serious adverse event reporting ............................................................................. 68 8.3 Pregnancies ............................................................................................................ 70 8.4 Data Monitoring Committee .................................................................................. 70 8.5 Reporting angioedema-like events ........................................................................ 70 9 Data review and database management ............................................................................. 71 9.1 Site monitoring ...................................................................................................... 71 9.2 Data collection ....................................................................................................... 71 9.3 Database management and quality control ............................................................ 72 10 Data analysis ...................................................................................................................... 73 10.1 Populations for analysis ......................................................................................... 73 10.2 Patient demographics/other baseline characteristics ............................................. 73 10.3 Treatments (study drug, rescue medication, other concomitant therapies, compliance)............................................................................................................ 74 10.4 Analysis of the primary objective .......................................................................... 74 10.4.1 Primary efficacy variable ...................................................................... 74 10.4.2 Statistical hypothesis, model, and method of analysis .......................... 74 10.4.3 Handling of missing values/censoring/discontinuations ....................... 74 10.4.4 Supportive analyses ............................................................................... 75 10.4.5 Subgroup Analyses................................................................................ 75 10.5 Analysis of secondary objectives........................................................................... 76 10.5.1 Secondary efficacy variables................................................................. 76 10.5.2 Analysis of secondary efficacy variables .............................................. 76 10.6 Analysis of exploratory objectives ........................................................................ 78 10.7 Safety ..................................................................................................................... 79 10.8 Resource utilization ............................................................................................... 80 10.9 Health-related quality of life .................................................................................. 80 10.10 Pharmacokinetics ................................................................................................... 80 10.11 Pharmacogenetics/pharmacogenomics .................................................................. 81 10.12 Biomarkers ............................................................................................................. 81 10.13 Pharmacodynamics ................................................................................................ 81 10.14 Sample size calculation.......................................................................................... 81 10.15 Power for analysis of critical secondary variables ................................................ 82 10.16 Interim analysis ...................................................................................................... 82 This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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10.17 End of the study ..................................................................................................... 84 Ethical considerations ........................................................................................................ 84 11.1 Regulatory and ethical compliance ........................................................................ 84 11.2 Informed consent procedures ................................................................................. 84 11.3 Responsibilities of the investigator and IRB/IEC/REB ......................................... 85 11.4 Publication of study protocol and results............................................................... 85 Protocol adherence ............................................................................................................ 85 12.1 Protocol Amendments ........................................................................................... 85 References ......................................................................................................................... 86 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 89 Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than or equal to 5.3 mmol/L) ..................................................................................................... 90 Appendix 3: Guidelines for the management of blood pressure ....................................... 91 Appendix 4: Guidelines for the management of renal dysfunction ................................... 92 Appendix 5: Kansas City Cardiomyopathy Questionnaire ............................................... 93 Appendix 6: EuroQoL (EQ-5D) ........................................................................................ 97



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List of tables Table 4-1 Table 4-2 Table 6-1 Table 6-2 Table 7-1 Table 7-2

Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs .................................................................................. 34 Safety monitoring criteria that must be met at Visit 1 (screening), Visit 3, and Visit 5 ................................................................................ 35 Study drug dispensed during the active run-in period by study visit .... 46 Study drug dispensed during the double-blind period .......................... 46 Assessment schedule ............................................................................. 54 Routine laboratory examinations .......................................................... 62



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Timeframes between the visits of the active run-in period ................... 33 Overall study design and timeframe between study visits occurring during the active run-in and double-blind periods ................................ 36 Illustration of weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary hypotheses............ 77



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List of abbreviations ACE

angiotensin converting enzyme

ACEI(s)

angiotensin converting enzyme inhibitor(s)

AE(s)

adverse event(s)

AF

atrial fibrillation

AHU377

pro-drug that is metabolized to the active moiety LBQ657

ALT

alanine aminotransferase

ANCOVA

analysis of covariance model

ANP

atrial natriuretic peptide

APP

aminopeptidase P

ARB(s)

angiotensin receptor blocker(s)

ARNi(s)

Angiotensin Receptor Neprilysin Inhibitor(s)

AST

aspartate aminotransferase

AT1

angiotensin type 1

AUC

area under the curve

bid

twice a day

BP

blood pressure

CHF

chronic heart failure

CPO

Country Pharma Organization

CRF

Case Report/Record Form

CRO

Contract Research Organization

CRT-D

cardiac resynchronization therapy defibrillator

CRT-P

cardiac resynchronization therapy pacemaker

CSR

Clinical Study Report

CV

cardiovascular

DBP

diastolic blood pressure

DMC


DS&E

Drug Safety and Epidemiology

EC(s)

Ethics Committee(s)

ECG

electrocardiogram

eCRF

electronic case report form

eGFR

estimated glomerular filtration rate



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EOS

end of study

EQ-5D

EuroQol

ER

emergency room

ESRD

end stage renal disease

HF

heart failure

HTN

hypertension

IA

interim analysis(es)

ICD

implanatable cardioverter defibrillator

ICH

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

ICU

intensive care unit

IEC

Independent Ethics Committee

IFCC

International Federation of Clinical Chemistry and Laboratory Medicine

IRB(s)

Institutional Review Board(s)

i.v.

intravenous(ly)

IVRS

Interactive Voice Response System

KCCQ

Kansas City Cardiomyopathy Questionnaire

LCZ696

Novartis compound code

LVEF

left ventricular ejection fraction

MDRD

Modification of Diet in Renal Disease

mg

milligram

MI

myocardial infarction

mmHg

millimeter mercury

MRI

magnetic resonance imaging

MUGA

multiple gate acquisition scan

NEP

neutral endopeptidase

NODM

new onset diabetes mellitus

NP(s)

natriuretic peptide(s)

NYHA

New York Heart Association

o.d.

once a day

PK

pharmacokinetic(s)

p.o.

oral(ly)



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PCI

percutaneous coronary intervention

PRA

plasma renin activity

RAAS

renin angiotensin aldosterone system

REB

Research Ethics Board

SAE(s)

serious adverse event(s)

SBP

systolic blood pressure

SHF

systolic heart failure

UACR

urinary albumin to creatinine ratio

ULN

upper limit of normal

VAD

ventricular assistance device

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Glossary of terms Assessment

A procedure used to generate data required by the study

Control drug

A study drug used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drug Point/time of patient entry into the study; the point at which informed consent must be obtained (i.e. prior to starting any of the procedures described in the protocol)

Enrollment

Investigational drug

Medication number Patient number

Period

Premature patient withdrawal

Randomization number Stop study participation

The study drug whose properties are being tested in the study; this definition is consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new drug.” A unique identifier on the label of each medication package in studies that dispense medication using an IVR system A number assigned to each patient who enrolls in the study. When combined with the center number, a unique identifier is created for each patient in the study. A major subdivision of the study timeline; begins and ends with major study milestones such as enrollment, randomization, completion of treatment, etc. Point/time when the patient exits from the study prior to the planned completion of all study drug administration and assessments; at this time all study drug administration is discontinued and no further assessments are planned A unique identifier assigned to each randomized patient, corresponding to a specific treatment arm assignment Point/time at which the patient came in for a final evaluation visit or when study drug was discontinued whichever is later

Study drug

Any drug administered to the patient as part of the required study procedures; includes investigational drug and any control drugs

Study drug discontinuation

Point/time when patient permanently stops taking study drug for any reason; may or may not also be the point/time of premature patient withdrawal Information used in the data analysis; derived directly or indirectly from data collected using specified assessments at specified timepoints

Variable



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Amendment 3 Amendment rationale Recruitment in Study CLCZ696B2314, also known as PARADIGM-HF, began on 8-Dec2009. As of 1-Mar-2013, the study has been fully recruited. This is the third amendment to be released for protocol CLCZ696B2314. The purpose of the current amendment is to elevate a pre-specified exploratory objective, i.e., comparing the effects of LCZ696 and enalapril on delaying time to new onset atrial fibrillation, to a secondary objective. The rationale for this change is based on the Recent published data from Study CLCZ696B2214, also known as PARAMOUNT, which demonstrated that LCZ696 treatment in heart failure with preserved ejection fraction results in significant reductions in left atrial volume and left atrial dimension (Solomon et al 2012). In addition, safety analysis of this study showed that fewer patients treated with LCZ696 experienced atrial fibrillation as an adverse event than those treated with the comparator (data on file). Therefore, it is hypothesized that LCZ696 may reduce new onset atrial fibrillation to a greater extent than enalapril in patients with heart failure. Changes to specific sections of the protocol are shown in the track changes version of the protocol using strike through red font for deletions and red underlined for insertions. A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and Health Authorities. Changes described in this amended protocol require IRB/IEC approval prior to implementation, although they do not affect the patient informed consent. Summary of previous amendments The first amendment of protocol CLCZ696B2314 (v02 of the protocol) was dated 15-Dec2010. The main purpose of the first amendment was to (1) modify the left ventricular ejection fraction entry criterion from ≤40% to ≤35%; (2) modify the estimated glomerular filtration rate (eGFR) reduction criterion for continuation in the run-in period to ≤ 35% from ≤ 25%; (3) instruct investigators to consider use of aldosterone antagonists for all patients with heart failure (HF) rather than advanced HF only; (4) Incorporate input from health authorities on the unblinding of suspected unexpected serious adverse events (SUSARs) to avoid the unblinding of serious adverse events which are also efficacy endpoints in the trial (and, hence, the potential unblinding of investigators and patients to randomized treatment allocation); and (5) make other miscellaneous modifications, including addition of a pharmacogenetic substudy. The second amendment of this protocol (v03 of the protocol) was dated 14-Jun-2011. The main purpose of the second amendment was to (1) add more details on the pharmacogenetic substudy assessments, quality control, and data analysis; (2) clarify that study bioanalytical monitor and the bioanalyst at the bioanalytical site will be unblinded to facilitate timely pharmacokinetic analysis of LCZ696 samples; (3) change abbreviated chemistry panel at Visit 3 (end of enalapril run-in /before LCZ696 run-in) and at Visits 8 and 9 (2 and 4 months after This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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start of randomized, double-blind treatment period, respectively) to complete serum chemistry assessments; (4) add more instructions on appropriate follow-up of adverse events and clinically relevant laboratory abnormalities; (5) clarify long-term follow-up procedures during the double-blind period in this outcome trial to reduce loss to follow-up; (6) add guidance on frequency of re-screening; and (7) provide other miscellaneous clarifications.



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Protocol synopsis Title of study: A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction. Purpose and rationale: A number of compensatory neurohormonal mechanisms are activated in heart failure (HF). While increases in the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activity are believed to be harmful in the long-term, the increase in natriuretic peptides (NPs) are thought to be a beneficial compensatory response, leading to vasodilation, natriuresis, and ameliorating many of the pathophysiological abnormalities of HF. Increasing the concentration of NPs by inhibiting neprilysin (neutral endopeptidase 24.11, NEP) represents a promising therapeutic approach which, so far, remains unexploited in clinical practice. Prior research has suggested that the potential clinical benefits from NEP inhibition can only be leveraged if the RAAS system is inhibited concomitantly. However, bradykinin, the putative mediator of angioedema, is broken down by angiotensin converting enzyme (ACE), and, to a modest degree, by NEP and concomitant ACE and NEP inhibition has been associated with an increased risk of angioedema. LCZ696, a dual-acting angiotensin receptor neprilysin inhibitor (ARNi), provides angiotensin receptor blockade via its valsartan moiety and NEP inhibition via the pro-drug AHU377 moiety. In contrast to ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs) have a lower risk of inducing angioedema, likely due to their neutral effect on the metallopeptidases involved in bradykinin breakdown. Therefore, LCZ696 is expected to deliver the benefits of combined RAAS and NEP inhibition without an increased risk of angioedema relative to ACEIs. ®

Prior studies have shown that LCZ696 200 mg provides valsartan exposure similar to Diovan 160 mg and results in approximately 90% NEP inhibition. In addition, a study in hypertensive patients showed the complementary effect of NEP inhibition to valsartan delivered by LCZ696 compared to valsartan alone. Therefore, the LCZ696 200 mg bid regimen delivers similar valsartan exposure as the ® evidence-based Diovan regimen approved for HF (160 mg bid), while potentially providing added benefits of NEP inhibition, i.e., antiproliferative/antihypertrophic effects, vasodilation, and natriuresis. The purpose of this study is to evaluate the effect of LCZ696 200 mg bid compared to enalapril 10 mg bid (the standard of care for RAAS blockade in patients with chronic heart failure [CHF]) in delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in patients with stable CHF New York Heart Association (NYHA) class II - IV and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 35%) receiving conventional CHF treatment. Data from this study are intended to be used to support a worldwide registration submission of LCZ696 for treatment of patients with CHF and reduced ejection fraction. Objectives: The primary objective: • To test if LCZ696 is superior to enalapril in delaying time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization, in patients with CHF (NYHA class II – IV) and reduced ejection fraction. The secondary objectives: • To test whether LCZ696, compared to enalapril, improves the clinical summary score for HF symptoms and physical limitations (as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ]) at 8 months. •

To test whether LCZ696 is superior to enalapril in delaying the time to all-cause mortality.

•

To test whether LCZ696 is superior to enalapril in delaying time to new onset atrial fibrillation (AF).

•

To test whether LCZ696 is superior to enalapril in delaying the time to first occurrence of either (1) a 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, (2) >30



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mL/min/1.73 m decline in eGFR relative to baseline to a value below 60 mL/min/1.73 m , or (3) reaching end stage renal disease (ESRD). The exploratory objectives: • To compare the effects of LCZ696 and enalapril on delaying time to first occurrence of a composite of CV death, hospitalization for HF, non-fatal myocardial infarction (MI), non-fatal stroke or resuscitated sudden death. •

To compare the effects of LCZ696 and enalapril on reducing the number of patients hospitalized and number of hospital admissions (all-cause and cause-specific).

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To compare the effects of LCZ696 and enalapril on increasing days alive out of the hospital at Month 12.

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To test whether LCZ696 is superior to enalapril in slowing the rate of decline in eGFR (eGFR slope).

•

To compare the effects of LCZ696 and enalapril on delaying time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month.

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To compare the effects of LCZ696 and enalapril on the clinical composite score (as assessed by NYHA classification and patient global assessment) at 8 months.

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To compare the effects of LCZ696 and enalapril on delaying time to new onset diabetes mellitus (NODM).

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To compare the effects of LCZ696 and enalapril on improving health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and the total score of the EuroQol [EQ-5D] for health status).

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To compare the effects of LCZ696 and enalapril on reducing coronary revascularization procedures.

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To compare the effects of LCZ696 and enalapril on pre-specified biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers) from baseline to predefined timepoints.

•

To compare the effects of LCZ696 and enalapril on reducing healthcare resource utilization, e.g., number of days/stays in ICU, number of rehospitalizations, and number of ER visits for heart failure.

•

To characterize the pharmacokinetics (PK) of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or non-compartmental based methods.

Population: Patients with CHF (NYHA Class II-IV), aged 18 years or older with LVEF ≤ 35%. The target projected sample size is 7,980 patients (3,990 patients in each arm). It is estimated that approximately 16,000 patients will be screened at up to approximately 1,200 study sites because a screen failure rate of approximately 50% is anticipated based on previous experience. Key inclusion criteria: 1. Outpatients ≥ 18 years of age, male or female. 2. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction: •

LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI, or ventricular angiography is acceptable, provided no subsequent measurement above 35%)

•

BNP ≥ 150 pg/ml (or NT-proBNP ≥ 600 pg/ml) at Visit 1 OR BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/ml) at Visit 1 and a hospitalization for HF within the last 12 months 3. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1. •

For this protocol, doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include benazepril 20 mg/d, captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d,



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lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d. •

For this protocol, doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 4. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication). 5. An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for heart failure should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines. Key exclusion criteria: 1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs. 2. Previous history of intolerance to recommended target doses of ACEIs or ARBs. 3. Known history of angioedema. 4. Requirement of treatment with both ACEIs and ARBs. 5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy). 6. Symptomatic hypotension and/or a systolic blood pressure (SBP) < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization). 2 7. Estimated GFR < 30 mL/min/1.73m as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5. 8. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (randomization). 9. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1. 10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1. 11. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 months before Visit 1 or intent to implant such a device. Also, patients who had implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or other device leads within 1 month before Visit 1 are excluded. 12. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD. 13. History of severe pulmonary disease. 14. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1. 15. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1. 16. Symptomatic bradycardia or second or third degree heart block without a pacemaker. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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17. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation. 18. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis. 19. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: •

History of active inflammatory bowel disease during the 12 months before Visit 1.

•

Active duodenal or gastric ulcers during the 3 months prior to Visit 1.

•

Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x upper limit of normal (ULN) at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt.

• Current treatment with cholestyramine or colestipol resins. 20. Presence of any other disease with a life expectancy of < 5 years. 21. Presence of bilateral renal artery stenosis. Investigational and reference therapy: Active run-in All eligible patients will enter an active run-in period during which they will be exposed to enalapril 10 mg bid followed by LCZ696 (100 mg bid and then up titrated to 200 mg bid). The following study drugs will be provided: • Enalapril 5 mg tablets (enalapril dose level 2) •


•

Enalapril 10 mg tablets (enalapril dose level 3)

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•


•


•


•


Patients will be required to take the single-blind enalapril or LCZ696 dose and placebo to match the opposite treatment at the corresponding dose level twice daily in addition to their conventional concomitant therapy (except for ACEI or ARB, which will be substituted with study drug). During the enalapril run-in period, the investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs (ACEI-naïve), or (2) currently treated with the lowest required doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, hyperkalemia). Double blind treatment All eligible patients will be randomized to receive either LCZ696 200 mg bid or enalapril 10 mg bid in addition to optimal CHF therapy, as considered appropriate by the investigator and in accordance with standard therapy guidelines, with the exception of an ACEI or an ARB as this will be replaced by the study drug. The following study drugs will be provided: • LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) •


•


•


•




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•


•

Enalapril 2.5 mg film-coated tablets (enalapril dose level 1)

•

Placebo to match enalapril 2.5 mg film-coated tablets (placebo matching enalapril dose level 1)

•


•


•


•


Target doses: LCZ696 200 mg bid and enalapril 10 mg bid Patients not tolerating the target dose (LCZ696 200 mg bid or enalapril 10 mg bid) will be titrated down to the lower dose level, at the investigator’s discretion, based on the defined safety and tolerability criteria (Appendices 15, 16, and 17). All tablets (LCZ696 50 mg, LCZ696 100 mg, LCZ696 200 mg, enalapril 2.5 mg, enalapril 5 mg, enalapril 10 mg) have different shapes and colors. Therefore, the study will be designed as a doubleblind, double-dummy trial to ensure the blinding during the entire course of the study. To maintain the blinding, patients will be required to take their assigned active treatment tablet along with placebo matching the opposite treatment twice daily (morning and evening dose) in addition to their conventional concomitant therapy. The use of an ACEI or an ARB concomitantly with the study drug after randomization is strictly prohibited. Study design: This is a randomized, double-blind, parallel group, active-controlled study to evaluate the superiority of LCZ696 200 mg bid as compared to enalapril 10 mg bid, on morbidity and mortality reduction in patients with CHF (NYHA class II-IV) and reduced ejection fraction defined by a LVEF ≤ 35%. The trial consists of two main periods: (1) a single-blind run-in period, which will last ranging from 5 to 10 weeks, and (2) a double-blind randomized treatment period, which is projected to last up to 43 months. A subset of patients (approximately 400 worldwide of those participating in the biomarker sub-study) will participate in a population PK sub-study, which will be conducted at selected centers. Participating patients will provide four blood samples while at LCZ696 steady state at Visits 4 and 7 or 10 for analysis of valsartan, AHU377, and LBQ657 plasma levels. The trial will be event-driven and all randomized patients will remain in the trial until either the targeted number of patients with primary events has been reached or the trial is terminated prematurely at the recommendation of the Data Monitoring Committee (DMC) when pre-specified early-stopping criteria for efficacy (i.e., crossing pre-specified statistical limits for both the composite endpoint and the CV mortality component) or safety criteria are met. To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients who have reached 4 weeks of double-blind treatment is completed by an external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed. Since a total of 2,410 patients with primary events are targeted, it is anticipated that 7,980 patients will be required assuming the trial duration will be approximately 43 months, with a recruitment period of 22 months, and a mean follow up of approximately 30 to 32 months. The double-blind treatment stage will vary from 21 months to 43 months for each patient.



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Screening and the active run-in period At Visit 1 (screening), if the patient agrees to be in the study, he/she will be evaluated against the entry criteria and will be asked to sign an informed consent form prior to performing any study-related procedures. Visit 1 (Screening visit) At Visit 1, patient’s eligibility for entering the study will be assessed by the investigator by evaluating all inclusion/exclusion criteria. Any local measurement of LVEF made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography will be acceptable, provided no subsequent measurement above 35%. Screening BNP (and NT-proBNP) and potassium levels and eGFR will be assessed by sending blood samples to the central laboratory and only patients with the required values per the entry criteria will be eligible for entering the run-in period. At selected sites, if the patient has provided informed consent to participate in the biomarker sub-study, the site should give the patient a urine collection container and instructions regarding collection of the first morning urine void before attending Visit 2. Visit 2 (enalapril run-in visit) At Visit 2, patients who meet all entry criteria, including the required clinical laboratory values, will be eligible to start the enalapril single-blind run-in period, during which patients will continue taking all other prescribed background treatments for CHF (except for ACEI or ARB). Patients will be started on enalapril 10 mg bid for 2 weeks. The investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). Patients tolerating enalapril 10 mg bid (enalapril target dose) will proceed to Visit 3, when they will start the LCZ696 single-blind run-in period. The site personnel should instruct the patient not to take their study medication (enalapril 10 mg bid) on the day of Visit 3. Visit 3 (LCZ696 run-in titration visit) At Visit 3, patients’ tolerability to enalapril 10 mg bid will be assessed. Patients not tolerating enalapril 10 mg bid (Table 1) will be considered run-in failures and withdrawn from the study. If the patients are found to tolerate enalapril 10 mg bid, they will enter the single-blind LCZ696 run-in period and begin taking LCZ696 100 mg bid starting the day after Visit 3. Patients should be maintained on this dose for 1 to 2 weeks at the investigator’s discretion. All patients tolerating LCZ696 100 mg bid will be scheduled for Visit 4 when the dose of LCZ696 will be up titrated to 200 mg bid (target dose). Visit 4 (LCZ696 up-titration visit) At Visit 4, patients’ tolerability to LCZ696 100 mg bid will be evaluated. If the patients are found to tolerate LCZ696 100 mg bid, patients will be up-titrated to LCZ696 200 mg bid (LCZ696 target dose) for 2 to 4 weeks at the investigator’s discretion. At the end of the active run-in period, only patients tolerating LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for at least 2 weeks will be randomized. At the investigator’s discretion, a patient receiving LCZ696 200 mg bid who experiences adverse effects, such as hyperkalemia, hypotension, or renal dysfunction, may be temporarily down-titrated to LCZ696 100 mg bid until such time that the investigator believes the patient may be able to tolerate up-titration back to LCZ696 200 mg bid. If subsequently the patient is unable to tolerate LCZ696 200 mg bid for at least two weeks despite the temporary down-titration to 100 mg bid, this patient will be considered a run-in failure and will be withdrawn from the study. Every attempt should be made to complete the run-in period within 10 weeks regardless of any downtitration that may occur. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning. Approximately 400 patients will participate in the PK substudy which will be conducted at select study sites. Participating subjects will provide a trough (Cmin) PK sample on the morning of Visit 4, prior to up-titration. Safety and tolerability monitoring during the active run-in period Patients will be eligible for entering the enalapril run-in period at Visit 2, for entering the LCZ696 run-in period at Visit 3, and for randomization at Visit 5 if they meet all the inclusion criteria and none of the exclusion criteria, including the serum potassium, eGFR, blood pressure, and postural symptoms listed in Table 1. During the run-in period, non-disease modifying medications (such as nitrates, CCBs, α-blockers and diuretics) may be changed (dose reduced or discontinued) in response to the occurrence of adverse events, such as hyperkalemia, hypotension, and renal dysfunction, in an attempt to allow patients to meet the safety criteria in Table 1. The doses of background disease modifying drugs, such as βblockers or aldosterone antagonists, may be reduced to facilitate maintenance of study drug if in the opinion of the investigator they are believed to be the cause of the adverse effect in question. To ascertain patient’s eligibility for continuing in the study, Visit 3 (start of the LCZ696 run-in period) and Visit 5 (randomization) study drug should not be dispensed unless laboratory assessments of potassium and eGFR are available. This may require laboratory samples to be collected and analyzed approximately 72 hours before these Visits. The reason for patient discontinuation during the active run-in period must be documented in detail in the appropriate electronic case report form(s) (eCRFs). Patients who experience angioedema during the run-in period will be withdrawn from the study.

Table 1

Criteria that must be met at screening, visit 3, and visit 5

Parameter

Visit 1 (screening)

Visit 3 (end of enalapril run-in) and Visit 5 (end of LCZ run-in and randomization)


K ≤ 5.2 mmol/L

K ≤ 5.4 mmol/L




2

2


Double-blind study treatment period Patients who have met all the entry criteria and tolerate enalapril 10 mg bid and LCZ696 200 mg bid by the end of the single-blind active run-in period will be randomized to either enalapril 10 mg bid or LCZ696 200 mg bid in a 1:1 ratio. Other conventional background HF medications should remain This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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unchanged (particularly disease modifying treatments, such as β-blockers). All patients qualifying for randomization will have their LCZ696 active run-in medication stopped (not taken) starting on the day of Visit 5 (randomization) and will receive the first dose of double-blind randomization medication the morning after Visit 5. Patients will continue taking the target dose of the study drug and attending study visits every 2 to 8 weeks during the first 4 months of the double-blind period and every 4 months thereafter. In addition to the protocol-specified visits, patients may be seen at anytime throughout the study at the discretion of the investigator. All randomized patients, including any patient who has experience a health event, should continue to receive double-blind treatment until the trial is completed. The monitoring of safety and tolerability will include: (1) hyperkalemia; (2) symptomatic hypotension; (3) increase in serum creatinine or decrease in eGFR; (4) angioedema; and (5) other AEs and serious AEs (SAEs). Patients who no longer tolerate the target dose at any time during the course of the double-blind period can be down-titrated to the lower dose at the investigator’s discretion. If, in the opinion of the investigator, the patient cannot tolerate the target dose of study drug, the investigator should consider whether non-disease-modifying medication (e.g., calcium channel blockers [CCBs], diuretics, nitrates, α-blockers) can be reduced to rectify the situation before considering reducing the dose of the study drug to the next lower dose level. The doses of background disease modifying drugs, such as β-blockers or aldosterone antagonists, may be reduced to facilitate maintenance of study drug if in the opinion of the investigator they are believed to be the cause of the adverse effect in question. Every attempt should be made to re-challenge the patients so that they are kept on the maximal tolerated dose of study drug for as long a duration as possible throughout the trial. If the study drug is temporarily discontinued, it should be reintroduced as soon as medically justified in the opinion of the investigator. After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the study. On the contrary, even patients who have stopped taking study drug are expected to attend all the protocol specified study visits to perform all assessments as stipulated in the visit schedule. Patients participating in the PK sub-study will provide three blood samples at Visit 7 or at Visit 10 for analysis of valsartan, AHU377, and LBQ657 plasma levels at predose, 0.5 to 2 hours, and 3 to 5 hours post-dose. It is not required that all samples are obtained during the same study visit. All randomized patients will remain in the trial until either (1) the projected number of primary endpoints (CV death or HF hospitalization) is reached, or (2) the trial is terminated prematurely at the recommendation of the DMC when pre-specified early-stopping criteria for efficacy or safety are met. Primary assessment: •

Time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization

Secondary assessments: • Improvement in clinical summary score for HF symptoms and physical limitations domains of the KCCQ at Month 8 •

All-cause mortality

•

New onset AF

•

Composite renal endpoint defined as (1) 50% decline in eGFR relative to baseline, (2) >30 2 2 mL/min/1.73m decline in eGFR relative to baseline to a value below 60 mL/min/1.73m , or (3) reaching ESRD

Exploratory assessments: • Composite CV mortality and morbidity (CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death) •

Non-fatal stroke

•

Non-fatal MI



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•

Resuscitated sudden death

•

Days alive out of the hospital at 12 months

•

Decline in eGFR (eGFR slope)

•

Time to study treatment failure for HF

•

Change in clinical composite score (assessed by NYHA classification and patient global assessment) at 8 months

•

New onset diabetes

•

Improvement in quality of life and health status (KCCQ and EQ-5D)

•

Coronary revascularization procedures

•

BNP, NT-proBNP

•

Other predefined biomarkers

•

Days/stays in ICU

•

ER visits

•

Steady state plasma concentrations of valsartan, AHU377, and LBQ657 immediately before the study drug dose and at 0.5-2 hours and 3-5 hours after study drug dose

The analysis plan for pharmacogenetics profiling will be described in a separate sub-study protocol. Safety assessments: • AEs and SAEs •

Sitting systolic (SBP) and sitting diastolic BP (DBP)

•

Heart rate

•

Symptomatic hypotension

•

Angioedema

•

Laboratory values

•

Hyperkalemia

•

Renal dysfunction

•

ECG changes

Data analysis: The primary hypothesis to be tested is H10: λ2 ≥ λ1 versus H1a: λ2 < λ1, where λ1 and λ2 are hazards for enalapril and LCZ696 treatments, respectively. The primary efficacy variable is time to first occurrence of CV death or HF hospitalization. The primary efficacy variable will be analyzed using Cox proportional hazards model with treatment and region as two fixed-effect factors. The primary hypothesis will be tested at a one-sided significance level of 0.025 adjusted for interim analyses (IA). The Full Analysis Set (FAS) will be used for the primary analysis following the intent-to-treat principle. The PP (per-protocol population) will be used for supportive analyses. The hazards ratio and its associated two-sided confidence interval will be estimated from the Cox model. Kaplan-Meier curves will also be presented, by treatment group, to summarize the primary composite endpoint. Additionally, similar analyses will be performed for each of the components of the primary composite endpoint with all events for that component occurred during the double blind period of the study to quantify the strength of the effect for each component in the primary composite endpoint. The secondary hypotheses will be tested and statistical inference will be made only if the primary hypothesis is rejected. The four secondary efficacy variables will be tested for superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LCZ696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. Quality of life, as assessed by KCCQ clinical summary score, will be analyzed based on a repeated measures ANCOVA model in This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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which treatment, region, visit, and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance for each treatment group. The primary treatment comparison between LCZ696 and enalapril is to be made at Month 8. The analysis will be performed based on all available data in the FAS and based on likelihood method. The estimated treatment effect with the associated confidence interval at Month 8 will be provided. The time to all-cause mortality will be analyzed, similar to the primary efficacy variable, using Cox proportional hazards model with treatment and region as fixed-effect factors. The time to new onset AF will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. Time to composite renal endpoint will be analyzed using Cox proportional hazards model with treatment and region as fixed-effect factors. Safety analysis will be performed primarily with summary on the frequency of AEs, SAEs, and notable laboratory abnormalities with the safety population. The number of patients with confirmed angioedema and renal dysfunction will be compared as well. No formal statistical inference analysis will be performed for the safety analysis. The sample size evaluation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the interim efficacy analyses. For the CV mortality component, with a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril using the log-rank test. Assuming an annual event rate of 7% in the enalapril group, an enrollment period of 22 months, and a minimum follow-up 21 months, a total sample size of 7,980 patients will be required to obtain the targeted 1,229 CV mortality events. Assuming the same enrollment period and follow-up duration as above, a 15% reduction in hazard, and an annual event rate of 14.5% in the enalapril group, randomizing 7,980 patients will provide statistical power ≥ 97% for detecting a difference between the two treatment groups in the primary composite endpoint. This in turn will expect to have a total of 2,410 patients with primary events. It is planned to have three interim efficacy analyses. The cutoff dates for the interim analyses are planned to be approximately at 1/3, 1/2 and 2/3 of information time (i.e. approximately 804, 1205 and 1607 patients, respectively, with a primary event of either CV death or HF hospitalization). One-sided testing will be performed and appropriate statistical adjustments for the interim analyses actually performed will be made to control the overall type-I error of 0.025. The Haybittle-Peto type of boundary will be used for the interim efficacy analyses to assess superiority. The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (onesided) at the first interim analysis and 0.001 (one-sided and nominal) at the second and third interim analyses. In case additional interim efficacy analysis is required, the alpha spending function approach will be used to readjust the alphas used for the additional interim and final analyses (Lan and DeMets 1983). In addition to the primary composite endpoint, the CV mortality component will also be analyzed at each interim efficacy analysis. When 1/3, 1/2, and 2/3 of the total number of primary patient events occur, approximately 410, 614 and 819 CV deaths, respectively, are also expected. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the above planned boundary are obtained for both primary composite endpoint and CV death component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment for the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. The proposed futility boundaries are: -1.312, 0, and 0.5 in Z-scale, which corresponds to 1.100, 1.000, and 0.975 in hazard ratio scale (LCZ696 versus enalapril). These boundaries will not be the sole consideration in the futility analyses; futility will also require that there is no observed benefit on biomarkers such as change from baseline vs enalapril in NT-proBNP. Furthermore, these two considerations will be used only as a guideline for triggering discussion of stopping for futility.



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Background

Chronic heart failure (CHF) is a major public health problem characterized by significant mortality, frequent hospitalization, and poor quality of life, with an overall prevalence that is increasing throughout the world. In the United States (US) alone, approximately 5 million patients have heart failure (HF) and there are over half a million newly diagnosed cases annually (Hunt et al 2009, ESC Guidelines 2008). In Europe, the prevalence of HF is between 2 and 3%, and that in the elderly is estimated between 10 to 20% (ESC Guidelines 2008). HF is responsible for more hospitalizations than all forms of cancer combined and is the leading cause of hospitalization in patients older than 65 years of age (Adams et al 2006, American Heart Association 2006). In-hospital mortality is excessive and readmission is distressingly common. Frequent hospitalizations, along with other direct and indirect costs, also place an enormous financial burden on healthcare systems; more is spent annually in the US for the treatment of HF by Medicare than on any other Medicare diagnosis (Adams et al 2006, American Heart Association 2006) and HF accounts for approximately 2% of the national expenditure on health in the United Kingdom (Stewart et al 2002). A complex clinical syndrome with varying pathophysiological and clinical manifestations, HF is exhibited in patients with reduced left ventricular ejection fraction (LVEF) as well as preserved LVEF. Therapies targeted at improving outcomes in HF with a low EF have been well studied over the past two decades, leading to an improvement in survival as well as a decrease in morbidity, mostly in the form of decrease in re-hospitalization for HF, with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), βblockers and mineralocorticoid antagonists (CONSENSUS Trial Study Group 1987, Cohn and Tognoni 2001, SOLVD Investigators 1991, SOLVD Investigators 1992, RALES Investigators 1996, Pitt et al 1999, MERIT-HF Study group 1999, CIBIS II Investigators 1999, Packer et al 2002b, Pfeffer et al 2003, Flather et al 2005). However, despite advances in pharmacological (and device therapies), the outlook remains poor. Overall 50% of patients die within 4 years, and 40% of patients admitted to hospital with HF die or are readmitted within 1 year (ESC Guidelines 2008). Thus, HF still represents a major cause of cardiac mortality and morbidity with a clear need for better therapy. The neurohormonal response to cardiac injury is pivotal to the development and progression of heart failure. While increases in renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activity are believed to be harmful in the long-term, the increases in natriuretic peptides (NPs) are believed to be a beneficial compensatory response. As well as counteracting the effects of both RAAS and SNS, NPs have direct vasodilator and natriuretic actions, and exhibit antiproliferative and antihypertrophic effects, thereby, potentially, ameliorating many of the pathophysiological abnormalities in HF (Levin et al 1998, Gardner et al 2007, Pandey 2008). Therefore, therapy that increases circulating concentrations of NPs through inhibition of neprilysin (neutral endopeptidase 24.11, NEP), the enzyme responsible for breaking down NPs, is considered an attractive therapeutic approach for a number of cardiovascular (CV) diseases, such as hypertension (HTN) and HF. However, results from previous clinical studies indicated that the effects of NEP inhibition alone are not sustained in the longer term. For example, NEP inhibition alone failed to demonstrate clinically meaningful blood pressure This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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(BP) lowering despite significantly increasing atrial natriuretic peptide (ANP) concentrations (Bevan et al 1992). It has been hypothesized that the vasoconstriction induced by ancillary properties of NEP inhibitors on other physiological substrates (e.g., angiotensin II) and feedback mechanisms can offset the BP lowering effect of ANP (Richards et al 1993, Ferro et al 1998). Therefore, inhibition of NEP activity must be accompanied by inhibition of RAAS activity to achieve a beneficial effect. Vasopeptidase inhibitors constitute a class of drugs that simultaneously inhibit both NEP and ACE. Indeed, omapatrilat, the most extensively evaluated agent from this class, demonstrated greater BP lowering as compared to other therapeutic classes, including ACE inhibitors (ACEIs) and calcium channel blockers (CCBs) (Neutel et al 1999, Asmar et al 2000, Ruilope et al 2000). Additionally, omapatrilat also showed an encouraging trend toward reducing mortality and morbidity in patients with HF relative to enalapril (Packer et al 2002a). Unfortunately, omapatrilat treatment was associated with an increased incidence of angioedema compared with enalapril (2.17% vs. 0.68%) in hypertensive patients (Kostis et al 2004), though the increase in angioedema risk was less (0.8% and 0.5%, respectively) in HF patients (Packer et al 2002a). It was hypothesized that angioedema may have been a particular problem with omapatrilat because, in addition to inhibiting NEP and ACE, this compound also blocked a third key enzyme involved in bradykinin degradation, namely aminopeptidase P (APP) (Fryer et al 2008). Omapatrilat, thus, simultaneously blocked three key enzymes responsible for the breakdown of bradykinin, the putative mediator of angioedema (Fryer et al 2008, Sulpizio et al 2005). LCZ696, a dual acting RAAS and NEP inhibitor, is the most advanced dual angiotensin receptor neprilysin inhibitor (ARNi) compound in development. It delivers two moieties in a molar ratio of 1:1: a valsartan moiety, which is an orally active, potent, and specific competitive angiotensin type 1 (AT1) receptor antagonist, and an AHU377 moiety, which is a non-peptide, orally active pro-drug that is rapidly hydrolyzed to the active moiety LBQ657, a specific inhibitor of NEP. The molecular structure of LCZ696 conveys unique chemical and biological properties. LCZ696 has been shown to deliver 140-160% higher exposure of valsartan on an area-underthe-plasma-concentration-time-curve (AUC) basis than the Diovan® global formulation. Doses of LCZ696 (50 mg, 100 mg and 200 mg) deliver rates of valsartan exposures which are similar to those delivered from the Diovan® dose strengths (40 mg, 80 mg and 160 mg, respectively); for example, the exposure of valsartan following administration of LCZ696 200 mg (which contains 103 mg of valsartan) is similar on an AUC basis to that of the 160 mg Diovan® formulation. In addition, the half-life of valsartan following LCZ696 administration is comparable to that following Diovan® administration, suggesting that rate of elimination of valsartan for LCZ696 is similar to that for Diovan®. Biomarker analysis (i.e., increases in ANP and cGMP) indicates that LCZ696 at a dose of 200 mg dose delivers approximately 90% of its maximal NEP inhibition. The valsartan moiety delivered by LCZ696 has a peak plasma concentration (Tmax) of approximately 2 hours and a half-life (T½) of approximately 15 hours. Approximately 83% of an oral valsartan dose is recovered in feces, primarily as unchanged drug. Twenty percent of the dose is recovered as metabolites. Patients with mild to moderate hepatic insufficiency have an approximate 2-fold greater exposure (measured by AUC) compared to healthy This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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volunteers. LBQ657, the active NEPi moiety in LCZ696, has a Tmax of approximately 2 hours with a T½ of 12 - 16 hours. Approximately 50% of an oral dose is recovered as unchanged drug in urine. Patients with mild, moderate and severe renal insufficiency have an approximate 2.0, 2,4 and 2.7 fold greater exposure (measured by AUC), respectively, compared to healthy volunteers. No drug-drug interaction was observed between LCZ696 and warfarin (CYP2C9); LBQ657 showed little or no inhibition in in vitro assays against other human cyctochrome P450 (CYP) enzymes. To date, LCZ696 has been administered to a total of 255 subjects in completed short-term clinical pharmacology studies. LCZ696 was safe and well tolerated following administration of single doses up to 1200 mg and of daily doses of up to 900 mg in multiple doses (for 14 days) in healthy volunteers. Adverse events (AEs) were mostly mild, transient in nature and most were assessed as not suspected to be related to treatment. Most frequently reported AEs included postural orthostatic tachycardia, dizziness, headache, and orthostatic hypotension. No dose dependency of AEs was observed and there were no severe AEs or deaths reported. In a dose-ranging study (N=1328), a total of 497 hypertensive patients received LCZ696 (100 mg, 200 mg and 400 mg). This study showed that LCZ696 (400 mg/d and 200 mg/d) lowered BP to a greater extent than corresponding doses of valsartan 320 mg/d and 160 mg/d. Discontinuation rate due to AEs was similar to placebo. No dose related trends were observed for any specific AEs. The most frequent AE was headache, which was more frequent in the placebo group compared to any other group. A total of 2 SAEs occurred with LCZ696 treatment (road accident/limb fracture; back pain/dyspnea) with none suspected to be related to study drug. The incidence of hypotension and dizziness was low (< 1%) and there were no reported cases of angioedema over the 9-week duration of the study. The pharmacokinetics and tolerability/safety of LCZ696 were recently evaluated in 30 CHF patients with reduced ejection fraction (LVEF 5.5 mmol/L). Two patients experienced brief episodes of syncope, one due to hypoglycemia and the second due to a vasovagal reaction following blood drawing. There were no serious adverse events or angioedema reported in this study. Although the risk of angioedema due to NEP inhibition by LCZ696 is not fully characterized due to the availability of limited clinical data, NEP represents a relatively minor metabolic pathway of bradykinin breakdown (Fryer et al 2008). Furthermore, LBQ657, the active metabolite of the NEP inhibitor moiety in LCZ696, is a poor inhibitor of ACE and APP in vitro, which represent major degradation pathways for bradykinin. ARBs have a low risk of inducing angioedema likely due to their neutral effect on the metallopeptidases involved in bradykinin breakdown (Cicardi et al 2004). Therefore, LCZ696 may deliver the benefits of combined RAAS and NEP inhibition without an increase in the risk of angioedema. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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As a dual-acting ARB-NEP inhibitor, LCZ696 offers the therapeutic advantage of concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (i.e., blockade of RAAS via the ARB component), while stimulating an anti-fibrotic/anti-hypertrophic mechanism (i.e., increasing NP levels via the NEP inhibitor component) (Perlini 2005, Pu et al 2005). Therefore, it is anticipated that LCZ696 will confer a superior/additional cardio-renal protection than ARB therapy alone. Due to this unique mechanism of action, LCZ696 may fulfill the promise of providing a novel, more effective therapy for patients with CHF where vasoconstriction, volume expansion, as well as hypertrophy and fibrosis play key roles in the pathophysiology of disease development and progression. Study CLCZ696B2314 is a multicenter, randomized, double-blind, parallel group activecontrolled study to evaluate the efficacy of LCZ696 on morbidity and mortality compared to enalapril, the current gold standard for RAAS blockade in HF treatment, in patients with CHF and reduced ejection fraction. This study is outcome-driven and is designed to test the primary hypothesis that, compared to enalapril, simultaneous angiotensin receptor blockade and NEP inhibition with LCZ696 delays the time to first occurrence of either CV death or HF hospitalization. Secondary endpoints are change in the clinical summary score, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), time to all-cause mortality, and time to composite renal endpoint defined as (1) 50% decline in eGFR compared to baseline, (2) > 30 ml/min/1.73m2 decline in eGFR compared to baseline, or (3) reaching end stage renal disease (ESRD).

2

Purpose and rationale

The purpose of this study is to evaluate the effect of LCZ696 200 mg bid compared to enalapril 10 mg bid, in addition to conventional HF treatment, in delaying time to first occurrence of either CV death or HF hospitalization events in patients with stable CHF NYHA classes II-IV and reduced ejection fraction (LVEF ≤ 35%). Data from this study are intended to be used to support a worldwide registration submission of LCZ696 for treatment of patients with CHF and reduced ejection fraction.

3

Objectives

3.1

Primary objective

The primary objective of this study is to test if LCZ696 is superior to enalapril in delaying time to first occurrence of the composite endpoint, which is defined as either CV death or HF hospitalization, in patients with CHF (NYHA class II – IV) and reduced ejection fraction (LVEF ≤ 35%).

3.2 • • •

Secondary objectives

To test whether LCZ696, compared to enalapril, improves the clinical summary score for HF symptoms and physical limitations (as assessed by KCCQ) at 8 months. To test whether LCZ696 is superior to enalapril in delaying the time to all-cause mortality. To test whether LCZ696 is superior to enalapril in delaying time to new onset AF.



•

• • • •

• • • • • • •


To test whether LCZ696 is superior to enalapril in delaying the time to first occurrence of either (1) a 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline, (2) >30 mL/min/1.73 m2 decline in eGFR relative to baseline to a value below 60 mL/min/1.73 m2, or (3) reaching ESRD.

3.3 •

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Exploratory objectives

To compare the effects of LCZ696 and enalapril on delaying time to first occurrence of a composite of CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death. To compare the effects of LCZ696 and enalapril on reducing the number of patients hospitalized and number of hospital admissions (all-cause and cause-specific). To compare the effects of LCZ696 and enalapril on increasing days alive out of the hospital at Month 12. To test whether LCZ696 is superior to enalapril in slowing the rate of decline in eGFR (eGFR slope). To compare the effects of LCZ696 and enalapril on delaying time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month. To compare the effects of LCZ696 and enalapril on the clinical composite score (assessed by NYHA classification and patient global assessment) at 8 months. To compare the effects of LCZ696 and enalapril on delaying time to new onset diabetes mellitus (NODM). To compare the effects of LCZ696 and enalapril on improving health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and total score of the EQ-5D for health status). To compare the effects of LCZ696 and enalapril on reducing the incidence of coronary revascularization procedures. To compare the effects of LCZ696 and enalapril on the profile of pre-specified biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers) from baseline to predefined timepoints. To compare the effects of LCZ696 and enalapril on reducing healthcare resource utilization, e.g., number of days/stays in ICU, number of rehospitalizations, and number of ER visits for heart failure. To characterize the PK of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or non-compartmental based methods.

4

Study design

4.1

Overview

This study is a randomized, double-blind, double-dummy, parallel-group, active-controlled, two-arm, long-term trial to compare LCZ696 200 mg bid to enalapril 10 mg bid in CV This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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mortality and morbidity reduction in patients with stable CHF and reduced ejection fraction. Patients will enter a single-blind active run-in period ranging from 5 to 10 weeks in which they will receive enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid. Patients who tolerate the target dose of enalapril (10 mg bid) and the target dose of LCZ696 (200 mg bid) for at least 2 weeks will then be randomized in equal allocation to receive LCZ696 200 mg bid or enalapril 10 mg bid during the double-blind period. The investigator may consider initiating treatment with enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (see Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). A subset of patients (approximately 400 worldwide of those participating in the biomarker substudy) will participate in a population PK substudy, which will be conducted at selected centers (Section 7.6.5). Participating patients will provide 4 blood samples in total, while at LCZ696 steady state at Visits 4 and Visits 7 (or Visit 10 if not taken at Visit 7) for analysis of valsartan, AHU377, and LBQ657 plasma levels. This study will be event-driven in which patients will remain in the study (regardless of whether receiving study medications) until the projected number of patients with primary events (2,410 events) has been reached or early termination of the study when a pre-specified efficacy or safety criterion is met. To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients to complete 4 weeks of double-blind treatment is completed by the external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed. Three interim efficacy analyses are planned when approximately 1/3, 1/2, and 2/3 of the projected primary events occur to assess if the study should be terminated early for futility or efficacy. Interim safety assessments will be performed twice a year. It is planned that the total trial duration will be approximately 43 months, with a projected recruitment period of 22 months and a follow-up period of 21 months after the enrollment of the last patient into the trial. It is expected that the average follow-up time will be approximately 32 months.

4.2

Justification of key elements of the study design

4.2.1

Selection of the primary endpoint

Apart from improving symptoms, there is general agreement that the major goal of treating HF with a reduced LVEF is to reduce the major fatal and non-fatal consequences of this illness, i.e., CV death and hospitalization for worsening HF. CV death accounts for approximately 80% of all deaths in HF patients and most CV deaths are due to either sudden (presumed arrhythmic) death or death due to worsening heart (i.e., pump) failure. Only a small proportion of CV deaths is due to other CV events. Hospitalization for worsening HF is the single most common cause of hospital admission in this patient population and is an ominous development in that it portends high subsequent risk – both of readmission and of This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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death. HF hospitalization is also the main driver of the huge economic burden of this syndrome. As CV death and HF hospitalization both reflect disease-specific endpoints related to progressive worsening of the HF syndrome, they should both be modifiable by treatments improving this condition, which has generally proved to be the case with both drugs (ACEIs, aldosterone antagonists, and β-blockers) and devices (cardiac resynchronization therapy). This understanding of HF and its treatment has led to the disease-specific composite outcome of CV death or HF hospitalization becoming the most commonly used primary endpoint in current HF outcomes trials. Importantly, this study is sized sufficiently to detect a reduction in cardiovascular mortality. 4.2.2

Choice of enalapril as the comparator

Major clinical trials have established ACEI treatment as the standard of care for RAAS blockade and are recommended by treatment guidelines as the treatment of choice for all patients with CHF and reduced LVEF, unless ACEI-intolerant. Since the ultimate goal of the LCZ696 development program is to replace ACEIs as the guideline-recommended RAASbased agent in HF with reduced LVEF, an ACEI has been selected as the control in this study. As a well-studied ACEI in HF, enalapril is used as the comparator in this study. Enalapril was studied in a number of previous large, outcome-driven studies, such as OVERTURE (Packer 2002a), CONSENSUS (CONSENSUS Trial Group 1987), SOLVD-Treatment (SOLVD Investigators 1991), and SOLVD-Prevention (SOLVD Investigators 1992). Enalapril dose of 10 mg bid has been selected as the comparator target dose for this study based on its ability to reduce the risk of death or hospitalization as demonstrated in the SOLVD-Treatment study (SOLVD Investigators 1991). 4.2.3

LCZ696 dose and dosing regimen

A strong rationale exists for the selection of LCZ696 200 mg bid as the target dose. Importantly, a dose of LCZ696 200 mg bid delivers similar exposures of valsartan (assessed by AUC) as Diovan® 160 mg bid, the maximal approved Diovan® dose for HF and the dose recommended in international guidelines for the treatment of HF. In addition, biomarker analysis (increase in ANP and cGMP) indicates that this dose delivers approximately 90% of its maximal NEP inhibition. The biomarker data are also consistent with results obtained in a dose ranging study in HTN, which demonstrated additive effects of the ARB moiety and the NEPi moiety with LCZ696 400 mg and 200 mg once daily, with a minimal incremental BP reduction from LCZ696 200 mg/d to LCZ696 400 mg/d. LCZ696 400 mg/d and 200 mg/d were well tolerated in this study. Rather than 400 mg once daily dosing of LCZ696 that was used in the HTN study, this dose will be split and LCZ696 will be dosed at 200 mg twice daily in the current study. This will ensure sustained NEP inhibition over 24 hours, which is thought to be critical for patients with HF. Furthermore, twice daily dosing will also mitigate the likelihood of hypotension, particularly in those with more severe HF impairment (NYHA III-IV).



4.2.4

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The single-blind active run-in period consists of enalapril 10 mg bid, followed by LCZ696 100 mg bid, and then LCZ696 200 mg bid over a duration of 5 to 10 weeks. During the run-in period, patients will continue their background HF medications. Patients unable to tolerate enalapril 10 mg bid and LCZ696 200 mg bid during the run-in will not be eligible for randomization, and will be discontinued from the study. This design will allow a careful assessment of the patients’ tolerability to the target doses of enalapril (10 mg bid) and LCZ696 (200 mg bid) prior to randomization. Importantly, this study design maximizes the number of randomized patients able to tolerate the target dose of either LCZ696 (200 mg bid) or enalapril (10 mg bid) during the long-term follow-up period. Thus, the study is comparing patients who are both ACEI and LCZ696 tolerant. Down titration from LCZ696 200 mg bid to LCZ696 100 mg bid will be allowed during the single-blind active run-in period. As a result of including the active run-in period in the current study design, it is anticipated that the average dose of enalapril achieved in the proposed study will be similar to, or will exceed, that achieved in the SOLVD-Treatment study (16.6 mg/d) (SOLVD Investigators 1991). There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning. On the other hand, the risk of HF deterioration associated with stopping concomitant ACEIs or ARBs for 36 hours, the duration of the ACEI/ARB-free period, will be minimal, especially since all patients will be allowed to continue receiving their background HF and CV medications. 4.2.5

Duration of the study

This study is an event driven, outcomes trial. The end of the study will occur when the prespecified number of patients achieves the primary composite endpoint of CV deaths or hospitalizations for heart failure (2,410 patients), unless the study is terminated early because of a statistically significant results in the efficacy interim analyses or because of a critical safety concern that arises at any of the safety interim analyses. In the event of an early trial termination, the secondary endpoints would be analyzed exactly as they would be if the study had not been stopped early. As an event driven trial, the actual length of the trial will depend on the observed event rates, the patient accrual rate, and length of the accrual period. As planned, it is expected to be up to 43 months: a recruitment period of approximately 22 months and a minimal follow-up of 21 months. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Early safety evaluation (seamless design)

To identify early in the course of the study any potential safety or tolerability issues, the number of patients enrolled into the active run-in phase of the study will be limited to 600 patients until a safety review of the first 200 patients who have reached 4 weeks of doubleblind treatment is completed by an external independent DMC. In addition, the safety data from the first 100, 300 and 600 patients to complete or discontinue the active run-in phase will be reviewed.

4.3

Study visits

4.3.1

Screening

Visit 1 (Screening Visit) All patients must provide informed consent before any study-specific procedure is performed. At Visit 1, patients’ eligibility for entering the active run-in period, including the required minimum daily doses of pre-study ACEI or ARB (Table 4-1), will be assessed by the investigator. LVEF measurements required for eligibility will be based on locally obtained echocardiograms, MUGA scans, CT scans, MRIs, or ventricular angiographies performed within the last 6 months provided that no subsequent measurements were above 35%. If a LVEF measurement from the last 6 months is not available, the patient may enter the trial based on a LVEF ≤ 35% obtained during the screening period, i.e., before assigning any runin study medication. If a patient has an implanted cardiac resynchronization therapy device, the LVEF values used to qualify for the study must be obtained after the implantation of that device by at least three months. Screening BNP (or NT-proBNP) and potassium levels and eGFR will be assessed by sending blood samples to the central laboratory (or other authorized laboratory) and only patients with the required values per the entry criteria will be eligible for entering the run-in period, which will begin at Visit 2. A patient may qualify for inclusion into the study based either on a BNP value or a NT-proBNP value according to the inclusion criteria mentioned in Section 5.1. Since it may take up to 72 hours to obtain the results of the clinical laboratory assessments to evaluate the patient’s eligibility for the study, it is recommended that at Visit 1 the site schedules Visit 2 approximately one week after Visit 1. At select sites, if the patient has provided informed consent to participate in the biomarker sub-study, the site should give the patient a urine collection container and instructions on how to collect the first morning urine void, which should be performed before returning to the site for Visit 2. 4.3.2


Patients who are successfully screened into the study at Visit 1 will enter the single-blind active run-in period, which includes an enalapril run-in followed by an LCZ696 run-in. Since this period will be a single-blind period, the site staff working with patients should exercise caution when discussing the study procedures and the study drug with patients to keep the patient blinded to the identity of the study drug. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Figure 4-1 is a schematic that illustrates the timeframe between the run-in period visits. Figure 4-1

Timeframes between the visits of the active run-in period

Every attempt should be made to complete the run-in period within 10 weeks regardless of any down-titration that may occur. Please refer to Section 6.5.5 for guidance on dose titration during the run-in period. Please refer to Table 7-1 for a detailed list of study procedures and assessment to be performed at each run-in period visit. Visit 2 (Enalapril run-in visit) Once patients’ eligibility has been ascertained, they will attend Visit 2 approximately one week after Visit 1 to start enalapril 10 mg bid for 2 weeks. Patients should continue to take their background medications for CHF, with the exception of ACEI or ARBs which must be discontinued. All patients tolerating enalapril 10 mg bid will be scheduled for Visit 3 when they will start the single-blind LCZ696 run–in period. Patients will continue to take all other prescribed background treatments for CHF and other CV conditions. The investigator may consider initiating treatment with enalapril 5 mg bid for 1 to 2 weeks in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACEIs (Table 4-1) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated (i.e., hypotension, renal dysfunction, and/or hyperkalemia). Visit 3 should be scheduled 2 weeks after Visit 2. The site personnel should instruct the patient not to take either the enalapril run-in medication (enalapril 10 mg bid) or the LCZ696 run-in medication on the day of Visit 3.



Table 4-1

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Minimum required pre-study daily doses of commonly prescribed ACEIs and ARBs

ACEIs

Minimum dose

ARBs

Minimum dose

Enalapril Benazepril Captopril Cilazapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril Zofenopril

10 mg 20 mg 100 mg 2.5 mg 20 mg 10 mg 7.5 mg 4 mg 20 mg 5 mg 2 mg 30 mg

Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan

16 mg 400 mg 150 mg 50 mg 10 mg 40 mg 160 mg

Visit 3 (LCZ696 run-in titration visit) Patients’ tolerability to enalapril 10 mg bid will be assessed at this visit. The site staff should instruct the patients to refrain from taking the enalapril 10 mg bid run-in medication on the day of Visit 3. The site staff will document the date and time of the last dose of the enalapril single-blind run-in medication. Patients not tolerating enalapril 10 mg bid (Table 4-2) will be considered run-in failures and withdrawn from the study. If patients meet the criteria in Table 4-2, they will start to take the LCZ696 100 mg bid run-in medication the day after Visit 3. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril 10 mg bid run-in medication after Tuesday evening. The patient will then start taking the first dose of LCZ696 100 mg bid run-in medication on Thursday morning. Patients must be stabilized on this dose of LCZ696 (100 mg bid) for 1 to 2 weeks, at the investigator’s discretion. Visit 4 (LCZ696 up-titration visit) Patients’ tolerability to LCZ696 100 mg bid (LCZ696 dose level 2) will be assessed at this visit. Patients will be up-titrated from LCZ696 100 mg bid to LCZ696 200 mg bid (dose level 3) for 2 to 4 weeks at the investigator’s discretion. Patients participating in the population PK substudy will provide a trough (Cmin) blood sample on the morning of Visit 4 prior to up-titration. At the end of the single-blind active run-in period, only patients who tolerate LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for 2 to 4 weeks will be eligible for randomization.



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Safety and tolerability monitoring during the active run-in period Patients will be eligible for entering the enalapril run-in period at Visit 2, for entering the LCZ696 run-in period at Visit 3, and for randomization at Visit 5 if they meet all the inclusion criteria and none of the exclusion criteria, including the serum potassium, eGFR, blood pressure, and postural symptoms listed in Table 4-2. During the run-in period, non-disease modifying medications (such as nitrates, CCBs, αblockers, and diuretics) may be changed (dose reduced or discontinued) in response to the occurrence of adverse events, such as hyperkalemia, hypotension, and renal dysfunction, in an attempt to allow patients to meet the safety criteria in Table 4-2. The doses of background disease modifying drugs, such as β-blockers or aldosterone antagonists, may be reduced to facilitate maintenance of study drug if in the opinion of the investigator they are believed to be the cause of the adverse effect in question. To ascertain patient’s eligibility for continuing in the study, Visit 3 (start of the LCZ696 runin period) and Visit 5 (randomization) study drug should not be dispensed unless laboratory assessments of potassium and eGFR are available. This may require laboratory samples to be collected and analyzed up to 72 hours before these Visits. The reason for patient discontinuation during the active run-in period must be carefully documented in the appropriate eCRFs. Patients who experience angioedema at any time during the run-in period must be withdrawn from the study. Table 4-2

Safety monitoring criteria that must be met at Visit 1 (screening), Visit 3, and Visit 5

Parameter

Visit 1 (screening)

Visit 3 (end of enalapril run-in) and Visit 5 (end of LCZ696 run-in and randomization)


K ≤ 5.2 mmol/L

K ≤ 5.4 mmol/L



4.3.3


2

2


Double-blind study treatment period

Please refer to Table 7-1 for a detailed list of study procedures and assessment to be performed at each double-blind period visit. The double-blind treatment period will begin at Visit 5. Only patients who tolerate LCZ696 200 mg bid (after tolerating enalapril 10 mg bid) for at least 2 weeks will be eligible for randomization. The study medication will be added to the prescribed background HF therapy, and as considered appropriate by the investigator. Concomitant administration of ACEIs or This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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ARBs with the study medication is strictly prohibited. Please refer to Section 6.5.7 for more information on co-administration of other medications. Reported trial outcome endpoint events and other pre-specified endpoint events of intent will be collected as they occur throughout the double-blind period. All laboratory evaluations for planned visits after randomization will be performed through the central laboratory or other authorized laboratory. Unscheduled laboratory assessments can be performed locally as necessary. Visit 5 will be considered the reference visit for all study visits during the double-blind period. Regardless of the occurrence of any unscheduled visits, scheduled visits must occur within the timeframe in relation to Visit 5 as outlined in Table 7-1. Figure 4-2 provides a schematic of the timeframe between study visits occurring during the double-blind period. Figure 4-2

Overall study design and timeframe between study visits occurring during the active run-in and double-blind periods

w = week; m = month a. Projected duration of the trial. Actual duration of the trial is event-driven.

Visit 5 (Randomization Visit) Patients who have met all the inclusion criteria and none of the exclusion criteria at the end of the active run-in period will be randomized to either enalapril 10 mg bid or LCZ696 200 mg bid in a 1:1 ratio. Site personnel should instruct the patient to refrain from taking their run-in medication on the day of Visit 5. Site personnel will document the date and time of the last dose of the LCZ696 run-in medication. This is necessary to minimize the potential risk of occurrence of angioedema. If appropriate, the patient will start to take the double-blind study medication (enalapril 10 mg bid or LCZ696 200 mg bid) the day after Visit 5. For example, if a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 200 mg bid run-in medication This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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after Tuesday evening. The patient will then start taking the first dose of the double-blind study medication on Thursday morning. Table 7-1 lists all procedures to be performed at Visit 5. Visits 6 up to end of study (EOS) visit In the first 4 months of the double-blind treatment period, patients will return to the site for study visits every two to eight weeks. Visits after the first four months of the double-blind period will be scheduled for every four months. In addition to the protocol-required visits, patients may be seen at anytime throughout the study at the discretion of the investigator to follow any new lab abnormalities or AEs. All randomized patients, including any patient who has experienced a health event, should continue to receive double-blind treatment until the trial is completed. Monitoring of safety and tolerability will include: (1) hyperkalemia; (2) symptomatic hypotension; (3) increase in serum creatinine; (d) angioedema; and (e) AEs and SAEs. If, in the opinion of the investigator, the patient cannot tolerate the target dose of study drug, the investigator should consider whether non-disease-modifying medication (e.g., CCBs, diuretics, nitrates, α-blockers) can be reduced to rectify the situation before considering reducing the dose of the study drug to the lower dose level. The dose of background disease modifying drugs, such as β-blockers and aldosterone antagonists, may be reduced to facilitate maintenance of study drug if they are believed to be the cause of the adverse effect in question. If the situation is not rectified despite adjusting/discontinuing other concomitant medications or if adjusting other concomitant medications is not possible, patients who no longer tolerate the target dose at any time during the course of the trial can be down-titrated to the lower dose level at the investigator’s discretion (please refer to Table 6-2 for dose levels available for titration). However, every attempt should be made to re-challenge the patients so that they are kept on the maximal tolerated dose of study drug for as long a duration as possible throughout the double blind period of the trial. Please refer to Section 6.5.5 for guidance on study drug dose adjustment. As in the case of other outcome trials, once a patient is randomized and receives study medication, he/she may not be withdrawn from the study for any reason, except if it is determined by the investigator that continuation in the trial will be detrimintal to the patient’s wellbeing or if the patient requests to be withdrawn from the study. If the study drug is temporarily discontinued, it should be reintroduced as soon as medically justified in the opinion of the investigator. After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the study. On the contrary, even patients who have stopped taking study drug are expected to attend all the protocol specified study visits and perform all measurements as stipulated in the visit schedule. In case it is not possible for the patient to attend any visit(s), the site staff will keep in touch with the patient by means of regular phone contact to the patient himself/herself or to a person pre-designated by the patient according to the patient’s study visit schedule. Data will continue to be collected about the patient’s health status, including information on developing of cardiovascular complications and vital status. This information may be provided by either the patient himself/herself or any person who This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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knows the patient. Data, such as information on survival information and potential protocolspecified endpoint, might be also collected from a health care provider, from public or medical records, or other sources as available. These data will be collected until the conclusion of the study, even if the patient is no longer attending the study visits in person. At Visit 7 or at Visit 10, blood samples will be obtained from patients participating in the PK substudy for analysis of valsartan, AHU377, and LBQ657 at steady state. Three samples will be obtained at either of those visits: pre-dose and at 0.5 to 2 hours and 3 to 5 hours post-dose. All randomized patients will remain in the trial until either (1) the projected number of primary endpoint (CV death or HF hospitalization) is reached, or (2) the trial is terminated prematurely at the recommendation of the DMC when pre-specified early-stopping criteria for efficacy and/or safety criteria are met. Table 7-1 lists all procedures to be performed at Visit 6 and all the remaining visits in the study.

5

Population

The study population will consist of patients with CHF (NYHA class II - IV), aged 18 years or older with LVEF ≤ 35%. Eligible patients should also be on a stable dose of an ACEI or an ARB for at least 4 weeks before entering into the study. The required minimum doses of prestudy ACEIs and ARBs are listed in Table 4-1. Patients from up to approximately 1,200 research sites worldwide will be randomized in a 1:1 ratio to either LCZ696 200 mg bid or enalapril 10 mg bid. In order to randomize 7,980 patients (3,990 patients in each arm) it is estimated that approximately 16,000 patients will have to be screened as the screen failure rate is anticipated to be approximately 50%.

5.1

Inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1. Patients must give written informed consent before any assessment is performed. 2. Outpatients ≥ 18 years of age, male or female. 3. Patients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction: o LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is acceptable, provided no subsequent measurement above 35%) o BNP ≥ 150 pg/ml (or NT-proBNP ≥ 600 pg/ml) at Visit 1 OR BNP ≥ 100 pg/mL (or NT-proBNP ≥ 400 pg/ml) at Visit 1 and a hospitalization for HF within the last 12 months 4. Patients must be on an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent for at least 4 weeks before Visit 1 o For this protocol doses of other ACEIs considered to be equivalent to enalapril 10 mg/d include benazepril 20 mg/d, captopril 100 mg/d, cilazapril 2.5 mg/d, fosinopril 20 mg/d, lisinopril 10 mg/d, moexipril 7.5 mg/d, perindopril 4 mg/d, quinapril 20 mg/d, ramipril 5 mg/d, trandolapril 2 mg/d, and zofenopril 30 mg/d. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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o For this protocol doses of ARBs considered to be equivalent to enalapril 10 mg/d include candesartan 16 mg/d, eprosartan 400 mg/d, irbesartan 150 mg/d, losartan 50 mg/d, olmesartan 10 mg/d, telmisartan 40 mg/d, and valsartan 160 mg/d. 5. Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented for patients not on CHF target doses per local guidelines, or in absence of that medication). 6. An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit 1. Other evidence-based therapy for heart failure should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.

5.2

Exclusion criteria

1.

Use of other investigational drugs at the time of enrollment, or within 30 days or 5 halflives of enrollment, whichever is longer 2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to the study drugs 3. Previous history of intolerance to recommended target doses of ACEIs or ARBs 4. Known history of angioedema 5. Requirement of treatment with both ACEIs and ARBs 6. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) 7. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening) or < 95 mmHg at Visit 3 or at Visit 5 (randomization) 8. Estimated GFR < 30 mL/min/1.73m2 as measured by the simplified MDRD formula at Visit 1 (screening), Visit 3 (end of enalapril run-in), or Visit 5 (end of LCZ696 run-in and randomization) or > 35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and Visit 5 9. Serum potassium > 5.2 mmol/L at Visit 1 (screening) or > 5.4 mmol/L at Visit 3 or Visit 5 (randomization) 10. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit 1 11. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1 12. Implantation of a cardiac resynchronization therapy pacemaker (CRT-P) or a cardiac resynchronization therapy defibrillator (CRT-D) or upgrading of an existing conventional pacemaker or an implantable cardioverter defibrillator (ICD) to CRT device within 3 months prior Visit 1 or intent to implant such a device. Also, patients who had implantation of a conventional pacemaker or an ICD or had a revision of a pacemaker or other device leads within 1 month before Visit 1 are excluded. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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13. Heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD 14. History of severe pulmonary disease 15. Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the 12 months prior to Visit 1 16. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1 17. Symptomatic bradycardia or second or third degree heart block without a pacemaker 18. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation 19. Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis 20. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: o History of active inflammatory bowel disease during the 12 months before Visit 1. o Current duodenal or gastric ulcers during the 3 months prior to Visit 1 o Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt o Active treatment with cholestyramine or colestipol resins 21. Presence of any other disease with a life expectancy of < 5 years 22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL) 23. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method (if accepted by the local regulatory authority and ethics committee) or a barrier method plus a hormonal method o Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progesterone agent. o Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. o Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. 24. Presence of bilateral renal artery stenosis. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients.

6

Treatment

6.1

Investigational and control drugs

Active run-in All eligible patients will enter an active run-in period during which they will be exposed to an enalapril run-in period, followed by an LCZ696 run-in period. The following study drugs will be provided: • Enalapril 5 mg tablets (enalapril dose level 2) • Placebo to match enalapril 5 mg tablets (placebo matching enalapril dose level 2) • Enalapril 10 mg tablets (enalapril dose level 3) • Placebo to match enalapril 10 mg tablets (placebo matching enalapril dose level 3) • LCZ696 100 mg film-coated tablets (LCZ696 dose level 2) • Placebo to match LCZ696 100 mg tablets (placebo matching LCZ696 dose level 2) • LCZ696 200 mg film-coated tablets (LCZ696 dose level 3) • Placebo to match LCZ696 200 mg tablets (placebo matching LCZ696 dose level 3) Dose level 1 for enalapril (2.5 mg bid) and LCZ696 (50 mg bid) will only be available in the double-blind period. Patients will be required to take the single-blind enalapril or LCZ696 dose and placebo to match the opposite treatment at the corresponding dose level twice daily in addition to their conventional concomitant therapy (except for ACEI or ARB, which will be substituted with study drug). Double blind treatment All eligible patients will be randomized to receive either LCZ696 or enalapril in addition to optimal CHF therapy, as considered appropriate by the investigator and in accordance with standard therapy guidelines, but with the exception of an ACEI or ARB as this will be replaced by study drug. The use of an ACEI or an ARB in addition to study drug after randomization is strictly prohibited. The following study drugs will be provided: • LCZ696 50 mg film-coated tablets (LCZ696 dose level 1) This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Placebo to match LCZ696 50 mg film-coated tablets (placebo matching LCZ696 dose level 1) LCZ696 100 mg film-coated tablets (LCZ696 dose level 2) Placebo to match LCZ696 100 mg film-coated tablets (placebo matching LCZ696 dose level 2) LCZ696 200 mg film-coated tablets (LCZ696 dose level 3) Placebo to match LCZ696 200 mg film-coated tablets (placebo matching LCZ696 dose level 3) Enalapril 2.5 mg film-coated tablets (enalapril dose level 1) Placebo to match enalapril 2.5 mg film-coated tablets (placebo matching enalapril dose level 1) Enalapril 5 mg film-coated tablets (enalapril dose level 2) Placebo to match enalapril 5 mg film-coated tablets (placebo matching enalapril dose level 2) Enalapril 10 mg film-coated tablets (enalapril dose level 3) Placebo to match enalapril 10 mg film-coated tablets (placebo matching enalapril dose level 3)

Target doses: LCZ696 200 mg bid and enalapril 10 mg bid Patients not tolerating the target dose (LCZ696 200 mg bid or enalapril 10 mg bid) will be titrated down to the lower dose level twice a day, at the investigator’s discretion, based on the defined safety and tolerability criteria (Appendices 15, 16, and 17). All tablets (LCZ696 50 mg, LCZ696 100 mg, LCZ696 200 mg, enalapril 2.5 mg, enalapril 5 mg, enalapril 10 mg) have different shapes and colors. Therefore, the study will be designed as a double- blind, double-dummy trial to ensure the blinding during the entire course of the study. To maintain the blinding, patients will be required to take their assigned active treatment tablet along with placebo matching the opposite treatment twice daily (morning and evening dose) in addition to their conventional concomitant therapy. LCZ696 and its matching placebo will be provided in HDPE bottles. Enalapril 2.5 mg and its matching placebo will be provided in HDPE bottles, while enalapril 5 mg and 10 mg and its matching placebo will be provided in blister packs. LCZ696 and enalapril will be packaged separately to limit the number of pack types which will allow more flexibility in the drug supply process to cover all the different treatment possibilities (treatment arm and medication level) (Section 6.5.4).

6.2

Treatment arms

Patients who are eligible for randomization at Visit 5 will be assigned to one of the following two treatment arms in a 1:1 ratio: • LCZ696 200 mg bid • Enalapril 10 mg bid This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Treatment assignment

At Visit 5, the investigator or his/her delegate will call the interactive voice response system (IVRS), enter the patient’s patient number, and confirm that the patient qualifies for randomization. The IVRS will assign a randomization number to the patient, which will be used to link the patient to a treatment arm and will specify unique medication numbers for the packages of the first supply of the study drugs to be dispensed to the patient. The IVRS will provide unique medication numbers for both the LCZ696 or its matching placebo and enalapril or its matching placebo. Subsequent supplies of study drug will be assigned in the following manner. The investigator or his/her delegate will call the IVRS and provide the patient’s number. The IVRS will ask the caller whether there is a change in the dose level of the study drug. If the caller indicates that there is no change in the dose level, IVRS will provide the unique medication numbers of study drug with the same dose level that was dispensed at the previous dispensing. If the caller indicates that the dose level has changed since the last dispensing, IVRS will ask the caller which dose level should be dispensed. The caller will enter the dose level to dispense, i.e., level 1 (LCZ696 50 mg or enalapril 2.5 mg bid), level 2 (LCZ696 100 mg or enalapril 5 mg bid), or level 3 (LCZ696 200 mg or enalapril 10 mg bid), or whether no study drug needs to be dispensed (in case of study drug withdrawal). If applicable, the IVRS will provide the unique medication numbers for the packages of the study drug supplies that should be dispensed at the new dose level. Randomization numbers will be generated using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. A patient randomization list will be produced by the IVRS provider using a validated system that automates the random assignment of patient numbers to randomization numbers. These randomization numbers are linked to the different treatment arms, which in turn will be linked to medication numbers. A separate medication randomization list will be produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs. The randomization scheme for patients will be reviewed and approved by a member of the Biostatistics Quality Assurance Group. In addition to the IVRS, a web-based system will also be available and will have the same functionalities as the IVRS.

6.4

Treatment blinding

Single-blind enalapril or LCZ696 will be dispensed to patients during the active run-in period. During the active run-in period, patients will receive LCZ696 or enalapril and placebo matching the appearance of the opposite treatment. The identity of the treatments will be concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, and odor to the supplies that will be used in the double-blind treatment period. Patients, investigator staff, persons performing the assessments, and data analysts will remain blind to the identity of the treatment from the time of randomization until database lock, using This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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the following methods: (1) Randomization data are kept strictly confidential until the time of unblinding, and will not be accessible by anyone else involved in the study with the exception of the members of the DMC (Section 8.4) and the independent biostatistician who will perform the IA, and (2) the identity of the treatments will be concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance, and odor. Unblinding will only occur in the case of patient emergencies (Section 6.5.9), at the time of the IA (Section 10.16), and at the conclusion of the study. The study bioanalytical monitor and the bioanalyst at the bioanalytical site of the study will be unblinded in order to identify the samples collected from patients who received LCZ696 in order to facilitate their timely pharmacokinetic analysis.

6.5

Treating the patient

6.5.1

Patient numbering

Each patient is uniquely identified in the study by a combination of his/her site number and patient number. The site number is assigned by Novartis to the investigative site and consists of 4 digits (e.g., 1234). After the patient has signed the informed consent form, the investigator or his/her staff will telephone the IVRS and provide the requested identifying information for the patient. The IVRS will then assign the patient number, which is a 5-digit sequential number that begins with “00” (e.g., 00001, 00002, 00003, etc.). Only the assigned patient number should be entered in the field labeled “Patient” on the EDC data entry screen. Once assigned to a patient, the patient number will not be reused. If the patient fails to be randomized, the IVRS must be notified regarding the patient’s screen-failure or run-in failure and the appropriate eCRFs should be completed within 3 days. In addition, the screening log should be completed for all patients. 6.5.2

Dispensing the study drug

Each study site will be supplied by Novartis with study drug in identically-appearing packaging for each medication (LCZ696 or enalapril). The study medication packaging has a 2-part label. A unique randomization medication number is printed on each part of this label, which corresponds to one of the two treatment arms and a dose level. Investigator staff will identify the study drug package to dispense to the patient by calling the IVRS and obtaining the study drugs medication numbers as described in Section 6.3. Immediately before dispensing the packages to the patient, investigator staff will detach the outer part of the label from the packaging and affix it to the source document (Drug Label Form) for that patient’s unique patient number. 6.5.3

Study drug supply, storage and tracking

Study drugs must be received by a designated person at the study site, handled, and stored safely and properly, and kept in a secured location to which only the investigator and designated assistants have access. Upon receipt, all study drugs should be stored according to the instructions specified on the drug labels. Clinical supplies are to be dispensed only in accordance with the protocol. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Medication labels will be in the local language and comply with the legal requirements of each country. They will include storage conditions for the drug, but no information about the patient, except for the medication number. The investigator must maintain an accurate record of the shipment and dispensing of study drug in a drug accountability ledger. Monitoring of drug accountability will be performed by the field monitor during site visits and at the completion of the trial. Patients will be asked to return all unused study drug and packaging at each visit, at the time of study drug discontinuation, and at the end of the study. At the conclusion of the study, and as appropriate during the course of the study, the investigator will return all unused study drug, including opened and unopened packaging, drug labels, and a copy of the completed drug accountability ledger to Novartis according to the instructions provided by Novartis or its agents. 6.5.4

Instructions for prescribing and taking the study drug

Novartis will supply the investigators with all medications sufficient for the course of the study. Patients will be provided with medication packs containing study drug corresponding to their assigned treatment arm and dose level, sufficient to last until the next scheduled visit. In order to adequately blind the study, patients will be required to take a total of two tablets (one tablet from the LCZ696/LCZ696 matching placebo pack and one tablet from the enalapril/enalapril matching placebo pack) twice a day for the duration of the study. Table 6-1 summarizes the study drug that will be taken during the active run-in period by visit and Table 6-2 summarizes the study drug that will be taken during the double-blind period.




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Study drug dispensed during the active run-in period by study visit Dose level

LCZ696

Visit 2A

2


Enalapril 5 mg bid

Visit 2

3


Enalapril 10 mg bid

Visit 3

2

100 mg bid


3

200 mg bid


a

b, c

Visit 4

Enalapril

a. Investigators may consider initiating treatment on enalapril 5 mg bid in those patients who are (1) currently treated with ARBs, or (2) currently treated with lower doses of ACE inhibitors (see Table 41) if the investigator is concerned that switching directly to enalapril 10 mg bid will not be tolerated. b. During the run-in period, patients may be temporarily down-titrated from LCZ696 200 mg bid to LCZ696 100 mg bid with subsequent re-challenge to ensure that they tolerate LCZ696 200 mg bid for at least 2 weeks. The run-in period should be completed within 10 weeks regardless of any down-titration that may have occurred. c. Patients unable to tolerate LCZ696 200 mg bid after re-challenge will be withdrawn from the study and will not be randomized.


Study drug dispensed during the double-blind period Dose level

LCZ696

Enalapril

a

Visit 5 and all 3 200 mg or matching placebo bid 10 mg or matching placebo bid subsequent visits b Available for any 2 100 mg or matching placebo bid 5 mg or matching placebo bid visit after Visit 5 c Available for any 1 50 mg or matching placebo bid 2.5 mg or matching placebo bid visit after Visit 5 a. This dose level must be maintained for as long a duration as possible. If down-titration is necessary due to side effects, the patient should be re-challenged as soon as medically possible per the investigator’s judgment. b. Only if dose level 3 is not tolerated despite modification of other non-disease-modifying HF medications. c. Only if dose levels 2 and 3 are not tolerated despite modification of other non-disease-modifying HF medications.

Patients will be instructed to take their morning study drug doses at approximately 08:00 (8 AM) and their evening study drug doses at approximately 19:00 (7 PM). The study medications should be taken with a glass of water with or without food. If the patient misses taking any study drug dose, he/she should take it as soon as possible, unless if it is almost time for the following scheduled dose. In this case, the patient should skip the missed dose and return back to his/her regular study drug administration schedule. All dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded in the IVRS and on the Dosage Administration Record eCRF. The investigator should promote compliance by instructing the patient to take the study drug exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the validity of the study. The patient should be instructed to contact the investigator if he/she is unable to take the study drug as prescribed for any reason. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Permitted study drug dose adjustments and interruptions

Every attempt should be made to maintain patients on the target study drug dose level for as long a duration as possible throughout the trial. If, however, in the opinion of the investigator, the patient does not tolerate the target dose of study drug (dose level 3), the investigator should consider whether non-disease-modifying medication (e.g., CCBs, diuretics, nitrates, αblockers) can be reduced to rectify the situation, before considering to reduce the dose of the study drug to the next lower dose level. Also, the investigator may adjust doses of diseasemodifying medications if it is believed that they are the most likely cause of the adverse effect. If adjustment/elimination of concomitant medications is not possible or does not alleviate the side effects of concern, the investigator may down-titrate the dose of the study drug to the next lower level up to complete withdrawal of the study drug. The patient should be rechallenged with the higher dose when the investigator feels it is appropriate to do so per the directions provided below in this section. If needed, the study drug may be stopped completely, but the patient should continue to attend the study visits and be followed until the completion of the study. Ultimately the goal is to keep the patient on the highest study drug dose possible for as long as possible and to follow the patient in the study as long as possible. Study drug dose level adjustments should mainly be based on overall safety and tolerability with special focus on a) hyperkalemia; b) symptomatic hypotension; and c) clinically significant decrease in eGFR/increase in serum creatinine (see Appendices 15, 16, and 17 for treatment guidelines for hyperkalemia, management of BP, and renal dysfunction, respectively). Adjustment of study drug dose level If despite adjustment of concomitant medications per the guidance provided above does not rectify the situation, the investigator may consider adjusting the study medication according the following instructions. Study drug dose adjustments during the single-blind run-in period – At the investigator’s discretion, LCZ696 200 mg bid can be down-titrated to LCZ696 100 mg bid until such time that investigator believes the patient may be able to tolerate titration back up to LCZ696 200 mg bid. If the investigator does not feel that the patient will ultimately be able to tolerate this dose, he/she may withdraw the patient from the study without re-challenge. Every attempt should be made to complete the run-in period within 10 weeks regardless of any downtitration that may occur. Study drug dose adjustments during the double-blind treatment period – During the double-blind treatment period down-titration of the study drug at any time will be allowed based on the safety and tolerability criteria defined in Appendices 15, 16, and 17. If downtitration is necessary, the patient should be down-titrated to the next lower dose level (Table 6-2). The patient may continue receiving the lower dose level for a recommended period of 1 to 4 weeks before re-challenging the patient with the next higher dose level. For example, a patient who encounters tolerability problems at the target dose level (dose level 3), should receive the study drug at dose level 2 for 1 to 4 weeks. Then, he/she should be re-challenged with up-titration back to dose level 3.



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If the tolerability issues are not alleviated despite down-titration by one dose level, the investigator may lower the study drug dose further to the next lower level for 1 to 4 weeks, up to temporary withdrawal of the study drug. Again, once stable, the patient should be rechallenged with up-titration to the next higher dose level every 1 to 4 weeks in an attempt to bring back the patient gradually to the target study drug dose level (dose level 3). The investigator may choose the next dose level for down- or up-titration according to his or her judgment (Table 6-2). As discussed in Section 6.3, the IVRS should be contacted to register any changes in the patient’s study drug dose level, including in cases of temporary and permanent withdrawal of the study drug, and to obtain the medication numbers of the study drug supplies required for the new study drug dose level. In some instances, according to the safety and tolerability criteria and the investigator’s judgment, dose level 1 or 2 could be maintained if he/she considers that the patient’s condition would not allow any further up-titration to the target dose of study medication (level 3). In this case it would be acceptable to maintain the patient at dose level 1 or level 2, whichever is the higher and tolerated dose level by the patient. Study drug restart after temporary treatment interruption Study drug should be reintroduced in those who temporarily discontinue it as soon as medically justified in the opinion of the investigator. Once the investigator considers the patient’s condition appropriate for receiving the study drug, the investigator should re-start the patient on the study drug at the most appropriate and allowable dose level (Table 6-2) per his/her medical judgment. If tolerated based on the safety and tolerability criteria in Appendices 15, 16, and 17, the patient should be up-titrated up to dose level 3 every 1 to 4 weeks, as per the investigator’s judgment. Patients re-started on the study drug will retain their original randomization and study identification numbers. Should the patient not tolerate the re-start study drug dose level, he/she may be down-titrated again (if appropriate) or discontinue the study medication again and a new attempt to up-titrate or reintroduce the study drug could be considered by the investigator as soon as medically justified in his/her medical judgment. Study visits should occur as close as possible to the time points indicated in Table 7-1. The timeframe between the regular visits should be maintained as scheduled, irrespective of the number of unscheduled visits that may be performed in between, according to the visit and time schedule described in Table 7-1. For example, if the patient’s treatment needs to be adjusted between Visit 9 and Visit 10, Visit 10 will still be planned 4 months after Visit 9, irrespective of the number of unscheduled visits that may have occurred between these two visits or the additional period that the medication pack dispensed could have covered. Any changes in the study drug dose level, including temporary/permanent withdrawal or restart of the study drug, must be recorded on the Dosage Administration Record eCRF and registered in the IVRS. In case of pregnancy discovered during the run-in period, the patient will be withdrawn from the study immediately. In case of pregnancy discovered during the double-blind treatment period, the patient should be instructed to stop taking the study drug immediately. Study drug intake should be resumed This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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as soon as possible after the completion of the pregnancy and lactation period. Meanwhile, the patient should continue to attend scheduled study visits. See Section 8.3 for further details on pregnancies and reporting guidelines. 6.5.6

Rescue medication

Guidance on handling hyperkalemia, hypotension, and renal dysfunction are provided to investigators in Appendices 15, 16, and 17, respectively. Patients may receive open-label ACEIs and/or ARBs during the study ONLY if the study medication has been discontinued either temporarily or permanently. 6.5.7

Other concomitant treatment

The investigator should instruct the patient to notify the study site staff of any changes in concomitant medications (new medications or changes in dose regimens of existing medications). All concomitant medications and significant non-drug therapies (including physical therapy and blood transfusions) administered after the patient starts treatment with the study medication must be listed on the Concomitant Medications/Significant Non-Drug Therapies eCRF. ACEIs and ARBs Patients’ pre-study ACEIs/ARBs will be replaced with the study medications. The concomitant use of open-label ACEIs or ARBs is strictly prohibited while the patient is receiving study medication, regardless of study period (active run-in period or double-blind period). If the investigator believes that addition of an ACEI or ARB is necessary, then study drug must be discontinued. Study medication should be stopped the day prior to addition of open-label ACEI and/or ARB. If not already treated with an aldosterone antagonist, consideration should be given to adding this therapy rather than an ACEI or ARB. Similarly, if study medication is to be restarted, the open-label ACEI and/or ARB should be discontinued the day prior to resuming study medication. Heart failure medications and other cardiovascular medications The patient should be on an optimal medical regimen of background HF medications. This must include an individually optimized dose of a β-blocker (i.e., maximally tolerated dose) at a stable dose for at least 4 weeks prior to study entry, unless contraindicated or not tolerated. Use of an aldosterone antagonist should be considered in patients eligible for this study. In self-identified black patients, the use of isosorbide dinitrate/hydralazine hydrochloride (e.g., BiDil®) should be considered. Every effort should be made to keep the dose level of these background, disease-modifying HF medications stable throughout the entire study. However, if the patient’s condition warrants a change in any of these medications (for example, if the investigator believes a disease-modifying medication is causing an adverse event), it is allowed at the discretion of the study investigator. Diuretics may be used and may be adjusted throughout the length of the study at the discretion of the investigator. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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If a patient experiences any AEs that may be contributed to by the study drug, other HF medications, or other CV medications, the investigator should adjust non-disease-modifying medications (e.g., CCBs, nitrates, a-blockers, and diuretics) first in an attempt to alleviate the AEs. Medications known to raise potassium levels Potassium-sparing diuretics, potassium supplements, aldosterone antagonists, and any other medications known to raise potassium levels should be used with caution while the patient is receiving the study medication due to the increased possibility of occurrence of hyperkalemia. The investigator is encouraged to assess patients’ potassium levels regularly, especially in those who are receiving these medications. Concomitant administration of renin inhibitors, such as aliskiren, is prohibited. Phosphodiesterase-5 (PDE-5) inhibitors PDE-5 inhibitors should be used with caution while the patient is receiving study medication due to the increased possibility of occurrence of hypotension. Neseritide and intravenous nitrates The concomitant administration of LCZ696 with neseritide and intravenous (i.v.) nitrates has not been studied. In the event a study patient requires the concomitant administration of neseritide and/or i.v. nitrates with the study medications, the investigator should consider starting them at a lower dose or a slower infusion rate while monitoring the patient’s blood pressure carefully. Other medications Bile acid sequestering agents, such as cholestyramine and colestipol, are prohibited to avoid interference with study drug absorption. 6.5.8

Study drug discontinuation and premature patient withdrawal

After randomization, study drug discontinuation for any reason does not constitute withdrawal from the study and should not lead to the patient being withdrawn from the entire study. On the contrary, even patients who have stopped taking study drug are expected to attend all the protocol specified study visits and perform all measurements as stipulated in the visit schedule (Table 7-1). If the patient does not attend the study visits, follow-up should continue according to the specified schedule by telephone to determine if any of the health events/endpoint prespecified in the protocol has occurred, except in the case that the patient specifically refuses such follow-up and withdraws his/her consent. The emergence of the following circumstances will require study drug discontinuation: • Withdrawal of informed consent • Pregnancy (Section 8.3) • Investigator thinks that continuation would be detrimental to the patient’s well-being This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


•

Confidential


Suspected occurrence of angioedema during the run-in period

Study medication may be discontinued at the investigator’s discretion if any of the following occurs: • Any severe suspected drug related AE • Suspected occurrence of angioedema. A patient with any signs or symptoms of clinically significant angioedema should be thoroughly evaluated by the investigator and constitute a reason for discontinuation of study medication. • Depending on the serum potassium, blood pressure, or eGFR, patients may need to have their study drug dose or the dose of another concomitant medication reduced or discontinued, or, if appropriate, have potentially contributing agents adjusted. Please refer to Appendices 15, 16, and 17 for treatment guidelines for hyperkalemia, hypotension, or renal dysfunction, respectively. In the case of study drug discontinuation, the patient should continue to complete all scheduled study visits and procedures. If the patient refuses, he/she should be contacted by telephone in place of protocol-specified visits unless the patient expressly refuses such contacts. The investigator must also notify the IVRS of the study drug discontinuation and record it on the drug administration form of the eCRF. 6.5.9

Emergency unblinding of treatment assignment

Emergency unblinding should only be undertaken when it is essential for effective treatment of the patient. Most often, study drug discontinuation and knowledge of the possible treatment assignments are sufficient to treat a study patient who presents with an emergency condition. Emergency code breaks are performed using the IVRS. When the investigator telephones the system to unblind a patient, he/she must provide the requested patient identifying information and the date, time, and reason for unblinding. The investigator will then receive details of the drug treatment for the specified patient and a fax confirming this information. The system will automatically inform the Novartis site monitor and the Clinical Trial Head that the code has been broken. It is the investigator’s responsibility to ensure that there is a procedure in place to allow access to the IVRS in case of emergency. The investigator will inform the patient how to contact his/her backup in cases of emergency when he/she is unavailable. The protocol number, study drug name if available, patient number, and instructions for contacting the local Novartis Country Pharma Organization (CPO) (or any entity to which it has delegated responsibility for emergency code breaks) will be provided to the patient in case emergency unblinding is required at a time when the investigator and backup are unavailable. Study drug must be discontinued after emergency unblinding. Study drug also must be discontinued for any patient whose treatment code has been broken inadvertently or for any non-emergency reason. 6.5.10

Study completion and post-study treatment

At the EOS visit (Visit 778) patients will be asked to return the remaining study drug. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Patients who do not fulfill the eligibility criteria during the run-in period should be discontinued from the study and the appropriate eCRF should be completed accordingly (e.g., run-in completion page, see Section 7.1). The investigator also must provide follow-up medical care for all patients who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care. When the patient has completed all scheduled study assessments, the investigator must call the IVRS within 3 days to record the patient completion in the IVRS. 6.5.11

Early study termination

The study can be terminated at any time for any reason by Novartis Pharmaceuticals. Should this be necessary, the patient should be seen as soon as possible and an EOS visit (Visit 778) must be conducted as described in Section 7. The investigator may be informed of additional procedures to be followed in order to assure that adequate consideration is given to the protection of the patient’s interests. The investigator will be responsible for informing institutional review boards (IRBs) and/or ethics committees (ECs) of the early termination of the trial.

7

Visit schedule and assessments

All patients, including those who discontinue the study medication before completing the study, should continue attending the scheduled visits as outlined in Table 7-1 until the study ends. At that point all patients will return to the study sites as soon as possible to undergo the EOS visit (Visit 778) assessments. If any patient refuses to return for these assessments or is unable to do so, every effort should be made to contact him/her or a knowledgeable informant by telephone to ask if any of the primary, secondary, or other endpoints (see Section 3.1 and Section 3.2) have occurred at the foreseen visit dates for the remaining duration of the study. Documentation of attempts to contact the patient should be recorded in the patient’s record. All data obtained from the assessments listed in Table 7-1 and described in detail in the subsections below must be supported in the patient’s source documentation (e.g., medical charts or patient notes). Table 7-1 indicates which data remain in source documents only (S), or may be entered directly into the database (D; i.e., these data are considered source documentation and do not require separate source documentation), or are entered into the database from separate source documents (DS). Assessments that generate data for database entry and are recorded on eCRFs are listed using the eCRF name. Assessments that are transferred to the database electronically (e.g., laboratory data) are listed by test name. With regards to timing of study visits of patients who participate in the biomarker and population PK substudies, the timing of study drug administration should be taken into account when scheduling study visits when blood and urine samples will be obtained. Please refer to Section 7.6.5 for more information on scheduling the PK sampling. If one visit is postponed or brought forward, it should not result in the next visit being postponed or brought forward. The next visit, if at all possible, should adhere to the original time schedule. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Patients will also be instructed to take study drug, as usual, on the morning of their site visits (except for Visits 3 and 5), with or without food. If a patient did not take his/her study drug on the morning of his/her scheduled visit, the study visit could nevertheless be conducted. The only exception to this rule is for visits when biomarker or population PK substudy patients are to provide the pre-study drug dose blood and urine samples. In this case, the patient should not take the study drug before attending the study visit, but the study visit should be scheduled so that the biomarker and PK samples are obtained immediately before the time when the patient usually takes his/her study medication. There are two short washout periods (approximately 36 hours for each) during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-NEP inhibition at Visit 3 and Visit 5 (Section 7.5.7): (1) after completing the enalapril run-in and prior to beginning the LCZ696 run-in at Visit 3, and (2) after completing the LCZ696 run-in and prior to starting randomized study drug at Visit 5. For example, if a patient’s Visit 3 is on Wednesday, he/she must not take any doses of the enalapril run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of the single-blind LCZ696 run-in medication on Thursday morning. The same is true for Visit 5. If a patient’s Visit 5 is on Wednesday, he/she must not take any doses of the LCZ696 run-in medication after the Tuesday evening dose. The patient will then start to take the first dose of double blind medication on Thursday morning.



Table 7-1


Assessment schedule

Phase

Screening

Visit

D/S*

Weeks (w) / Months (m)

1


2A

2

15

1

Call to IVRS

2

S

x

S

x

Inclusion/Exclusion criteria

DS

Demography/Medical history (including alcohol and smoking history)

DS

x

Heart Failure History

DS

x

Cardiovascular disease History

DS

x

3

x

x

2


LCZ696 run-in 3

4

-11 to -7w -10 to -6w -8 to -5w -6 to -3w -4 to -2w

Informed consent form

Physical Exam

Confidential

†

5/777 0

x

x

x

x

(x)

x

x

x

6

7

8

9

10

11

12

13

14

15

16

17

18

19 999° 778°°

2w 4w 8w 4m 8m 12m 16m 20m 24m 28m 32m 36m 40m 44m Uns EOS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

S

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

DS

H/W

W

W

W

W

W

W

W W W

W

W

W

W

W

W

W

W

W

W

W

W

Vital signs

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Waist/hip circumference

DS

NYHA Classification (HF signs and symptoms)

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Heart Failure and CV Medications

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Concomitant Medications

DS

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

Height (H) / Weight (W)

Endpoint information

DS

AEs / SAEs

DS

Pregnancy tests

4

DS

x

Plasma BNP and NT-proBNP

DS

x

Plasma/serum biomarkers (including BNP & NT-proBNP) 5 and biobanking

DS

5

x

x

18

x

x

5

x

5

x

5

x

18

x

x x

x

x


x

x

x

Novartis Amended Protocol Version v04 Clean Phase

Screening

Visit

D/S*

Weeks (w) / Months (m) st

1 Urine morning void

6

DS 7

14

2A

2

15


LCZ696 run-in 3

4

†

5/777

8

Complete laboratory assessments 12-lead ECG evaluation

9

Screening log

DS 10

x

(x)

DS

Drug accountability

DS

x

19

x (x) x

x

(x)

x

x

15

16

17

18

19 999° 778°°

(x) x

19

x

x

x x

x x

x

x

x x

x

x

x x

x

x

(x) (x)

x

x

x

x

(x)

x

x

x

x x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

(x)

18

x

12

14

x

DS

KCCQ

13

16

x

Double blind medication dispense Patient Global Assessment

12

x

19

x

x

S

11

x

18

DS

11

10

x

Randomization

Urinalysis (local dipstick)

9

17, 18

x

13

8

x

x

x

DS

Run-in medication dispense

x

7

x x

DS DS

6


x

DS DS

0 18

x

DS

Local laboratory assessments

Abbreviated chemistry panel

x

DS

Pharmacogenetic sampling


Single-blind active run-in Enalapril run-in


Pharmacokinetic sampling

Run-in completion log

1

Confidential

18

x

x

DS

x

x

x

(x)

x

x

x

x

x

x

x

18

x

x

x

x

x

x

18

x

x

x

x

x

x

DS

x

EuroQol (EQ-5D)

DS

x

End of study information

DS


x

Novartis Amended Protocol Version v04 Clean Phase Visit Weeks (w) / Months (m)

Screening D/S*

1

Confidential



2A

2

15


LCZ696 run-in 3

4


†

5/777 0

6

7

8

9

10

11

12

13

14

15

16

17

18

19 999° 778°°


* D: to be documented in the clinical database, S: in the source data and DS: in the database from separate source documentation ** If the trial is extended, Visits 20, 21, 22 and so forth to be performed at the same intervals and with same measurements as at visits 17, 18, 19 and so forth. ° Visit 999 = Unscheduled visit. Assessments marked with (x) are optional procedures that may be performed at the investigator’s discretion. † Visit 5/777 (end of run-in visit) will be completed for patients upon completing or discontinuing from the run-in period. °° 778 (final visit: End Of Study [EOS]) scheduled upon the decision to close the study. 1

Except for unschduled visits when no dose changes will occur and only laboratory samples will be provided, phone calls to IVRS have to be performed at all visits (including unscheduled visits) and when the patient is on study drug interruption.

2

During the single-blind active run-in at Visits 2 (if Visit 2A is conducted), 3, 4 and 5, patient safety will be monitored to ensure eligibility to continue to the next phase until randomization at Visit 5. Reason for not qualifying for randomization must be documented in detail in the eCRFs.

3

Complete physical examination required at Visits 1 and 11 and yearly thereafter up until Visit 778 (end-of-study visit). Short physical exam at interim visits.

4

Women of childbearing potential only. At Visit 1 and in case of a positive urine pregnancy result, a confirmatory serum pregnancy test has to be performed at the central laboratory. A Urine pregnancy test will be performed locally at Visit 5, and yearly thereafter (or up to thrice annually based on local regulatory requirements) up until Visit 778.

5

Plasma/serum biomarkers, biobanking, and first morning urine void samples will be taken only in a subset of patients before morning study drug dose. These samples should be collected at Visit 2 or 2A, whichever occurs first. At Visit 3, only BNP and NT-proBNP plasma samples will be collected.

6

Sites will give the urine collection containers and instructions at Visits 1, 4, 6, and 9. If first morning urine void is collected for Visit 2A, it should not be collected at Visit 2.

7

Patients participating in the PK substudy must also be participating in the biomarker substudy. Pre-dose (trough) samples will be collected at Visits 4 and 7. PK samples will also be collected at pre-dose (trough) and at 0.5 to 2 hours and 3 to 5 hours post-dose at Visit 7.

8

Serum potassium and eGFR.

9

Abbreviated chemistry panel including potassium, BUN, and serum creatinine will be measured at interim visits at the central laboratory or other authorized laboratory.

10

Run-in completion page to be completed for all patients who entered into the run-in period. This may occur at Visit 2 (only if V2A is conducted), 3, 4, or 5.

11

Dipstick urinalysis will be conducted at Visits 1, 5, and yearly thereafter until visit 778. If dipstick is positive, a qualitative microscopic determination, including white blood cells high power field (WBCs/HPF) and red blood cells high power field (RBCs/HPF) will be performed.

12

KCCQ = Kansas City Cardiomyopathy Questionnaire.

13

Screening ECG performed within the 6 months before Visit 1 is accepted.

14

Visit 2A is an optional visit that will be performed only if investigator elects to start patient on single-blind enalapril 5 mg bid instead of directly on single-blind enalapril 10 mg bid.

15

Assessments marked with (x) will only be performed if a patient starts the active run-in period at Visit 2A.

16

PK sampling at pre-dose and at 0.5 to 2 hours and 3 to 5 hours post-dose will be performed at Visit 10 only if not already done at Visit 7.

17

A 10 ml whole blood sample will be collected from a subset of patients for pharmacogenetic testing. May be collected at a subsequent visit if not collected at Visit 5

18

Procedure completed only for patients to be randomized at Visit 777/5

19

Only serum chemistry will be collected at this visit



7.1

Confidential


Information to be collected on screening failures

Patients may discontinue from the study prior to randomization from Visit 1 through Visit 5, prior to any double-blind medication being administered. Patients discontinuing at: • Visit 1 (never received active run-in study drug) are considered screening failures • Visit 2A, Visit 2, Visit 3, Visit 4, or Visit 5 after entering into the run-in and prior to randomization, are considered run-in failures. If a patient discontinues before entering in the run-in treatment period, only the demographic information and Screening Log entry with the reason for discontinuation should be completed on the eCRF. It is not necessary to complete all the required evaluations at the time of discontinuation unless medically indicated. All required evaluations must be performed and clearly documented in the appropriate eCRFs of patients who entered the run-in period and received study medication. This information must include demographics, reason for discontinuation, and AEs and safety data (e.g., hyperkalemia, hypotension, renal dysfunction, and other AEs). Re-screening If a patient is not eligible to enter into the run-in period and screen-fails, the investigator may consider re-screening the patient at a later time if he/she believes that the patient’s condition has changed and may potentially be eligible. In this case, a completely new patient number will be allocated to the subject and he/she will need to re-perform all Visit 1 procedures. A patient who is successfully screened and enters into the active run-in period but is later found not to be eligible for randomization due to intolerance to target doses of enalapril or LCZ696 may be re-screened at a future time if the investigator feels that the circumstances that may have contributed to the patient’s intolerance are no longer present. In this case, a completely new patient number is to be allocated to the subject and he/she will need to reperform all Visit 1 assessments. A patient may be re-screened in this protocol up to two times. A minimum of 2 or 4 weeks must elapse between re-screenings if the patient was never exposed to study medication or if the patient was exposed to the run-in study medication, respectively. This is to ensure all the entry criteria are met, including the required minimum stability period on pre-study medications (refer to Section 5.1). Patient must provide new written informed consent before each time they are to be re-screened.

7.2


Patient demographic and baseline characteristic data to be collected on all patients include: date of birth, age, sex, race, ethnicity and source of patient referral. Relevant medical history/current medical condition data includes data until the start of study drug. Where possible, diagnoses and not symptoms will be recorded. HF medications and other CV medications will be recorded in eCRFs separately from other medications. Likewise, detailed This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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HF history and other relevant CV medical history will be recorded on eCRFs separately from other medical history.

7.3

Treatment exposure and compliance

Compliance will be assessed by the investigator and/or study personnel at each visit using pill counts and information provided by the care giver. This information should be captured in the source document at each visit. Patient compliance should be at least 80% during the doubleblind treatment period. The investigator and/or study personnel will counsel the patient if compliance is below 80%. Study drug accountability will also be determined by the site monitor while performing routine site visits and at the completion of the study. Duration of double-blind study drug exposure will be calculated based upon the start and stop dates recorded in the eCRF.

7.4

Efficacy

7.4.1

Primary and secondary efficacy endpoints

The primary composite endpoint consists of the following components: • CV death • HF hospitalization The target number of primary composite endpoint events is 2,410. The secondary endpoints are: • HF symptoms and physical limitation clinical summary score of the KCCQ (Appendix 5) • All-cause mortality • New onset AF • Composite renal endpoint defined as (1) 50% decline in eGFR compared to baseline, (2) >30 mL/min/1.73m2 decline in eGFR relative to baseline to a value below 60 mL/min/1.73m2, or (3) reaching ESRD. 7.4.2

Endpoint Committee

All of the following events, which could potentially fulfill the criteria for the primary, secondary, or other endpoints will be assessed during the study, including the active run-in period, and reported to the Endpoint Adjudication Committee for adjudication or assessment: • All death events • Unplanned hospitalization for HF • Non-fatal MI • Non-fatal stroke • Resuscitated sudden death (successful resuscitation following cardiac arrest) • New onset atrial fibrillation • Renal dysfunction • Others This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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The Endpoint Adjudication Committee will be responsible for classifying all death events and for determining whether pre-specified endpoint criteria were met for the non-fatal events. Sites are instructed to take a conservative approach when reporting endpoints; if the investigator suspects an endpoint may have occurred, it is best to report the event to the Endpoint Adjudication Committee for the final determination. Novartis’ reporting guidelines for AE and SAE as outlined in Section 8.1 and Section 8.2 must be followed, independent from the circumstance that an event is also reported as a suspected study endpoint. 7.4.3

Estimated glomerular filtration rate (eGFR)

The eGFR to determine eligibility of the patient for screening into the trial will be calculated at Visit 1 from the serum creatinine concentration which will be measured centrally. The eGFR will be further measured at each visit during the run-in period to guide the investigator to take any appropriate action as necessary (e.g., removing the patient from the trial) in case of eGFR decrease (according to the criteria defined in Table 4-2). Estimated GFR will only be calculated using the following formula (Stevens et al 2006): Estimated GFR (mL/min/1.73 m2) = 175 × (standardized SCr in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if female) × (1.212 if black), where SCr is the standardized serum creatinine value

7.4.4

Biomarkers

BNP and NT-proBNP will be obtained in all patients by using the central laboratory at Visit 1 to determine eligibility for screening into the trial. In addition, biomarker measurements will be obtained from serum, plasma, and first morning void (FMV) urine samples in a subset of patients at selected sites at Visits 2, 3 (only BNP and NT-proBNP), 5, 7, and 10 to determine effects of treatments on biomarkers of CV, CHF, or renal risk. These samples will be obtained before patients take their morning study drug dose. The selected biomarkers studied will be ones believed to be relevant to the pathophysiology of the disease processes of CHF, HTN, and/or renal dysfunction. Biomarkers studied may include, but are not limited to: • neurohormones, such as BNP and NT-proBNP, • RAAS biomarkers, such as plasma and urinary aldosterone and plasma renin activity (PRA; only at Visit 5), • renal biomarkers, such as cystatin-C and eGFR (enzymatic creatinine assay), and • the second messenger cGMP (measured both in plasma and FMV urine) To allow indexing of urinary biomarkers, creatinine in FMV urine will also be measured. The list may be changed or expanded further, as it is recognized that new, relevant (nongenomic) biomarkers may be discovered during the process of this study and after its completion. As such, plasma, serum and FMV urine will be biobanked for analysis of yet to be identified diagnostic biomarkers. Details on sample collection, handling and shipment of biomarker samples will be provided to investigators in the laboratory manual.



7.4.5

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Urine albumin to creatinine ratio (UACR) and first morning void urine sampling

First morning void urine samples will be collected from the biomarker substudy patients before taking the morning study drug dose at Visits 2, 5, 7, and 10 for analysis of renal biomarkers and/or electrolytes, such as urinary albumin to creatinine ratio (measured as UACR). The list of biomarkers may be changed or expanded further if new or more relevant (non-genomic) biomarkers are discovered during the process of this study. Details on sample collection, handling and shipment of biomarker samples will be provided to investigators in the laboratory manual.

7.5 7.5.1

Safety Physical examination

A complete physical examination will be performed at Visits 1 and 11 and then at yearly intervals thereafter until the EOS visit. It will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. A short physical exam will include the examination of general appearance and vital signs (BP and pulse). A short physical exam will be at all visits starting from Visit 2, except where a complete physical exam is required (see above). Information about the all physical examinations must be present in the source documentation at the study site. Significant findings that are present prior to the start of study drug must be included in the Relevant Medical History/Current Medical Conditions screen on the patient’s eCRF. Significant findings made after the start of study drug which meet the definition of an AE must be recorded on the AE screen of the patient’s eCRF. 7.5.2

Vital signs

Vital signs will be assessed at every visit. This will include BP and pulse measurements. BP will be measured by using a standard sphygmomanometer with an appropriate size cuff and the non-dominant arm in the sitting position after 5 minutes of rest. 7.5.3

Height, weight, and waist/hip circumference

Height in centimeters (cm) will be measured at Visit 1. Body weight (to the nearest 0.1 kilogram [kg] in indoor clothing without shoes) will be measured at all visits, until the EOS visit. Waist/hip circumference (to the nearest centimeter [cm] in indoor clothing) will be measured at Visit 5 and at the EOS visit. 7.5.4


A central laboratory will be used for analysis of all collected specimens. Details on the collections, shipment of samples and reporting of results by the central laboratory will be provided to investigators in the laboratory manual. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Clinically notable laboratory findings are defined in Appendix 1. Complete laboratory evaluations (hematology, blood chemistry, and urine; Table 7-2) for the assessment of safety in this study will be performed in a fasting state at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit). Complete serum chemistry evaluations for the assessment of safety will be performed at Visits 3, 8, and 9. Electrolyte laboratory evaluations will be included in the abbreviated laboratory assessments at Visits 3 and 4, and at the interim visits starting at Visit 6. Local laboratory may be used for the assessment of potassium values and eGFR during the active run-in period up to the randomization visit (Visit 2, Visit 3, Visit 4, and Visit 5). In addition, local laboratory assessments may be performed on an as-needed basis for unscheduled visits. Categorical renal endpoints (i.e., ≥ 50% decline in eGFR compared to baseline to a value below 60 ml/min/1.73 m2, decline in eGFR by ≥ 30 mL/min/1.73m2 to a value below 60 ml/min/1.73 m2 compared to baseline, and ESRD) have to be calculated and confirmed by two standardized serum creatinine measurements at least one month apart and analyzed by the central laboratory. For this purpose, patients may need to attend an unscheduled visit one month after the study visit. For visits other than the run-in period visits, study procedures may be performed without restriction while the laboratory results are pending. In these cases, the investigator or his/her designee should review the central laboratory results as soon as they become available to decide on whether any adjustments in the patient’s study drug or non-study drug regimen are needed. All central laboratory results will be communicated to the investigators and the sponsor, with the exception of plasma/serum and urinary biomarkers, of which only the Visit 1 BNP and NT-proBNP will be reported to the investigator and the sponsor. Details on the collection, shipment of samples and reporting of results by the central laboratory will be provided to investigators in the laboratory manual. Laboratory values that exceed the boundaries of a notable laboratory abnormality must be commented on by the investigator in the Comments screen of the patient's eCRF and additional laboratory evaluations should be performed, as judged appropriate by the investigator. If the laboratory abnormality induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or medical condition must be entered on the AEs screen of the patient's eCRF. If the laboratory abnormality is the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness category of an AE, then the procedure for rapid notification of SAEs must be followed. Likewise, if the laboratory abnormality leads to discontinuation from the study drug (temporarily or permanently), the patient must be followed until the abnormality resolves or until it is judged to be permanent. This investigation may include continued monitoring by repeat laboratory testing or by performing additional laboratory tests as deemed necessary by the investigator or the Novartis medical monitor.



Table 7-2

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Routine laboratory examinations

Hematology*

Biochemistry*

Urine measurements

Red Blood Cells count White Blood Cells count Platelet Count Hemoglobin Hematocrit WBC Differential

Glucose Sodium Potassium ** Chloride Calcium Blood urea nitrogen (BUN) ** Creatinine ** Total Bilirubin Fractionated bilirubin (if total bilirubin >2x ULN) Aspartate amino-transferase (AST) Alanine amino-transferase (ALT) Alkaline phosphatase Total protein Albumin Uric Acid a Serum Pregnancy Test Lipid profile (total cholesterol, LDL, HDL, and triglycerides) Hemoglobin A1C

UACR (to calculate urinary albumin/creatinine ratio) Urinalysis

b

* List of routine laboratory assessments performed at Visits 1, 3, 5, 8, 9, 11 and yearly thereafter until EOS. Routine assessments at Visits 3, 8, and 9 will include only those listed under Biochemistry, with exception of serum pregnancy test and hemoglobin A1C. ** Laboratory assessments for the abbreviated biochemistry test performed at visits where the complete laboratory test is not performed. a. At Visit 1 and in case of positive urine pregnancy test only. b. In a subset of patients only.

7.5.4.1

Hematology

Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count will be measured at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit) (Table 7-2). 7.5.4.2

Clinical chemistry

Blood urea nitrogen (BUN), glucose, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, hemoglobin A1C, total protein, albumin, uric acid, and lipid profile will be measured at Visits 1, 5, and 11 and then at yearly intervals until the end of the study and at Visit 778 (EOS visit). Routine serum chemistry performed at Visits 3, 8, and 9 will include BUN, glucose, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, total protein, albumin, uric acid, and lipid profile. Fractionated bilirubin will be performed for all patients whose total bilirubin value is > 2x ULN. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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BUN, serum potassium, and serum creatinine value for eGFR calculation will be obtained from patients at Visit 2 (only if Visit 2A is performed), Visit 4 and at every visit when a complete serum chemistry test is not done (i.e., Visits 6, 7, 10, 12, 13, 15, 16, 18, and 19). 7.5.4.3

Potassium and eGFR assessments by local laboratory

In addition to the central laboratory assessments, potassium and eGFR, may be measured locally during the active run-in period (Visit 2, Visit 3, Visit 4), up to the randomization visit (Visit 5) to determine eligibility of the patient into the trial. Local potassium and eGFR measurements may also be performed during the double-blind treatment period, mainly at the unscheduled visits, to monitor the tolerability to study medication dose administered and adjust medication dose if needed. The results of the local laboratory during the active run-in period will not be reconciled with the central laboratory measurements. 7.5.4.4

Urinalysis

Dipstick-test determination of specific gravity, pH, blood, total protein, bilirubin, ketones, and leukocytes will be measured at Visits 1, 5, 11 and then at yearly intervals until EOS. If dipstick is positive, a qualitative microscopic determination, including white blood cells high power field (WBCs/HPF) and red blood cells high power field (RBCs/HPF) will be performed. 7.5.5


A standard 12-lead ECG will be performed at screening (Visit 1, unless an ECG performed within the last 6 months is available), randomization (Visit 5), Visit 11, and at yearly intervals thereafter until the end of the study up till Visit 778 (EOS visit). Interpretation of the tracing must be made by a qualified physician and documented on the ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient initials, patient number, and date and kept in the source documents at the study site. Only clinically significant abnormalities should be reported on this page. Clinically significant abnormalities should also be recorded on the relevant medical history/current medical conditions or AE eCRF page. 7.5.6

Pregnancy and assessments of fertility

All female patients of childbearing potential will have a serum pregnancy test performed at Visit 1 (central laboratory). Additionally, these patients will have urine pregnancy tests performed at the investigational sites at Visit 5 and yearly thereafter until Visit 778. More frequent urine pregnancy testing during the double-blind treatment period (up to three times per year) will be performed in all females of childbearing potential based on local regulatory requirements. In case of a positive urine pregnancy result a confirmatory serum pregnancy test will be performed at the central laboratory. See Section 6.5.5 and Section 8.3 for details on pregnancies. 7.5.7

Angioedema

Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with airway This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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compromise. Although, the mechanism is not fully understood, bradykinin has been implicated as the putative mediator. Therefore, medications that raise the levels of endogenous bradykinin by inhibiting the enzymes responsible for its breakdown, such as ACE, aminopeptidase P, and NEP, may result in this potentially dangerous side effect. Simultaneous inhibition of multiple breakdown pathways of bradykinin is thought to significantly increase the risk of occurrence of angioedema (Sulpizio et al 2004). Section 4.3.2 details how to avoid the simultaneous inhibition of the ACE and NEP pathways by overlapping exposure to LCZ696 and enalapril at Visit 3 (start of LCZ696 run-in) and at Visit 5 (randomization). The method outlined in Section 4.3.2 is expected to provide at least 36 hours free of significant simultaneous inhibition of NEP and ACE, thereby minimizing the potential risk of occurrence of angioedema. This 36-hour washout period is expected to present minimal risk to patients, especially since all patients will continue using their other background HF medications during this period. The procedure for reporting angioedema-like events is outlined in Section 8.5.

7.6

Other assessments

7.6.1


Analyses will be undertaken, as appropriate, to assess the effects of treatments on healthcare resource utilization (RU) parameters. At Visit 1 (screening), prior hospitalizations for CV-related complications, relevant medical conditions and therapies, and prior procedures will be collected. At Visit 6 and each subsequent scheduled visit, the level of health care resource utilization will be assessed through procedures rendered during hospital stays. The frequency and duration of any inpatient hospitalization will be recorded along with the primary reason for the hospital admission and discharge. All attempts will be made to collect RU variables in all patients throughout the duration of the study in order to avoid selection bias. There may also be circumstances when the collection of such data after completion of the study may be warranted. 7.6.2

Heart failure symptoms reduction and reduction in physical limitation

The KCCQ is a self-administered questionnaire and requires, on average, 4-6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. A change of 5 points on the scale scores, either as a group mean difference or an intra-individual change appears to be clinically significant, based on comparisons of changes in the scale scores to clinical indicators and patient global reports of change. The KCCQ is a valid, reliable and responsive health status measure for patients with CHF and may serve as a clinically meaningful outcome in CV clinical research, patient management and quality assessment (Green et al 2000). The HF symptoms and physical limitation domains scores show the best the correlation for improvements following a CHF exacerbation (Green et al 2000). Thus, one of the secondary endpoints is a clinical summary score based on the HF symptoms and physical limitation This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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domains scores of the KCCQ at 8 months. All other domains will be analyzed as exploratory endpoints, as the instruments will be administered as a whole. The KCCQ questionnaire will be completed at Visits 5, 9, 10, 11, 14, 17, and 778 (EOS). The KCCQ is available in a number of validated translations. However, patients in whose language a validated translation of the KCCQ is not available will be exempt from completing this instrument. 7.6.3

Clinical composite score

The clinical composite score is one of the exploratory endpoints of this study. It is derived from two instruments: the patient global assessment and the NYHA functional classification. The patient global assessment is a seven-point patient self-evaluation scale. At Visit 5 (randomization), the investigator should call the patient’s attention to how he/she feels about his/her condition at that time and to explain that periodically the patient will be asked to rate how he/she feels compared to at this point in the study. Subsequently, patients will be asked to rate how well they feel compared to Visit 5 (randomization/baseline) (COPERNICUS Investigators 2002). This evaluation is combined with the NYHA functional class, one of the most reliable instruments for rating HF patients’ functionality, and with occurrence of death and hospitalization for heart failure to arrive at an overall evaluation of whether a patient is considered to have improved, worsened, or unchanged after a pre-specified period of time (Packer 2001). The patient global assessment will be conducted at Visits 9, 10, 11, 14, 17, and 778 (EOS). HF signs and symptoms/NYHA classification will be conducted at all visits. 7.6.4

EuroQol (EQ-5D)

The EuroQol (EQ-5D) (Appendix 6) is an instrument used to assess the current health status of patients. It consists of five domains and one visual analogue scale. This instrument assesses morbidity, self-care, usual activity, pain, and anxiety and depression of patients. The EQ-5D will be completed at Visits 5, 9, 10, 11, 14, 17, and 778 (EOS). The EQ-5D is available in a number of validated translations. However, patients in whose language a validated translation of the EQ-5D is not available will be exempt from completing this questionnaire. 7.6.5

Pharmacokinetics

Approximately 400 of the patients participating in the biomarker substudy will also participate in the population PK substudy during the run-in and double-blind treatment periods at select study centers. Plasma levels of valsartan, AHU377, and LBQ657 will be determined from these patients. During the run-in period, participating patients will provide a trough (Cmin) PK sample on the morning of Visit 4 prior to up-titration. During the double-blind treatment period, a total of 3 samples will be collected either at one visit or at multiple visits depending on the availability of the patient and site staff. The samples will be collected at the following intervals at Visit 7: • Sample #1: pre-dose trough (immediately before the administration of study drug) This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Sample #2: 0.5 to 2 hours post-dose Sample #3: 3 to 5 hours post-dose

If the PK samples are not taken at Visit 7, then they will be taken at Visit 10. Site should make every effort to collect sample as close to the interval periods as possible. The exact time of the treatment administration, dose of LCZ696, sample number, and time of sample collection will be recorded for each sample collected on the Pharmacokinetic Sample eCRF. Patients participating in the PK substudy are not required to provide all three required blood samples during the same study visit. However, samples should always be taken when the patient is expected to be at steady state, i.e., has been receiving the study drug regularly on the same dose level as prescribed for at least 1 week. Special instructions on preparation, labeling, storage, and shipment of PK samples will be provided to the sites in a separate document. 7.6.6


The study includes an optional pharmacogenetic component to be conducted in some of the participating sites, which requires a separate signed written informed consent if the patient agrees to participate. The Investigator where this component of the study is conducted will offer this option to the patient. Exploratory pharmacogenetics research studies are planned as a part of this study with the objectives of identifying inherited genetic factors which may (1) be related to chronic heart failure, (2) predict response to treatment with LCZ696, (3) predict genetic predisposition to side effects. The goal is to develop a better understanding of chronic heart failure and how subjects respond to LCZ696. The genetic markers (or polymorphisms) that may be studied that relate to the etiology of chronic heart failure include ACE I/D, which was reported to be associated with event-free survival in patients with heart failure. Polymorphisms in genes that relate to the mechanism of action may include AGT1R +1166A/C, AGT1R -535C/T, AGT1R +573C/T, AGT1R 810A/T and AGT M235T. Despite continuing advances in genetics research, not all of the polymorphisms relevant to drug metabolism, drug action and chronic heart failure have been identified. Therefore, additional polymorphisms may be added within the restricted scope of these studies as described above. In addition, recent advances in genotyping technologies have made genome-wide association (GWA) studies possible. GWA studies may also be undertaken within the restricted scope of these studies as described above. Sample collection: One blood sample will be collected from these patients at Visit 5 (randomization visit) or any visit thereafter. After collection, the sample must be inverted several times to prevent clotting. Only one blood sample should be taken from the patient for this pharmacogenetic study. These samples will be shipped to the central lab for DNA extraction. The extracted DNA will then be transferred to Novartis Pharmaceuticals Corporation for pharmacogenetic analysis and storage. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Any DNA derived from the sample that remains after analysis may be stored for up to 20 years to address scientific questions related to LCZ696, chronic heart failure or reduced ejection fraction. 7.6.7

Other biomarkers

New, relevant, biomarkers that may be discovered during the process of this study and after its completion may be analyzed in addition to those already defined in Sections 7.4.4 and 7.4.5.

8

Safety monitoring

8.1

Adverse events

An AE is the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. Study drug includes the investigational drug under evaluation and the comparator drug or placebo that is given during any phase of the study. Medical conditions/diseases present before starting study drug are only considered AEs if they worsen after starting study drug. Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, or require therapy. The occurrence of AEs should be sought by non-directive questioning of the patient at each visit during the study. AEs also may be detected when they are volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. All AEs must be recorded on the Adverse Events CRF with the following information: 1. the severity grade [mild, moderate, severe] 2. its relationship to the study drug(s) (suspected/not suspected) 3. its duration (start and end dates or if continuing at final exam) 4. whether it constitutes a serious adverse event (SAE) An SAE is defined as an event which: •

is fatal or life-threatening

•

results in persistent or significant disability/incapacity

•

constitutes a congenital anomaly/birth defect

•

requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: • routine treatment or monitoring of the studied indication, not associated with any deterioration in condition • elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since the start of study drug



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treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission social reasons and respite care in the absence of any deterioration in the patient’s general condition

is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above

Unlike routine safety assessments, SAEs are monitored continuously and have special reporting requirements; see Section 8.2. All AEs should be treated appropriately. Treatment may include one or more of the following: no action taken (i.e. further observation only); study drug dosage adjusted/temporarily interrupted; study drug permanently discontinued due to this AE; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The action taken to treat the AE should be recorded on the Adverse Event CRF. Once an AE is detected, it should be followed until its resolution or until it is judged to be permanent, and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the outcome. Novartis may request additional information on specific adverse events of interest and may make requests to perform additional diagnostic tests to further assess the safety profile of the study medications. Such information may include diagnostic procedure reports, discharge summaries, autopsy reports, and other relevant information that may help in assessing the reported adverse event. All additional information will be de-identified prior to collection by Novartis or its agents. Information about common side effects already known about the investigational drug can be found in the Investigator’s Brochure (IB) or will be communicated between IB updates in the form of Investigator Notifications. This information will be included in the patient informed consent and should be discussed with the patient during the study as needed.

8.2

Serious adverse event reporting

To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has provided informed consent and until 30 days after the patient has stopped study participation must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after this 30 day period should only be reported to Novartis if the investigator suspects a causal relationship to the study drug. Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode, regardless of when the event occurs. This report must be submitted within 24 hours of the investigator receiving the follow-up information. An SAE that is considered completely unrelated to a previously reported one should be reported separately as a new event. In addition if required by the local health authority or ethics committee, the investigator should report all expected and unexpected serious adverse events to these authorities and also inform the institutional review board at the study institution. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form. The investigator must assess the relationship to study drug, complete the SAE Report Form in English, and send the completed, signed form by fax within 24 hours to the local Novartis Drug Safety and Epidemiology (DS&E) Department. The telephone and telecopy number of the contact persons in the local department of DS&E, specific to the site, are listed in the investigator folder provided to each site. The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site. Follow-up information is sent to the same person to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the blind was broken or not, and whether the patient continued or withdrew from study participation. If a SAE is unexpected, i.e., the event is not previously documented in the Investigator’s Brochure (new occurrence) and is suspected to be related to the Novartis study drug, this event is considered a Suspected Unexpected Serious Adverse Reaction (SUSAR). A DS&E associate may urgently require further information from the investigator for Health Authority reporting purposes. In general, it is Novartis policy to unblind SUSARs for regulatory reporting. If the unblinding shows that the Novartis drug is involved, Novartis will issue an Investigator Notification (IN) to inform all investigators participating in any study with the same drug that this SUSAR has been reported. In addition, SUSARs will be collected and reported to the competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory requirements in participating countries. Study-specific unblinding rules for SUSARs that are disease related and present efficacy endpoints The integrity of this study may be compromised, if the blind is systematically broken for SUSARs that could also be efficacy endpoints [for relevant EU guidance please see European Commission ENTR/CT13 Guideline (2006), Chapter 5.1.9. Managing adverse reactions/events in trials with high morbidity and high mortality diseases and where efficacy end-points could also be SUSARs]. Therefore, the rules for unblinding will apply as follows. • A SUSAR will not be unblinded, if it could represent one of the following pre-specified disease related endpoints: CV death, HF hospitalization, worsening of renal function, non-fatal MI, non-fatal stroke, CV hospitalizations and prolongation of existing CV hospitalization, new onset of atrial fibrillation, coronary revascularization procedures. In addition, no report to competent authorities and relevant Ethics Committees (EC) and no issuance of an IN will occur. An external independent Data Monitoring Committee (DMC) (see Section 8.4) has been previously appointed and will review efficacy and safety data of the ongoing trial on a regular basis. DMC opinion and recommendations will be notified by Novartis as soon as possible to the competent authorities and the ECs where they qualify for expedited reporting. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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If specifically requested by a local Health Authority, pre-specified endpoints (see above) that also meet the criteria for SUSARs will be expedited to this Health Authority as blinded reports. INs will not be issued for these events. Any other SUSAR that will not meet the pre-specified disease related endpoints as mentioned above will be unblinded and a report to competent authorities and relevant ethics committees and issuance of an IN will occur.

8.3

Pregnancies

In case a patient becomes pregnant, or plans to become pregnant, the study drug must be interrupted before contraception is discontinued (or, from the date the pregnancy becomes known) for the entire duration of the pregnancy and lactation period (or, for the entire duration that contraception is discontinued). To ensure patient safety, each pregnancy in a patient on study drug must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the investigator to the local Novartis DS&E Department. Pregnancy follow-up should be recorded on the same form and should include an assessment of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form.

8.4


An external data monitoring committee (DMC) independent of Novartis will be appointed to monitor the study conduct and to review the results of the IA from the study and to determine if it is safe to continue the study according to the protocol. If applicable, the recommendation may include any new relevant safety issues(s) identified by the DMC during the evaluation or recommendation to stop for early proof of efficacy. Any major recommendation from the DMC will be communicated to the Executive Committee and must be reviewed and ratified by the Executive Committee prior to its enactment. The membership of the DMC and the responsibilities of the DMC and Novartis will be defined in a separate document entitled the ”Data Monitoring Committee Charter.” The DMC Charter will include information about data flow, purpose and timing of DMC meetings, guidance in the decision making process, communication strategy, procedures for ensuring confidentiality, procedures to address conflicts of interest and statistical monitoring guidelines.

8.5

Reporting angioedema-like events

It is important that the investigator pays special attention to any swelling or edema that may resemble angioedema or angioedema-like events that may be reported by patients. If such an event occurs, the investigator will complete an Adjudication Questionnaire for an Angioedema-like Event form (provided by Novartis) to summarize the event, its treatment, and its ultimate outcome and communicate this report to Novartis as soon as possible. Followup reports must be communicated to Novartis as soon as new information regarding the event This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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becomes available. All hospital records related to the event must be communicated to Novartis. Occasionally, the investigator may be contacted by the Novartis regarding AEs that were reported on behalf of patients that may resemble an angioedema-like event. The investigator or his/her delegated staff must complete the required report forms and supply the required medical records for such events, regardless of whether the investigator views the event in question as angioedema or not. All angioedema reports will be forwarded to an angioedema adjudication committee by Novartis for assessment. Submission of an angioedema report is not a substitution for the submission of a SAE report. If an angioedema-like event satisfies the definition of a SAE, the investigator must submit a SAE report (as described in Section 8.2) in addition to the Adjudication Questionnaire for an Angioedema-like Event.

9

Data review and database management

9.1

Site monitoring

Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis representative will review the protocol and eCRFs with the investigators and their staff. During the study, the field monitor will visit the site regularly to check the completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug is being stored, dispensed, and accounted for according to specifications. Key study personnel must be available to assist the field monitor during these visits. The investigator must maintain source documents for each patient in the study, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, laboratory data, electrocardiograms, and the results of any other tests or assessments. All information on eCRFs must be traceable to these source documents in the patient's file. Data not requiring a separate written record will be defined before study start and will be recorded directly on the CRFs. The investigator must also keep the original informed consent form signed by the patient (a signed copy is given to the patient). The investigator must give the monitor access to all relevant source documents to confirm their consistency with the eCRF entries. Novartis monitoring standards require full verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will be used for all primary and safety variables. Additional checks of the consistency of the source data with the eCRFs are performed according to the study-specific monitoring plan. No information in source documents about the identity of the patients will be disclosed.

9.2

Data collection

Designated investigator staff will enter the data required by the protocol into the Electronic Case Report Forms using fully validated software that conforms to 21 CFR Part 11 This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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requirements. Designated investigator site staff will not be given access to the EDC system until they have been trained. Automatic validation programs check for data discrepancies and, by generating appropriate error messages, allow the data to be confirmed or corrected before transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify that the data entered into the Electronic Case Report Forms are complete and accurate. After database lock, the investigator will receive a CD-ROM or paper copies of the patient data for archiving at the investigational site.

9.3

Database management and quality control

Novartis staff, or CRO staff working on behalf of Novartis, review the data entered into the eCRFs by investigational staff for completeness and accuracy and instruct the site personnel to make any required corrections or additions. Obvious errors are corrected by Novartis personnel or CRO staff working on behalf of Novartis. Queries are sent to the investigational site using an electronic data query. Designated investigator site staff is required to respond to the query and confirm or correct the data. If the electronic query system is not used, a paper Data Query Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff who will make the correction to the database. The signed copy of the Data Query Form is kept at the investigator site. Concomitant medications entered into the database will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. Medical history/current medical conditions and AEs will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology. Laboratory samples will be processed centrally and the results will be sent electronically to Novartis (or a designated CRO). Randomization codes and data about all study drug dispensed to the patient and all dosage changes will be tracked using an Interactive Voice Response System. The system will be supplied by a vendor, who will also manage the database. The database will be sent electronically to Novartis (or a designated CRO). At the conclusion of the study, the occurrence of any emergency code breaks will be determined after return of all code break reports and unused drug supplies to Novartis. The occurrence of any protocol deviations will be determined. After these actions have been completed and the database has been declared to be complete and accurate, it will be locked and the treatment codes will be unblinded and made available for data analysis. Any changes to the database after that time can only be made by joint written agreement between the Global Head of Biostatistics and Statistical Reporting and the Global Therapeutic Area Head. Pharmacogenetic samples To maximize confidentiality, all samples and the information associated with the samples will be double-coded to prevent the exposure of the subject’s information and identity. This double-coding process allows Novartis to go back and destroy the sample at the subject’s request. In addition, sample information is stored in one secured database while genetic data is stored in an independent secured database. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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The use of pharmacogenetics to search for biomarkers of disease and drug action is exploratory. Any results from this pharmacogenetic study will not be placed in the patient’s medical records.

10

Data analysis

10.1

Populations for analysis

The following populations will be used for the statistical analyses: The full analysis set (FAS) will consist of all randomized patients with the exception for those patients who have not been qualified for randomization and have not received study drug, but have been inadvertently randomized into the study. Following the intent-to-treat principle, patients will be analyzed according to the treatment to which they were assigned at randomization. Efficacy variables will be analyzed based on the FAS as the primary population. The Safety Population (SAF) will consist of all randomized patients who received at least one dose of study drug. Patients will be analyzed according to the treatment actually received. The safety population will be used for the analyses of safety variables. The Per-protocol (PP) population will be a subset of the FAS which will consist of the patients who do not have major deviations from the protocol procedures in the double-blind study stage. Major protocol deviations will be pre-specified prior to unblinding treatment codes for analyses. This supplemental efficacy population will be used to support the primary analysis results.

10.2


Baseline value is defined as the last non-missing assessment prior to the first dose of randomized study medication unless specified otherwise. Summary statistics will be provided by treatment group for demographics and baseline characteristics, including age, age group ( median) • AF at baseline (yes/no) • Hypertension at baseline (yes/no) This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Prior RAAS drug at screening (ACEI/ARB) Use of β-blocker at baseline (yes/no) Use of aldosterone antagonists at baseline (yes/no) Previous hospitalization for HF (yes/no) Time since diagnosis of HF (three groups: ≤1 year; 1 to 5 years; >5 years)

10.5

Analysis of secondary objectives

10.5.1

Secondary efficacy variables

Please refer to Section 3.2 for the secondary efficacy objectives. The corresponding secondary efficacy variables are listed below: • Change from baseline to month 8 in clinical summary score for HF symptoms and physical limitations assessed by KCCQ • Time to all-cause mortality • Time to new onset AF • Time to the first occurrence of (1) a 50% decline in eGFR relative to baseline, (2) >30 mL/min/1.73 m2 decline in eGFR relative to baseline, or (3) reaching ESRD. 10.5.2

Analysis of secondary efficacy variables

The secondary hypotheses will be tested and statistical inferences will be made only if the primary hypothesis is rejected. The four secondary efficacy variables will be tested for superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LCZ696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. As indicated in Figure 10-1, after rejection of the primary null hypothesis (H10), the sequentially rejective multiple test procedure for the secondary variables is illustrated below: • The initial allocation of significance levels are 0.2α, 0.8α, 0α, and 0α for the comparisons of KCCQ clinical summary score (noted as H210), all-cause mortality (noted as H220), new onset AF (noted by H230), and the composite renal endpoint (noted as H240), respectively. • If both of the hypotheses H210 and H220 are rejected at the initially assigned alpha levels, then H230 (the new onset AF endpoint) will be tested at the level of alpha. • If H230 is rejected at this level, then full α will be passed to test H240. • If H230 is not rejected at this α level, then no further hypothesis will be formally tested. • If the hypothesis H220 is rejected and H210 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.8α. • If H230 is rejected at this 0.8α level, then 0.8α will be passed to test H240. If H240 is rejected at 0.8α level, then 0.4α (1/2 of 0.8α) will be passed to H210. Subsequently, H210 will be re-tested at 0.6α level (0.2α + 0.4α). This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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•

•

If H230 is not rejected at this 0.8α level, then no further hypothesis will be formally tested. If the hypothesis H210 is rejected and H220 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.2α. • If H230 is rejected at this 0.2α level, then 0.2α will be passed to test H240. If H240 is rejected at 0.2α level, then 0.1α (1/2 of 0.2α) will be passed to H220. Subsequently, H220 will be re-tested at 0.9α level (0.8α + 0.1α). • If H230 is not rejected at this 0.2α level, then no further hypothesis will be formally tested.

Figure 10-1


0.2α

0.8α

H210

H220 0α

1

1

H230 1/2

0α

1

1/2

H240 H210 denotes the null hypothesis for the comparison of KCCQ clinical summary score. H220 denotes the null hypothesis for the comparison of all-cause mortality. H230 denotes the null hypothesis for the comparison of new onset AF. H240 denotes the null hypothesis for the composite renal endpoint.

For publications, these secondary variables may be further assessed using full level of alpha without consideration of multiplicity adjustment. Analysis of KCCQ clinical summary score as continuous variable The KCCQ instrument includes several domains. Only the domains that address HF symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is computed as the mean of the following available domain scores: • Physical limitation score • Total HF symptom score The clinical summary score of KCCQ will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit, and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance for each treatment group. The primary treatment comparison between LCZ696 and This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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enalapril is to be made at Month 8. The analysis will be performed based on all available data in the FAS and based on likelihood method. The estimated treatment effect with the associated confidence interval at Month 8 will be provided. Analysis of time to all-cause mortality The time to all-cause mortality will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided confidence interval will be provided in the FAS. The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of all-cause mortality will be provided by treatment group. Analysis of time to new onset AF The time to new onset AF will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided confidence interval will be provided in the FAS (subset of patients without AF history). The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of new onset AF will be provided by treatment group. Analysis of time to composite renal endpoint The time to composite renal endpoint will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided confidence interval will be provided in the FAS. The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of composite renal endpoint will be provided by treatment group.

10.6

Analysis of exploratory objectives

10.6.1.1 Analyses of exploratory variables The variables planned to be analyzed are provided in the exploratory objectives in Section 3.3. In general, exploratory variables (Section 3.3) will be analyzed in the FAS unless specified otherwise. Statistical tests will be performed at the two-sided significance level of 0.05. To better satisfy the normality assumption, the log-transformation will be taken on each biomarker prior to statistical analysis. There will be no multiplicity adjustment for analysis of exploratory variables. Analysis of time-to-events Time-to-event variables will be analyzed using the Cox proportional hazard model with treatment and region as fixed effect factors. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided.



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Analysis of continuous variables Continuous variable will be analyzed using ANCOVA model with treatment and region as fixed effect factors. Additionally, the baseline value of the corresponding variable may be included as a covariate if appropriate. The estimated treatment effect and the corresponding two-sided 95% confidence interval will be provided. The last-observation-carried-forward (LOCF) technique will be used to impute the missing value if the last observation is assessed at post-randomization. Analysis of ordinal variables Binary variables will be analyzed using logistic regression with treatment and region as fixedeffect factors and baseline value as a covariate, if appropriate. Other ordinal variables will be analyzed using Cochran-Mantel-Haenszel (CMH) test for different row (treatment) means, adjusted for region, based on modified ridit scores which are also referred to as standardized midranks. The LOCF technique will be used to impute the missing value if the last observation is assessed at post-randomization. Analysis of eGFR slope For each patient, the eGFR slope will be calculated by fitting the patient’s eGFR assessments into a linear regression model with time as the independent variable. The derived eGFR slope will be analyzed using an ANCOVA model with baseline eGFR as the covariate and treatment and region as fixed-effect factors. The estimated treatment effect and the associated confidence interval for the eGFR slope will be provided. Days alive out of the hospital during the first 12 months The duration in days of hospital-free survival at Month 12 will be summarized by treatment group, and descriptive statistics (n, mean, standard deviation, median, max, and min) will be provided. Death within the first 12 months will be treated as zero-duration of hospital-free survival, regardless of how many days the patient was alive and out of the hospital prior to month 12. The mean difference between treatment groups will be compared using t-test and 95% confidence interval will be provided.

10.7

Safety

The safety and tolerability assessments are listed below: • AEs and SAEs • Sitting systolic, diastolic BP, and pulse pressure • Heart rate • Symptomatic hypotension • Angioedema • Laboratory values • Hyperkalemia This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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Renal dysfunction ECG changes

The assessment of safety will be based primarily on the frequency of adverse events, SAEs, and laboratory abnormalities. Other safety data will be summarized as appropriate. The incidence of treatment-emergent adverse events (new or worsened) will be summarized by primary system organ class, preferred term, severity, and relationship to study drug. In addition, the incidence of death, SAEs, and AEs leading to discontinuation will be summarized separately by primary system organ class and preferred term. Laboratory data will be summarized by presenting shift tables using extended normal ranges (baseline to most extreme post-baseline value), by presenting summary statistics of raw data and change from baseline values (mean, medians, standard deviations, ranges) and by the flagging of notable values in data listings. Data from other tests (e.g., ECG or vital signs) will be listed, notable values will be flagged, and any other information collected will be listed as appropriate. Safety analyses will be performed based on the safety population. There will be no formal statistical inference analysis. In addition to the above safety analyses for the randomized double-blinded treatment period, the AEs, SAEs, and reasons for active run-in failures will be summarized for the active run-in period. A frequency table will be provided by dose and reason for those patients who are unable to tolerate LCZ696 during the active run-in period.

10.8


Data relating to resource utilization will be used to describe medical resources used by the study participants. Only descriptive statistics of resources utilization data will be provided by treatment group.

10.9

Health-related quality of life

The reduction in combination of HF symptoms and physical limitation scores assessed by the clinical summary score of the KCCQ is one of the secondary efficacy endpoints. Please refer to Section 7.6.2 for more details. As discussed in Section 10.5.2, the clinical summary score will be analyzed using ANCOVA. All other domains will be analyzed similarly as exploratory endpoints, as the instruments will be administered as a whole.

10.10

Pharmacokinetics

Steady-state PK time profile of valsartan, AHU377, and LBQ657 will be analyzed by graphical methods to determine the appropriate structural PK model to fit the data. Following this, a population PK model will be developed using the plasma time profile patient-level data from this study and/or in combination with PK data from other studies with LCZ696 to quantify the PK of valsartan, AHU377, and LBQ657 and test for significant covariates that influence their PK. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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The exploratory pharmacogenetic studies are designed to investigate the association between genetic factors (genotypes) and clinical assessments (phenotypes) which are collected during the clinical trial. Without prior evidence of a strong association, a number of possible associations are evaluated with exploratory analyses. A range of statistical tests (chi-square tests, ANCOVAs, linear and logistic regression) are used for the analyses. Additional data, from subsequent clinical trials, are often needed to confirm associations. Alternatively, if the numbers of subjects enrolled in the study are too small to complete proper statistical analyses, these data may be combined, as appropriate, with those from other studies to enlarge the data set for analysis.

10.12

Biomarkers

Biological markers will be collected in a subset of patients (see Sections 7.4.4 and 7.4.5). Visit 1 will be considered baseline for BNP and NT-proBNP, while Visit 2 will be considered baseline for all other biomarkers. For the FAS, summary statistics by treatment group will be performed for the baseline values, the post-baseline values, and the change from baseline and from Visit 5 (randomization visit) to Visit 6 (2 weeks) and Visit 10 (8 months).

10.13

Pharmacodynamics

Not applicable.

10.14

Sample size calculation

The sample size estimation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the efficacy interim analyses currently planned (Section 10.16). The targeted sample size mainly is driven by the CV mortality component of the primary composite endpoint. With a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril for CV mortality, using the log-rank test. Assuming an annual CV death rate of 7% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months, a total sample size of 7,980 patients will be required to obtain 1,229 CV deaths. By randomizing 7,980 patients in the study, assuming the same enrollment period, follow-up duration same as above, 15% reduction in hazard, and an annual primary event rate of 14.5% in the enalapril group, it is expected to attain greater than 97% power to detect a difference between treatments for the primary composite endpoint. This, in turn, corresponds to a total number of at least 2,410 patients with primary events during the course of the trial. The assumption of 14.5% annual event rate for the primary composite endpoint is based on the CHARM-Added trial (CHARM Investigators and Committees 2003). In that study the reported annual event rate was 14.1% in the candesartan group and 16.6% in the placebo group. In CHARM-Added all patients received ACEIs, such as enalapril, as background therapy, although the ACEIs may not have been administered at their top doses. Hence, an estimate of the annual primary event rate between the candesartan and placebo group in CHARM-Added would provide a reasonable estimate for event rate for the active comparator This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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enalapril in the current study. Assuming further improvement in underlying HF therapy within the past 5 years since CHARM-Added was conducted, a more conservative annual rate of 14.5% was chosen for sample size calculation. The 7% CV mortality annual event rate is estimated from the CHARM-Added trial in a similar manner.

10.15

Power for analysis of critical secondary variables

The tests of secondary variables are part of the global testing strategy. For the change from baseline to Month 8 in clinical summary score assessed by KCCQ, the above sample size will provide 96~99% individual power to detect a treatment difference of 2 points at the one-sided significance level of 0.00463 (i.e., 0.02314 × 0.2), assuming a standard deviation between 15 and 20. A standard deviation of 15 was observed in the published literature (Flynn et al 2009). For time to all-cause mortality, the above sample size will provide approximately 87% individual power to detect a 15% reduction in hazard at one-sided significance level of 0.0185 (i.e. 0.02314 × 0.8). Assuming an annual event of 9% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months. The numbers in the assumption are estimated based on the CHARM-low LVEF trial (Young et al 2004). For time to new onset of AF, the results from the previous published studies suggest that the annual event rate of the comparator group will be around 4%. There is an enrollment period of 18 to 22 months and a minimum follow-up of 21 months. It is expected that two-thirds of patient population will have no AF history, therefore about 5320 patients (2660 per treatment group) will be included in the analysis of NOAF. Based on these assumptions, at one-sided significance levels of 0.004628 (i.e., 0.02314 × 0.2), 0.0185 (i.e., 0.02314 × 0.8) and 0.02314, the above sample size will provide about 87%, 95% and 96% power, respectively, to detect a reduction of 30% in hazard. The numbers in the assumption are estimated based on the EMPHASIS-HF and Val-HeFT trials (Swedberg et al 2012, Maggioni et al 2005). For time to composite renal endpoint, the above sample size will provide about 80% power to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.02314 and 0.004628 (i.e., 0.02314 × 0.2), respectively. The above sample size will provide about 75% and 90% power, respectively, to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.0185 (i.e., 0.02314 × 0.8). It is assumed for the annual rate to be 0.021 based on the CHARM trials and AASK trial (Wright, Jr 2002).

10.16

Interim analysis

It is planned to have three interim efficacy analyses. The cutoff dates for the interim analyses are planned to be approximately at 1/3, 1/2 and 2/3 of information time (i.e. approximately 804, 1205 and 1607 patients, respectively, with a primary event of either CV death or HF hospitalization). However, some adjustment to the frequency and time for interim analyses may be made to coincide with the DMC meetings. One-sided testing will be performed and appropriate statistical adjustments for the interim analyses actually performed will be made to control the overall type-I error of 0.025. For each interim analysis, the analysis dataset will comprise all patients who were randomized before the cutoff date. This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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The Haybittle-Peto type of boundary will be used for the interim efficacy analyses to assess superiority. The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (one-sided) at the first interim analysis and 0.001 (one-sided and nominal) at the second and third interim analyses. In case additional interim efficacy analysis is required, the alpha spending function approach will be used to readjust the alphas used for the additional interim and final analyses (Lan and DeMets 1983). In addition to the primary composite endpoint, the CV mortality component will also be analyzed at each interim efficacy analysis. When 1/3, 1/2, and 2/3 of the total number of primary patient events occur, approximately 410, 614 and 819 CV deaths, respectively, are also expected. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the above planned boundary are obtained for both primary composite endpoint and CV death component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment for the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. The proposed futility boundaries are: -1.312, 0, and 0.5 in Z-scale, which corresponds to 1.100, 1.000, and 0.975 in hazard ratio scale (LCZ696 versus enalapril). The impact on statistical power is 50% increase, >20% decrease

Hemoglobin


Hematocrit


WBC count


Platelet count


Blood Chemistry ALT (SGPT)

>150% increase

AST (SGOT)

>150% increase

BUN

>50% increase

Creatinine

>50% increase



Total bilirubin

>100% increase

CPK

>300% increase

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Alkaline phosphatase >100% increase Potassium


Chloride


Calcium


Uric acid

>50% increase

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Appendix 2: Treatment guidelines for hyperkalemia (serum potassium greater than or equal to 5.3 mmol/L)

General principles Elevation of potassium levels above the predefined values should be repeated and confirmed before any action is taken. Any patient who experiences a potassium level ≥ 5.5 mmol/L confirmed by repeated testing at Visit 3 or at Visit 5 should be withdrawn from the study. Any patient with a serum potassium > 5.3 mmol/L after randomization requires regular, repeated checks of potassium concentration (beyond that prescribed in the protocol) until it is clear that the potassium concentration is stable and not rising into the range of concern (≥ 5.5 and < 6.0 mmol/L) or potential danger (≥ 6.0 mmol/L). Investigators should not randomize a patient with a serum potassium ≥ 5.5 mmol/L during the run-in period. Patients with elevated potassium value will be managed according to the corrective actions outlined below. Hyperkalemia should be followed until resolution. Corrective action for management of hyperkalemia Serum potassium > 5.3 and less than or equal to 5.5 mmol/L • • •

Confirm potassium concentration in a non-hemolyzed sample Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. orange juice, melon, bananas, low-salt substitutes etc.) Review medical regimen (including dietary supplements and over-the-counter medications) for agents known to cause hyperkalemia. Consider reduction in dose or discontinuation of these agents: • Aldosterone antagonists (if they are believed to be the most likely cause of hyperkalemia) • Potassium-sparing diuretics (e.g. amiloride and triamterene) including in combination products with thiazide or loop diuretics • Potassium supplements, e.g., potassium chloride • Salt substitutes



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• • •

• • •

Non-steroidal anti-inflammatory drugs (NSAIDs) Cyclo-oxygenase-2 (COX-2) inhibitors Trimethoprim and trimethoprim-containing combination products, such as Bactrim® and Septra® (trimethoprim/sulfamethoxazole fixed combination) • Herbal Supplements: • For example, Noni juice, alfalfa (Medicago sativa), dandelion (Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian ginseng, hawthorn berries Repeat serum potassium measurement within 3 to 5 days If serum potassium remains > 5.3 and ≤ 5.5 mmol/L, regularly monitor serum potassium levels to ensure stability (suggested once monthly) Consider down-titration of study medication, according to investigator’s medical judgment.

Serum potassium > 5.5 and < 6.0 mmol/L • • • • •

Confirm potassium concentration in a non-hemolyzed sample Consider down-titration or temporarily discontinue study drug according to investigator medical judgment. Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L Repeat serum potassium measurement after 2-3 days If serum potassium < 5.5 mmol/L, consider resumption of study drug at lower dose with repeat potassium within 5 days

Serum potassium greater than or equal to 6.0 mmol/L • • • •

Immediately discontinue study drug Confirm potassium concentration in a non-hemolyzed sample Urgently evaluate patient and treat hyperkalemia as clinically indicated Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L

No resumption of study drug without individualized case discussion with and permission from Novartis medical monitor or his/her designee.

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Appendix 3: Guidelines for the management of blood pressure

Guidelines 1. Investigator should monitor blood pressure closely 2. If symptomatic hypotension occurs: a. Correct any treatable cause, e.g. hypovolemia This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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b. If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, such as diuretics, CCBs, nitrates, and α-blockers, should be down-titrated or stopped first before down-titration of the study drug is considered c. If hypotension persists, the study drug should be down-titrated or even temporarily withdrawn. The dose re-challenge and medications adjust guidelines described in Section 6.5.5 should be adhered to as much as possible.

17

Appendix 4: Guidelines for the management of renal dysfunction

General principles: Glomerular filtration rate in HF patients depends on intrinsic renal function and on a balance between afferent and efferent glomerular arterial tonicity. This tonicity is partly regulated by a stimulation of angiotensin II and could be affected by either study medication. Moreover, renal dysfunction may develop or may deteriorate in some patients after study drug administration. These recommendations have been developed to guide the investigators in managing patients with renal dysfunction after randomization. Any patient who experiences a decline in eGFR > 35% from Visit 1 or an eGFR < 30 mL/min/1.73m2 at Visit 3 or at Visit 5 will be considered a run-in failure and withdrawn from the study. Two types of response to serum creatinine increase are described: Surveillance situation If, at any time after randomization, eGFR decreases by ≥ 25% from baseline (Visit 5) (or if serum creatinine concentration increase to 2.5 mg/dL [221 µmol/L]), the investigator will check for potentially reversible causes of renal dysfunction such as: • Non-steroidal anti-Inflammatory drug intake, antibiotics, or other treatments known to affect creatininemia • Volume decrease, including that resulting from excessive dosing of diuretics • Urinary infection • Urinary tract obstruction • Study medication Action situation If a patient eGFR decreases by ≥ 40% from baseline (Visit 5) (or if serum creatinine concentration rises above 3 mg/dL (265 µmol/L), the investigator will check for potentially reversible causes of renal dysfunction (see above). If the investigator judges that study medication has to be stopped, he/she will have to contact the Novartis medical monitor or his/her designee. Thereafter, serum creatinine assessments will have to be repeated at least each week until levels return to acceptable values. If study This document (090095af838eff57 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI. Signatures manifested as of 3/7/2013 4:36:12 PM, signing status at this time: Completed (1 of 1 signatures) Approved for report publication by Rizkala Adel in East Hanover at Thu, 07 Mar 2013 11:36:01 AM EST


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medication was stopped, every effort will be done to restart it again, according to clinical conditions.

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Appendix 5: Kansas City Cardiomyopathy Questionnaire



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Appendix 6: EuroQoL (EQ-5D)



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Clinical Development

LCZ696B

Protocol number CLCZ696B2314


RAP Module 3 – Detailed Statistical Methodology

Author:

Jim Gong, Trial Statistician

Document type:

RAP Documentation

Document status:

Final version 1.0

Release date:

September 30, 2012

Number of pages:

52

Property of Novartis Confidential May not be used, divulged, published or otherwise disclosed without the consent of Novartis

Novartis RAP Module 3

Confidential 10-Oct-2012 (9:53)

Page 2 CLCZ696B2314

Table of contents Table of contents ................................................................................................................. 2 List of tables ........................................................................................................................ 4 List of figures ...................................................................................................................... 4 GENERAL INSTRUCTIONS.................................................................................................... 5 Statistical and analytical plans.................................................................................................... 5 1 Introduction ......................................................................................................................... 5 2 Analysis sets ........................................................................................................................ 5 3 Subgroup definitions and subgroup analyses ...................................................................... 8 3.1 Subgroups ................................................................................................................ 8 3.2 Subgroup analyses ................................................................................................. 10 4 Definitions of baseline, post baseline, close-out and analysis cut-off ............................... 10 5 Missing date handling........................................................................................................ 12 5.1.1 Visit date missing .................................................................................. 12 5.1.2 Event date missing or partially missing ................................................ 12 5.1.3 Medication stop date missing ................................................................ 13 6 Subject Disposition, background and demographic characteristics .................................. 14 6.1 Subject disposition ................................................................................................. 14 6.2 Background and demographic characteristics ....................................................... 15 6.3 Medical history ...................................................................................................... 16 7 Study medication ............................................................................................................... 16 7.1 Run-in phase .......................................................................................................... 16 7.1.1 Duration of treatment exposure ............................................................. 16 7.1.2 Dose levels ............................................................................................ 18 7.2 Double blind phase ................................................................................................ 18 7.2.1 Duration of treatment exposure ............................................................. 18 7.2.2 Dose levels ............................................................................................ 20 7.2.3 Other exposure analyses ........................................................................ 20 7.2.4 Treatment exposure in subgroups ......................................................... 20 7.3 Study exposure....................................................................................................... 21 8 Concomitant medication .................................................................................................... 22 8.1 Run-in phase .......................................................................................................... 22 8.2 Double blind phase ................................................................................................ 23 9 Efficacy evaluation ............................................................................................................ 24 9.1 Event counting for efficacy ................................................................................... 26 9.2 Variables ................................................................................................................ 26 9.3 Statistical hypothesis, model, and method of analysis .......................................... 29


10

11 12 13

14


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9.3.1 Primary analysis .................................................................................... 29 9.3.2 Secondary analysis ................................................................................ 30 9.3.3 Exploratory analysis .............................................................................. 32 9.3.4 Missing data handling in efficacy analysis ........................................... 37 9.4 Efficacy measurements in run-in ........................................................................... 40 Safety evaluation ............................................................................................................... 40 10.1 Allocation of AEs .................................................................................................. 42 10.2 Analysis for the identified and potential risks in the risk management plan ......... 43 10.3 Adverse events (AEs) ............................................................................................ 44 10.4 Laboratory data ...................................................................................................... 46 10.4.1 General laboratory data ......................................................................... 46 10.4.2 Specific laboratory data......................................................................... 47 10.5 Vital signs .............................................................................................................. 48 10.6 Electrocardiogram (ECG) ...................................................................................... 48 Resource utilization ........................................................................................................... 48 Interim analyses ................................................................................................................. 49 Power and sample size considerations .............................................................................. 50 13.1 Power for primary endpoint ................................................................................... 50 13.2 Power for secondary endpoints.............................................................................. 50 Reference ........................................................................................................................... 51



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List of tables Document History – Changes compared to previous version of RAP module 3. ...................... 5 Table 2-1 Rules for subject classification in the analysis sets based on protocol deviations and non-protocol deviation classification criteria ..................................................................................................... 7 Table 2-2 Specification of protocol deviations which lead to exclusion from analysis sets ............................................................................................. 8 Table 3-1 Specification of subgroups ...................................................................... 9 Table 9-1 Sketch of efficacy analyses ................................................................... 24 Table 10-1 Sketch of safety evaluation ................................................................... 41 Table 10-2 Allocation of AEs .................................................................................. 42 Table 10-3 Identified and potential risks ................................................................. 43 Table 10-5 Clinically notable changes in vital signs ............................................... 48


Analysis sets ............................................................................................ 6 Definition of study completer ............................................................... 14 Illustration of weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary hypotheses............ 31



Page 5 CLCZ696B2314

Document History – Changes compared to previous version of RAP module 3. Version

Date

Changes

GENERAL INSTRUCTIONS To ensure consistency across studies within the project, the RAP refers to the CSU harmonization MAP for heart failure (version number Final 1.0) and can be found in Novartis Clinical Research Documentation and Information system (CREDI) under: Cabinets/CREDI Projects/L/LCZ696B/Administrative files /CIS (Clinical Information Sciences)/ Biostatistics/ MAP module 3 OR MAP module 3 amendment 1.

Statistical and analytical plans 1

Introduction

Data will be analyzed according to the data analysis section 10 of the study protocol which will be available in Appendix 16.1.1 of the CSR. Important information is given in the following sections 9 (Efficacy evaluation), 10 (Safety evaluation), 12 (Interim analysis) and 13 (Powers and sample size considerations).

2

Analysis sets

The following analysis populations will be defined for statistical analysis: •

Screened set (SCR) – All patients who signed the informed consent. The screened set includes only unique screened patients, i.e., in the case of re-screened patients only the chronologically last screening data is counted.

•

Enrolled set (ENR) (run-in phase) – All patients who received at least one dose of run-in study drug and had at least one run-in phase safety or tolerability assessment.

•

Enalapril run-in set (ERS) – All patients who are in the ENR and received at least one dose of run-in enalpril.

•

LCZ696 run-in set (LRS) – All patients who are the ERS and received at least one dose of run-in LCZ696.

•

Randomized set (RAN) – All patients who received a randomization number, regardless of receiving trial medication.

•

Full analysis set (FAS) – All randomized patients. This is the primary efficacy population applied in efficacy analyses for all efficacy endpoints. Following the intentto-treat principle, patients are analyzed according to the treatment they have been



Page 6 CLCZ696B2314

assigned to at randomization. However, patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive study medication may be excluded from FAS. Further exclusions from the FAS may only be justified in exceptional circumstances (e.g., serious GCP violations). These potential incidences imply the possibility that the FAS may be smaller than the RAN. •

Per protocol set (PPS) – A subset of the FAS, consists of all randomized patients in FAS who received at least one dose of study drug during the double blind period of the study and have no major protocol deviations. Major protocol deviations are those affecting the primary endpoint analyses, which will be identified prior to the final database lock.

•

Safety set (SAF) – All randomized patients who received at least one dose of study drug during the double blind period of the study. Patients will be analyzed according to treatment received. Treatment received will be considered identical to the randomized treatment if the patient has received at least one dose of the randomized treatment.

A graphic display of the defined analysis sets is illustrated in the following figure. Figure 2-1

Analysis sets

PPS FAS SAF RAN

ERS SCR

LRS ENR

All cases of prospectively defined protocol deviations will be identified prior to clinical database lock/unblinding and entered into a dedicated data panel as part of the locked database. Certain deviations may stipulate that only data up to the time of infraction will be included in the per-protocol analysis, i.e. for analyses of the PPS data beyond this time-point will be ignored. This supplemental efficacy population is used to assess robustness of the primary analysis results for study to claim superiority.



Page 7 CLCZ696B2314

All exceptional cases and problems and the final decisions on the allocation of patients to populations will be fully defined and documented before database lock (in particular before breaking the blind where applicable) and will be fully identified and summarized in the clinical study report according to ICH E9. Criteria defining protocol deviations are referenced in the EDC VAP module 3--data processing document. Protocol deviations severity codes defined in VAP module 3 that lead to subject classification into the analysis populations as follows: Severity Codes

Actions

0

Exclude from all efficacy analyses (FAS, PPS)

1

Exclude from Per-Protocol analysis (PPS)

5

Exclude from Main safety analyses (SAF)

6

Exclude from Main Analysis Set (RAN, FAS, PPS)

8

Exclude from all analysis

Table 2-1

Rules for subject classification in the analysis sets based on protocol deviations and non-protocol deviation classification criteria

Analysis set Screened Enrolled Randomized

PD severity codes that cause a subject to be excluded NA NA 6

Safety

5, 8*

Full Analysis Set (FAS)

0, 6, 8*

Non-PD criteria that cause a subject to be excluded NA NA - Patient without a randomization number - Patients not receiving any dose of double-blind study medication

- Patient without a randomization number Per Protocol set (PPS) 0, 1, 6, 8 * - Patient without a randomization number * E.g.: Patient randomized twice with full parallel administration of double blind (DB) medication with severity code. With the severity code the data is kept into the database and no elimination of the efficacy data due to questionable GCP adherence is necessary. The team can re-evaluate patients post CDBL and after unblinding. E.g. it could happen that the patient is randomized to exactly the same treatment group or randomized to placebo in the one center and active medication in the other one. In both cases the patient could be eligible for further sensitivity analysis. For the latter one the patient can be considered as randomized to one active medication group.

The following Table 2-2 contains a sample of current study specific important protocol violations that lead to exclusion from analysis sets in the study. The final list may be different from this and will be signed before DBL.


Table 2-2


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Specification of protocol deviations which lead to exclusion from analysis sets

Category

Description of Protocol Deviation

Inclusion / Exclusion in analyses

Identificati on method

General

GCP issue present at site

Excluded from PPS,FAS Excluded from PPS Excluded from PPS Excluded from SAF

Manual

Blind broken locally Wrong treatment allocation Study treatment

Exclusion criteria

Inclusion criteria

Patient enrolled in Run-in period but no study medication taken. Patient was misrandomized (patient randomized in error and no DB study medication taken). Diagnosis of peripartum or chemotherapy induced cardiomyopathy within 12 months prior to Visit 1. History of severe pulmonary disease. LVEF > 40% at Visit 1 (Original Protocol). LVEF >35% at Visit 1 (Amendment 1) Heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD Current acute decompensated heart failure. Informed consent missing

NYHA Class I or no heart failure at Visit 1

Manual

Person responsible for identification Field monitor (FM) FM

Manual

FM

Programma ble

TDM

Excluded from PPS, FAS, SAF, RAN

Manual

FM

Excluded from PPS

Manual

FM

Excluded from PPS Excluded from PPS

Manual

FM

Programma ble

TDM

Excluded from PPS

Manual

FM

Excluded from PPS

Manual

FM

Excluded from PPS,FAS, SAF, RAN Excluded from PPS

Manual

FM

Manual

FM

3

Subgroup definitions and subgroup analyses

3.1

Subgroups

Subgroups will be formed for the analyses for the FAS or SAF depending on the parameters under consideration to explore the consistency of treatment effects and safety profiling between the subgroups and the overall population.



Page 9 CLCZ696B2314

In general, subgroups will be defined based on baseline information. In this study, since we have a run-in phase to test patients’ tolerability to the study drugs before they can enter the double blind phase, we have defined two baselines (Section 4): the run-in baseline and the double blind baseline. Subgroups will be formed using one of these baselines according to their analysis purposes. In Table 3-1, we have listed all subgroups defined for this study and the ways to derive them. In different analysis, such as efficacy analysis or safety analysis, a different subset of them will be selected. Also, additional subgroups may be formed later for regional or country-wise analyses. Table 3-1

Specification of subgroups

Subgroup

Method of Derivation

Disposition /Background & demo. /Exposures

Age groups: median Baseline LVEF ≤35% vs. >35% Atrial Fibrillation at baseline based on ECG at V5: yes/no Baseline NTproBNP**: ≤ median and > median Hypertension at baseline: yes/no Prior use of ACEi

Health economic s (KCCQ and EQ5D only)

Safety

x x x x

x

x x

Randomization

x

Screening

x

Screening

x

Screening

x

x

x

Novartis RAP Module 3 Prior use of ARB Use of Aldosterone antagonist at baseline: yes/no Time since diagnosis of HF: ≤ 1 year, 1-5 years, > 5 years UK***

Confidential 10-Oct-2012 (9:53) Screening Randomization (Derived) Screening

x

Page 10 CLCZ696B2314 x x

x

x

x

x

x

* North America: USA, Canada Latin America (including Central America): Argentina, Brazil, Chile, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Panama, Peru, Venezuela Western Europe: Belgium, Denmark, Finland, France, Germany, Iceland, , Italy, Netherlands, Portugal, Spain, Sweden, UK Central Europe: Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Rep. of Slovakia, Romania, Russia, Turkey Asia/Pacific and other: China, Hong Kong, India, Israel, Rep of Korea, Malaysia, Philippines, Singapore, South Africa, Taiwan, Thailand, ** It is not pre-specified in the protocol; ***It is not pre-specified in the protocol and it will be performed only for limited analyses.

3.2

Subgroup analyses

Subgroup analyses will be performed depending on the analysis purposes. Subgroups selected and types of analyses are specified in Table 3-1 and will be detailed later in the sequel sections. In principle, there will be no adjustment for multiple comparisons for subgroup analyses.

4

Definitions of baseline, post baseline, close-out and analysis cut-off

Single-blind run-in phase (run-in phase) The run-in phase is defined as the period between start of study drug and prior to randomization. The run-in phase will be divided further into the enalapril run-in phase and the LCZ696 run-in phase. The start of enalapril phase is the date the patient receives the run-in dose of enalapril. In principle, the day before a patient receives the first dose of LCZ696 (any dose level) will be the end of the enalapril run-in phase and the day patient receives the first dose of LCZ696 will be the start day for the LCZ696 run-in phase for that patient. If the date of the start day of receiving LCZ696 is missing, then the date of Visit 3, which is the protocol specified run-in drug switching day, will be used as the start date for the LCZ696 phase. If the date of the last dose of enalapril run-in medication falls on the same day of the first dose of LCZ696 run-in medication, this day will be considered the end of the enalapril run-in phase and the following day will be considered as the start of the LCZ696 run-in phase. The LCZ696 run-in phase ends at the time when the patient receives the randomization drug. During these two run-in phases, patients will be on the run-in drugs in a single blind manner.




Randomized treatment phase The randomized treatment phase begins at the time of randomization and ends with the last study drug intake or the death of the patient, whichever is earlier. During the randomized treatment phase, subjects will return for scheduled clinic visits. For all related safety analyses randomized treatment starts with the first intake of randomized, double-blind study medication. Temporary discontinuation of the study drug will not be counted as treatment phase discontinuation. Post-randomized treatment phase Post-randomized treatment phase (after unscheduled drug discontinuation) begins after last study drug intake + 1 day and ends up on the date last seen (or vital status confirmed by indirect contact). Double-blind (DB) phase Combined on-randomized treatment and post-randomized treatment phase. Baseline for run-in phase The run-in baseline is defined as the last available measurement prior to or at time of Visit 2 or Visit 2A, whichever is earlier. Baseline for double blind phase Baseline for the double blind phase is defined depending on the parameter considered. In general, based on the principle described in the protocol, the baseline for the double blind phase is defined as the last available measurement during the LCZ696 run-in phase including the time of randomization (general Visit 5/Randomization). For the parameters that were not designated to have measurements collected during the LCZ696 run-in or at randomization, the run-in baseline may be used as the baseline for the double blind phase. The following parameters will have the double blind phase baseline at randomization visit: NYHA class, HF signs and symptoms, vital signs, waist/hip circumference, plasma BNP/NTproBNP, biomarkers (sub-study patients only), eGFR, safety laboratory values, endpoints, 1st morning urine (sub-study patients only), lab assessments, ECG, patient global assessment (it is assumed that patients will assess their status comparing to that at randomization), KCCQ scores and EQ-5D assessments. The following parameters will have their double blind phase baseline measured at screening phase, i.e., prior or at visit 2 or 2A: Height/weight, heart failure and CV medications, histories (CV disease, HF, and medical), demography, and incl/excl criteria. Note that since the values of patient characteristics will change during run-in, the double blind phase baselines for some parameters will be derived based on the data collected at randomization, such as diabetes status and atrial fibrillation status.




Post-baseline definition Any measurements taken after baseline will be considered as post-baseline measurements. In analysis, this will be further classified according to run-in phase and double blind phase: runin post-baseline and double blind post-baseline. Unscheduled visit Only for the analysis of safety laboratory evaluation unscheduled measurements will be taken into account. For efficacy evaluations, measurements from unscheduled visits will generally not be used for analysis, unless specifically specified, such as eGFR. Analysis cut-off date (Study endpoint for analysis) The trial was designed to be terminated when 2410 patients have experienced a confirmed primary composite event. The analysis cut-off date is a predicted date when either the targeted number of 2410 patients experienced a primary composite event has met with confidence based on available data or a study termination date has decided based on other study termination decisions. Final visit Final visit will be the last time a patient’s study record being taken. For a patient who is still alive and in the study the final visit will be his/her last clinical visit. For a patient who died or lost to follow-up (see Figure 6-1 for the illustration of lost-to-follow-up) before the analysis cut-off date, the final visit will be his/her death/lost-to-follow-up day. For a patient who is alive but no longer visits clinic regularly and whose study records only can be obtained by telephone or indirect contact, the final visit will be the day the study records being taken. Close-out date The close-out date will be the date when the study sites are informed to schedule patients’ final visits for those patients who are still alive. It is expected to occur within three months before the analysis cut-off date, depending on the timing the final visits can be scheduled in each site.

5

Missing date handling

5.1.1

Visit date missing

In any analysis or evaluation, if visit date(s) is used but it is missing, then the date(s) calculated base on the planned date(s) in the schedule specified in the protocol should be used to impute the missing date(s). 5.1.2

Event date missing or partially missing

If the date of an event is not known or is incomplete, the imputation rules are: a) If the day of the event is unknown, then the 15th day of this month will be imputed for a missing day;




b) If only the month is unknown, then July will be used for imputation of the missing; c) If only the year of the event is known, then the 1st of July will be imputed for a missing day and month; d) The above rules are only for general case. If there is additional information available for the missing date, then the information should be used and the imputation of missing date should be treated differently. For example, if an event occurs between two visits and its date is missing, then the date in the middle of these visits may be used. 5.1.3

Medication stop date missing

If medication stop date is unknown or is incomplete, the imputation rules are: a) If only day field of the drug stop is missing, then the missing date is imputed by using the 15th of the month; b) If year and month are missing, then use the next scheduled visit date (using the protocol specified visit schedule) from the previous last non-missing visit date to replace the missing drug stop date; c) If the drug stop date is completely missing, then: a. If patient had fatal AEs (identified as either start or end date is equal to the date of death and the AE is flagged as an SAE), handling rules are (in the specified order): i. AE end date is not missing: use the AE end date to replace the missing drug stop date; ii. AE end date is completely missing but AE onset date not missing: use the AE onset date to replace the missing drug stop date; iii. AE end date is partially missing (only day field is missing): use Novartis standard procedure to impute the AE end date, and then use the imputed AE end date to replace the missing drug stop date; iv. AE end date is completely missing and AE onset date is partial missing (missing the date field only): impute the AE onset date using Novartis standard procedure, and then use the imputed AE onset date to replace the missing drug stop date; v. If both the AE onset and end dates are completely missing, then use the last previous non-missing visit date plus 35 days to replace the missing drug stop date. b. If patients had no fatal AEs, handling rules are the same with the case that year and month are missing.




6

Subject Disposition, background and demographic characteristics

6.1

Subject disposition

The number and percentage of patients successfully screened will be presented. In addition, the reasons for screen failures will be provided. For patient who was screened more than once, the information from the last screen will be used in the summary. The analysis set is the SCR. The number and percentage of subjects enrolled, completed, and failed in run-in will be summarized for the enalapril run-in and LCZ696 run-in separately. The reasons for run-in failures will be provided. The analysis set is the ENR. The same information for the ERS and LRS will also be provided. The number of subjects randomized (RAN) and included in the full analysis set (FAS) will be presented by treatment group. The number and percentage as well as the reasons that subjects had been excluded from the RAN will be summarized by treatment group. The number and percentage of subjects in the FAS who completed the study (“Study completer” see also Figure 6-1), who discontinued the study and the reasons for discontinuation will be presented for each treatment group. The number and percentage of subjects with protocol deviations as well as the criteria leading to exclusion from analysis sets will be presented in separate tables for the FAS. Furthermore, the number of subjects enrolled and randomized per region and per country will be presented descriptively for the ENR and the FAS, respectively. Figure 6-1

Definition of study completer Last visit after start of close-out = completer Died before close-out = completer Died during close-out = completer Follow-up* obtained during close-out w/o office visit = completer No follow-up* at least to start of close-out = lost to follow-up

Run-in

Close-out

Randomization

Start of close-out

CDBL

Analysis cut-off

*: Follow-up means patient’s vital/medical status information. It may be obtained through indirect contact.

As described in Section 3, the disposition analysis will be repeated for the following subgroups: •

Age group 30 mL/min/1.73 m2 decline in eGFR relative to baseline to a value below 60 mL/min/1.73 m2, or (3) reaching ESRD




Exploratory variables •

Time to first occurrence of a composite event of CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death o Time to first occurrence of a composite event of CV death, non-fatal MI, nonfatal stroke or resuscitated sudden death o Time to first occurrence of a composite event of CV death, non-fatal MI, and non-fatal stroke o Time to first occurrence of MI and stroke o Time to first occurrence of MI o Time to first occurrence of stroke o Time to first occurrence of resuscitated sudden death

•

Time to first all-cause hospitalization

•

Time to first cause-specific hospitalization, such as cardiovascular hospitalization

•

Number of hospitalization admissions (all-cause and cause-specific)

•

Number of days alive out of the hospital at Month 12

•

Rate of change in eGFR from baseline to last available value

•

Time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month

•

Change in the clinical composite assessment at Month 8

•

Time to new onset AF

•

Time to new onset diabetes mellitus (NODM)

•

Changes in health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and assessments of the EQ-5D for health status)

•

Time to first coronary revascularization procedures

•

Changes from baseline to pre-defined time-point in pre-selected biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers)

•

Number of days/stays in ICU, number of re-hospitalizations, and number of ER visits for heart failure

•

Variables for measuring the PK parameters of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or noncompartmental based methods

•

Number of recurrent HF hospitalization; number of recurrent composite events of CV mortality and HF hospitalization; number of recurrent composite events of CV death, HF hospitalization, MI, stroke, and resuscitated sudden death; number of recurrent composite events of CV mortality, MI, and stroke; number of recurrent composite




events of MI, and stroke; number of recurrent events of MI; number of recurrent events of stroke (This item is not specified in the protocol.) •

Indicator of re-hospitalization within 30 days (This item is not specified in the protocol.)

Among the variables above, some of them or their components need to be adjudicated to confirm the reported types and occurrences based on the unified criteria for analyses. The adjudication of these events is based on an adjudication process through an independent Endpoint Adjudication Committee. The following events will be assessed by the Endpoint Adjudication Committee during the study: •

All death events

•

Unplanned hospitalization for HF

•

MI

•

Stroke

•

Resuscitated sudden death (successful resuscitation following cardiac arrest)

•

Renal dysfunction (including occurrence of end stage renal disease)

•

Others (NOAF, NODM)

In the analysis, unless specified specifically, only adjudicated events will be utilized if the events included in the analysis are required to be adjudicated. Note that in the sensitivity analysis, the reported events may be used for the analysis. As specified before, all events and endpoints occurred or measured prior to or at the specified analysis time-points (such as Month 8, Month 12, etc.), including the analysis cut-off date, will be counted. Censoring variables Number of events and time-to-event variables are usually subject to censoring. The censoring can be caused by withdrawal of consent, lost to follow-up, other competing events, or administrative reasons (interim or final analysis cut off date). Below are the rules for deriving censoring variables in the analyses (primary, secondary, exploratory) except for the perprotocol analysis: •

For all-cause death, the censoring will occur at minimum (date of withdrawal of consent, last known alive date, analysis cut off date)

•

For CV death, the censoring will occur at minimum(date of withdrawal of consent, last known alive date, analysis cut off date, date when patient died for non-CV causes)

•

For non-mortality and non-composite endpoint, the censoring will occur at minimum(date of withdrawal of consent, date of lost to follow-up, analysis cut off date, date when patient died)

•

For composite endpoint, the censoring will occur at the earliest censoring date among components.




On-treatment analysis is referring to the sensitivity analysis for the primary endpoint based on the FAS and with events censored after premature discontinuation of study drug. The events occurred after having major protocol deviations need to be censored. The censoring variables for the on-treatment analysis are: •

For CV death, the censoring will occur at minimum(date of withdrawal of consent, last known alive date, analysis cut off date, date patient died for non-CV causes, date of premature discontinuation of study drug (end of on-treatment phase))

•

For non-mortality and non-composite endpoint, the censoring will occur at minimum(date of withdrawal of consent, date of lost to follow-up, analysis cut off date, date patient died, date of premature discontinuation of study drug)

•


Per-protocol analysis is referring to the sensitivity analysis for the primary endpoint based on the PPS. The events occurred after having major protocol deviations need to be censored. The censoring variables for the per-protocol analysis are: •

Minimum(the censoring time defined for the primary, secondary, exploratory analyses, date of the first major protocol deviation).

9.3

Statistical hypothesis, model, and method of analysis

9.3.1

Primary analysis

All primary events occurred between randomization and the analysis cut-off date will be included in the primary analysis. 9.3.1.1

Analysis for primary endpoint

The primary hypothesis to be tested is H10: λ2 / λ1 ≥ 1 versus H1a: λ2 / λ1 < 1, where λ1 and λ2 are hazards for enalapril treatment and LCZ696 treatment, respectively. The primary efficacy variable will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The overall type I error rate will be controlled at 2.5% (one-sided). Thus one-sided significance level of α will be used for the final analysis, which has been adjusted for the interim efficacy analyses and will be decided after the last interim analysis. The estimated hazards ratio and the corresponding two-sided (1- α)100%-confidence interval will be provided. The FAS will be used for the primary analysis. 9.3.1.2

Supportive analyses

In addition to the primary analysis, the primary efficacy variable will also be analyzed using the same primary analysis model for the PPS and for the on-treatment analysis. A supplemental log-rank test will be performed for all the analyses. Survival function for each treatment group will be estimated by Kaplan-Meier method and the Kaplan-Meier curves will be presented in all the analyses. The frequency and percentage of patients who reach the primary composite endpoint will be provided by treatment group for all the analyses.




Additionally, similar analyses will be performed for each of the components of the composite endpoint with all events for that component that occurred during the double blind period of the study to quantify the strength of the effect for each component in the primary composite endpoint. The estimated hazards ratios and the corresponding two-sided 95%-confidence intervals will be provided. Their Kaplan-Meier curve estimates will also be provided. The FAS will be used for the analysis. Time to first investigator reported composite event of CV death and heart failure hospitalizations will also be performed using the Cox regression model with treatment a factor and stratified by region. Effect size based on hazard ratio, its confidence interval, and KMestimates will also be provided. Note that when there is a difference in CV death between treatment groups in favor of LCZ696, the estimated reduction in hazard ratio for non-CV mortality endpoint will be smaller than its actual size. However when the difference is not in favor of LCZ696, then the estimated reduction for non-CV mortality endpoint may be greater than its actual size. Further analysis that can model the impact on non-CV mortality endpoints from the CV mortality may be needed. The joint-frailty modeling method (Zeng and Lin 2009; Cowling, Hutton, Shaw 2006) will be utilized for this analysis. 9.3.1.3

Subgroup analysis

A full set of subgroups will be looked at for subgroup analysis for the primary endpoint and its components, as outlined at Section 3. Subgroup analyses will be performed for the FAS. To explore beneficial effects in subgroups or homogeneity of beneficial effects among subgroups, the estimated hazard ratio, two-sided 95% confidence interval, and within subgroup p-value and p-value for the test for the treatment-by-subgroup interaction will be provided for each of the subgroups based on the Cox’s proportional hazards model in which treatment, subgroup, and treatment-by-subgroup are included as fixed-effect factors. It should be aware that positive findings from these subgroup analyses have to be interpreted with caution since there is a non-negligible chance of false positives. Kaplan-Meier estimates will be provided for each subgroup. Additionally, the frequency and percentage of patients reaching primary composite endpoint will be presented by treatment group for each of the subgroups. The Kaplan-Meier curves and hazards ratios from each subgroup will be graphically displayed using forest plot. 9.3.1.4

Model checking

The assumption of proportionality between treatment groups in the Cox proportional hazards model used for the primary analysis will be checked graphically. If a critical departure from the proportionality assumption is observed, further investigation on the adequacy of the primary analysis results, such as estimated effect size, will be granted. 9.3.2

Secondary analysis

9.3.2.1

Multiplicity adjustment among secondary comparisons

The secondary null hypotheses will be tested and statistical inferences will be made only if the primary null hypothesis is rejected. The three secondary efficacy variables will be tested for




superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LCZ696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. As indicated in Figure 9-1, after rejection of the primary null hypothesis (H10), the sequentially rejective multiple test procedure for the secondary variables is illustrated below: • The initial allocation of significance levels are 0.2α, 0.8α, and 0 for the comparisons of KCCQ clinical summary score (noted as H210), all-cause mortality (noted as H220), and the composite renal endpoint (noted as H230), respectively. • If both of the hypotheses H210 and H220 are rejected at the initially assigned alpha levels, then the composite renal endpoint will be tested at the level of alpha. • If the hypothesis H220 is rejected and H210 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.8α. • If the hypothesis H210 is rejected and H220 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.2α. o If H230 is rejected at this 0.2α level, then 0.2α will be added to 0.8α and H220 will be further tested at a level of alpha. o If H230 is not rejected at this 0.2α level, then no further hypothesis will be tested for influence Figure 9-1


H210 denotes the null hypothesis for the comparison of KCCQ clinical summary score. H220 denotes the null hypothesis for the comparison of all-cause mortality. H230 denotes the null hypothesis for the composite renal endpoint.

For publications, these secondary variables may be further assessed using full level of alpha without consideration of multiplicity adjustment.


9.3.2.2



Analysis of KCCQ clinical summary score at 8 months

The KCCQ instrument includes several domains. Only the domains that address HF symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is computed as the mean of the following available domain scores: • Physical limitation score • Total HF symptom score Change from baseline in the clinical summary score of KCCQ will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit (Month 4, and Month 8), and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance matrix among visits for each treatment group. The treatment comparison between LCZ696 and enalapril for the secondary objective is to be made at Month 8. The analysis will be performed based on all available data up to 8 months in the FAS and based on likelihood method with an assumption of missing at random for missing data. The estimated between and within treatment effects with the associated twosided 95% confidence intervals at Month 8 will be provided. Missing data handling in forming the KCCQ scores follows the algorithms defined in Section 9.3.4.2. 9.3.2.3

Analysis of time to all-cause mortality

The time to all-cause mortality will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided. The Kaplan-Meier curves by treatment group will be presented. Additionally, the frequency and percentage of all-cause mortality will be provided by treatment group. 9.3.2.4

Analysis of time to composite renal endpoint

The time to composite renal endpoint will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided. The Kaplan-Meier curves by treatment group will be presented for the FAS. Additionally, the frequency and percentage of composite renal endpoint will be provided by treatment group. 9.3.2.5

Subgroup analysis

Subgroup analysis for each of the secondary variables will also be performed similarly as described in Section 8.3.1.3 for the primary variable. 9.3.3

Exploratory analysis

In general, exploratory variables (Section 8.2) will be analyzed in the FAS unless specified otherwise. Statistical tests will be performed at the two-sided significance level of 0.05. To better satisfy the normality assumption, the log-transformation will be applied to data on each biomarker prior to statistical analysis. There will be no multiplicity adjustment for analysis of exploratory variables.


9.3.3.1



Analysis for time-to-event variables

Time-to-event variables will be analyzed using a Cox proportional hazards model with treatment and region as fixed effect factors. The estimated hazards ratio and the corresponding two-sided 95% confidence interval will be provided. The Kaplan-Meier estimates may also provided by treatment group, in tables and graphs. Below are the time-to-event variables that will be analyzed •

Time to first occurrence of a composite event of CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death during the double blind period o Time to first occurrence of a composite event of CV death, MI, stroke or resuscitated sudden death o Time to first occurrence of a composite event of CV death, MI, and stroke o Time to first occurrence of MI and stroke o Time to first occurrence of MI o Time to first occurrence of stroke o Time to resuscitated sudden death

•

Time to study treatment failure during the double blind period

•

Time to new onset of AF during the double blind period

•

Time to new onset of diabetes mellitus during the double blind period

•

Time to first all-cause hospitalization during the double blind period

•

Time to first cause-specific hospitalization during the double blind period

•

Time to first coronary revascularization procedures during the double blind period

Note that the censoring variables will be defined following the rules described in the paragraph for Censoring variables in Section 9.2. 9.3.3.2

Analysis of continuous variables normally distributed

Below are the continuous variables, which are assumed to be normally distributed, listed in the protocol for exploratory analysis: •

Rate of change in eGFR from double blind phase baseline to endpoint;

•

Changes in health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and scores of the EQ-5D for health status (EQ-5D index derived from EQ-5D descriptive system and EQ-5D VAS) from double blind phase baseline to pre-defined time-points;

•

Changes from baseline to pre-defined time-points in pre-selected biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers);

•

Days alive out of the hospital during the first 12 months.




For the rate change in eGFR, the eGFR slope will be calculated by fitting the patient’s eGFR assessments with a linear regression model with time as the independent variable. The derived eGFR slopes will be then analyzed using an ANCOVA model with treatment and region as fixed effect factors, and baseline eGFR value as a covariate. The estimated treatment effects, based on the least-squared means for within and between treatment groups, and the corresponding two-sided 95% confidence intervals will be provided. Patients without postbaseline eGFR measurement will be removed from the analysis since the proportion of patients with this type of missing data is very low and is not expected to have impact on the analysis results. Changes from baseline in KCCQ scores (the clinical summary score of KCCQ and all subdomain scores) will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit (Month 4, Month 8, year 1, year 2, and year 3), and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance matrix among visits for each treatment group. Treatment comparisons and effect size estimates and their 95% confidence intervals at different visits and averaged over-all-visits will be provided. The analysis will be performed based on all available data up to 3 years in the FAS and based on likelihood method with an assumption of missing at random for missing data. Missing values occurred during KCCQ data collection will be treated according to the rules defined in Section 3.3.4.2. Change from baseline in EQ-5D VAS (and EQ-5D index similarly) will be compared between treatment groups and be analyzed using the same repeated measures ANCOVA model described above for the KCCQ scores. Similarly, treatment comparisons and effect size estimates and their 95% confidence intervals at different visits and averaged over-all-visits will be provided. The analysis will be performed based on all available data in the FAS and based on likelihood method with an assumption of missing at random for missing data. For pre-selected biomarkers, change from baseline to a pre-defined time-point (Week 4 and Month 8) in logarithmic scale will be analyzed using a repeated measures ANCOVA model with treatment, region, visit and treatment-by-visit interaction as fixed effect factors and the logarithmic baseline biomarker value as a covariate. The estimated treatment effects in terms of ratios of geometric means, based on the least-squared means for within and between treatment groups from the ANCOVA model, and the corresponding two-sided 95% confidence intervals will be provided. The analysis will be performed based on all available data in the FAS and based on likelihood method with an assumption of missing at random for missing data. For the variable of days alive out of the hospital (DAOH) during the first 12 months, it will be treated as a continuous variable. The mean difference between treatment groups will be compared using an ANCOVA model with factors of region and treatment group. The estimated treatment difference and its 95% confidence interval will be provided. Statistical summary will include descriptive statistics of N, mean, SD, median, minimum and maximum by visit (if applicable) and treatment group for all visits (if applicable). Changes from baselines will also be presented by visit and treatment group for KCCQ scores and EQ5D assessments described above. The Ns, means and SDs for these continuous variables will be graphically displayed using line plots.




Note that since the EQ-5D descriptive system contains ordinal variables (the dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with each having 3 levels (no problems, some problems, severe problems)), besides the continuous scores of index and VAS, frequencies and percentages of patients in each category will be provided by treatment group and visit. 9.3.3.3

Categorical and ordinal variables

Categorical variable is: •

Indicator (yes/no) of re-hospitalization within 30 days

This variable will be analyzed using a logistic regression model with region and treatment as factors. Treatment will be compared based on the model. The odds ratio and 95% confidence intervals will be provided. The categorical ordinal variables are: •

Assessment in the clinical composite assessment (improved, unchanged, and worsened) at post-randomization visits

•

Change in NYHA class from randomization

•

Changes in heart failure (HF) signs and symptoms from randomization

These ordinal variables will be analyzed, at Month 8, 1 year, 2 years, and 3 years, using Cochran-Mantel-Haenszel (CMH) test for different row (treatment) means, stratified for region, based on the modified ridit scores which are also referred to as the standardized midranks. Note that in this analysis we assume that the follow-up durations are equally distributed between treatment groups. To further estimate the effect sizes and their 95% confidence intervals, a mixed-effect proportional odds (repeated measures proportional odds model) model for ordinal data (category changes from baseline to given time points) will be utilized. The model will include patient as a random effect and the double-blind phase baseline category (only for NYHA class and HF signs and symptoms), region, treatment, visit (all available post-randomization visits) and treatment-by-visit interaction as fixed effect factors. This model assumes that the treatment effect sizes across measurement categories are the same. The visit-wise effect size estimates and their 95% confidence intervals will also be provided. Model fittings will be based on likelihood with all available data. The SAS procedure of GLIMMIX (SAS/STAT 9.3) can be used for this analysis. Frequencies and percentages of patients in each category will be provided by treatment group and visit. For the NYHA class and the HF signs and symptoms, shift tables from double-blind baseline to the study end will also be provided. 9.3.3.4

Count variables for multiple events

Count variables include: •

Number of hospitalization admissions

•

Number of days/stays in ICU



•

Number of re-hospitalizations

•

Number of ER visits for heart failure


The first four variables will be analyzed using a negative binomial model (McCullagh and Nelder 1989) with the count data as the dependent variable and treatment group and region as fixed-effect factors and log(follow-up duration) as the off-set. The model estimated event rates (intensities/risk rate) and their 95% confidence intervals will be provided by treatment group. The treatment comparison will be performed through the estimated ratio of risk rates. The estimated reduction in risk rate and its 95% confidence interval will also be provided. Note that, in case when the follow-up durations depend on the treatments (informative censorings), the estimated rate reduction should be interpreted with caution. However, when LCZ696 has a reduction in mortality, the rate reduction estimated from the negative binomial model will become conservative. Descriptive statistics (n, mean, standard deviation, median, max, and min) will be provided for these variables by treatment group. For each variable, the annualized count for each patient is calculated as the total counts during the study divided by the total duration of the double blind treatment phase, multiplied by 365.25. The annualized counts will be summarized according to treatment groups. 9.3.3.5

Recurrent events

Recurrent events (including the first) data include, during the double blind period: •

Recurrent hospitalizations for heart failure;

•

Recurrent composite events of CV mortality and HF hospitalization;

•

Recurrent composite events of CV death, HF hospitalization, non-fatal MI, non-fatal stroke, and resuscitated sudden death;

•

Recurrent composite events of CV mortality, MI, and stroke;

•

Recurrent composite events of MI, and stroke.

For each type of non-fatal event, such as hospitalization for heart failure, MI, etc., frequency and percentage of patients with the non-fatal recurrent events will be summarized by number of the non-fatal recurrent events per-patient and treatment group. These data will be analyzed using a proportional rate function model (Lin, Wei, Ying, and Yang, 2000, abbreviated as LWYY) with fixed-effect factors of region and treatment group. Regardless of an event containing CV death as a component, death time will always be considered as a censoring time and furthermore an independent censoring time in the model fitting of LWYY. Treatment comparisons and effect size estimates will be provided based on the fitted model. The mean rate functions of the recurrent event component conditional on being alive, by treatment group, will be provided graphically using a Nelson-Aalen estimate (Cook and Lawless 1997) and the mean rate functions recognizing no further event after death will be provided by an integrated Nelson-Aalen estimate (Ghosh-Lin 2000). For non-fatal recurrent events: hospitalizations for heart failure, recurrent composite events of non-fatal MIs and non-fatal strokes, a semi-parametric joint gamma frailty model will be utilized to further evaluate the consistency of the effect size estimated from LWYY. In the




joint model, recurrent events will be modeled jointly with CV mortality event through a gamma frailty to account for the correlation between the recurrent events and the terminal event of CV death. The recurrent event part that will be modeled by an Anderson-Gill model (Anderson and Gill 1981) is assumed to be independent of the CV mortality part that will be modeled by a Cox’s proportional hazards model, given the gamma frailty. The effect sizes and their 95% CIs, conditional on the frailty, for both component parts will be provided. In case the semi-parametric joint modeling cannot converge numerically with the existing SAS procedures, a parametric joint gamma-frailty model may be used instead. The parametric joint gamma-frailty model will model the recurrent event component using a Poisson regression model and model the CV mortality component using an exponential model (Cowling, Hutton, and Shaw 2006). In addition to the recurrent event analysis, time to 1st (which is done in the primary analysis), time to 2nd,…, up to time to 6th each type of event, if possible, will be analyzed by the WLW method (Wei, Lin, Weissfeld 1989) for the purpose of sensitivity analysis. 9.3.3.6

Subgroup analysis for exploratory analysis

Subgroup analysis for the exploratory objectives will only be performed for the KCCQ scores and the EQ-5D assessments, mainly focused on descriptive statistics, for •

the United Kingdom

•

Region: North America; Western Europe; and Central Europe

•

Prior use of ACEi

•

Prior use of ARB

•

Time since diagnosis of HF: ≤ 1 year, 1-5 years, > 5 years.

9.3.4

Missing data handling in efficacy analysis

9.3.4.1

Time to event variables

For time-to-event variables, the censoring rules are presented in Section 9.2. 9.3.4.2

KCCQ clinical summary score

The clinical summary score is a mean of the physical limitation and total symptom scores. The total symptom score is the mean of the symptom frequency and symptom burden scores. Each scale score (the physical limitation, symptom frequency or symptom burden) is calculated as the mean of its item scores and transformed to a 0–100 scale, with higher score indicating higher level of functioning. A score of 100 represents perfect health whereas a score of 0 represents dead. For patients who die, a worst score (score of 0) will be imputed for the clinical summary score at all subsequent scheduled visits after the date of death where the clinical summary score would have been assessed. Below are the rules each scale score being calculated: 1. Physical Limitation •

Code responses to each of Questions 1a-f as follows:




Extremely limited = 1 Quite a bit limited = 2 Moderately limited = 3 Slightly limited = 4 Not at all limited = 5 •

Limited for other reasons or did not do =

If at least three of Questions 1a-f are not missing, then compute •

Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4

Note: references to “means of questions actually answered” imply the following. If there are n questions in a scale, and the subject must answer m to score the scale, but the subject answers only n-i, where n-i >= m, calculate the mean of those questions as (sum of the responses to those n-i questions) / (n-i) not (sum of the responses to those n-i questions) / n 2. Symptom Frequency Code responses to Questions 3, 5, 7 and 9 as follows: Question 3 •

Every morning = 1

•

or more times a week but not every day = 2

•

1-2 times a week = 3

•

Less than once a week = 4

•

Never over the past 2 weeks = 5

Questions 5 and 7 •

All of the time = 1

•

Several times a day = 2

•

At least once a day = 3

•


•


•


•


Question 9 •

Every night = 1



•


•


•


•



If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: •

S3 = [(Question 3) – 1]/4

•

S5 = [(Question 5) – 1]/6

•

S7 = [(Question 7) – 1]/6

•

S9 = [(Question 9) – 1]/4

Symptom frequency score = 100*(mean of S3, S5, S7 and S9) 3. Symptom burden Code responses to each of Questions 4, 6 and 8 as follows: •

Extremely bothersome = 1

•

Quite a bit bothersome = 2

•

Moderately bothersome = 3

•

Slightly bothersome = 4

•

Not at all bothersome = 5

•

I’ve had no swelling/fatigue/shortness of breath = 5

If at least one of Questions 4, 6 and 8 is not missing, then compute Symptom burden score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4 4. Total symptom score = mean of the following available summary scores: Symptom frequency score Symptom burden score 5. Clinical summary score = mean of the following available summary scores: •

Physical limitation score

•

Total symptom score

9.3.4.3

Other variables

For the variables other than those mentioned above, double blind post-baseline LOCF will be utilized for imputing missing data unless specific rules are mentioned in the analysis sections. If it deems necessary, multiple imputations method may be used in addition to the available




data analysis for each variable when the missing at random assumption is considered reasonable.

9.4

Efficacy measurements in run-in

Because of the different lengths of durations and sequential follow-up nature for the two subrun-in phases, the analysis results for the two sub-run-ins must be interpreted with caution. Percentage without adjusting exposure duration is apparently not meaning for comparison between the two phases. Even the exposure adjusted rates will not be adequate for treatment comparisons due to the sequential follow-up nature of the two sub-run-ins. Many efficacy parameters discussed above are also measured during run-in phase, such as the information of endpoints, new onset of diabetes mellitus, new onset of atrial fibrillation, and NYHA classification and heart failure signs/symptoms. Since all patients will take the same study drugs during run-in, the focus of our efficacy analysis for the run-in data will be on checking balances of efficacy profiles between the two treatment groups assigned at randomization based on the FAS, though the total summary will also be provided sequentially based on the ERS and LRS for providing the information over time prior to randomization. The frequency of patients with endpoint events, including the composite endpoints (first event), occurred during run-in will be summarized separately for the enalapril and LCZ696 run-ins and the treatment exposure adjusted event rates (annualized incidence rates) will be provided, based on the ERS and LRS. Similar summaries will also be provided for all patients in the FAS and for each treatment group as assigned at randomization in the FAS. The frequency and percentage of patients in each NYHA classification or HF signs/symptoms category will be summarized similarly for the FAS and for each visit where data were collected during run-in. The endpoint information summary will be provided for both investigator reported and CEC adjudicated.

10

Safety evaluation

Safety will always be evaluated based on the ERS and LRS for run-in phase and the SAF for double blind phase. For the purpose of simplifying the description of the analysis methods, in the following, the terms “by treatment group” in the safety analysis will always mean in sequential order of enalapril (ERS) then LCZ696 (LRS) for the two run-in periods. The safety evaluation will include: •

Specific identified and potential risk and safety factors evaluation

•

Adverse events

•


•

Vital signs

•

Electrocardiogram




The following subgroups will be evaluated for safety, except for the specific identified and potential risk analysis: •

Age group 6.0 mEq/L and >6.5 mEq/L by treatment. 1. Blood pressure summary (mean, standard deviation, median, and range) including measurement at each visit and change from baseline will be provided by treatment 2. Summary with frequency and percentage by treatment for patients with: a. systolic blood pressure (SBP) 50%, and >30 mL/min/1.73 m2;

Novartis RAP Module 3 Risks

Gastric lesions Hypersensitivity reaction (excluding angioedema) Hepatotoxicity

Change in bone growth/bone mineral density Stimulation of lipolysis Change in cognitive function QT-Prolongation (Routine risk)

10.3



Analysis b. Serum creatinine increase by >50%; c. Serum creatinine level >0.5 mg/dL, >2.0 mg/dL, >2.5 mg/dL, >3.0 mg/dL 3. Subgroup analyses on the relationship between eGFR < 60 and >60 mL/min/1.73 m2 at baseline and incidence rate/severity of AEs/laboratory parameters indicating newly occurred/worsening of renal impairment. Standard statistical analysis Standard statistical analysis

1. Summary with frequency and percentage by treatment for patients with: a. ALT or AST >3x ULN; b. ALT or AST >5x ULN; c. ALT or AST >8x ULN; d. ALT or AST >3x ULN and TB >2x ULN; e. TB >3x ULN and AST or ALT are ≤3 x ULN and alkaline phosphatase ≤1.5x ULN; f. AP >3x ULN and AST, ALT, TB are within normal range. 2. A cross-tabulation of baseline and worst post-baseline values by below, within and above normal range categories will be provided. Shift tables will be provided for the parameters AST, ALT, TB and AP. Standard statistical analysis

Standard statistical analysis Standard statistical analysis Standard statistical analysis

Adverse events (AEs)

Any AE occurred during the study period will be included in AE summary tables as described in Section 10.1, i.e., AEs occurred in run-ins, double blind period, and SAEs up to one-month after the study completion. The incidence of treatment-emergent adverse events (new or worsened) will be summarized by primary system organ class, preferred term, severity, and relationship to study drug according to the Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the study will be described in a footnote. Within each reporting phase (run-ins or double blind, see Table 10-2), the following rules are applicable. If a subject reported more than one adverse event with the same preferred term, the adverse event with the greatest severity will be presented. If a subject reported more than one adverse event within the same primary system organ class, the subject will be counted only once with the greatest severity at the system organ class level, where applicable. Statistical analyses, which will only be performed for the double blind or later phase, will include all




post-baseline AEs up to and including the analysis cut-off (AEs up to the final visit and SAEs up to 30 days after the final visit for each patient) irrespective of how long after the last day of study treatment they occurred. The number and percentage of subjects reporting any adverse event during each reporting phase will be summarized by primary system organ class, preferred term and treatment. The most common adverse events reported (≥ 1 % in any group for each preferred term in the SOC-PT table) will be presented in descending frequency according to its incidence in the LCZ696 group starting from the most common event. Separate summaries, for each reporting phase (run-ins and double blind), will be provided for study medication related adverse events, death, serious adverse event, other significant adverse events leading to study discontinuation and adverse events leading to dose adjustment. Specific interested AEs will be summarized separately in addition to the above analysis. These specific interested AEs are: angioedema, hyperkalemia, hypotension, renal dysfunction, liver. Due to the different durations in the two sub-run-in phases, besides providing percentages, the annualized exposure duration adjusted event rates will also provided. In summary, we will have: Run-ins The following summaries will be generated for AEs during the enalapril and LCZ696 run-ins: •

All adverse events

•

Serious adverse events

•

Adverse events causing study drug discontinuation

•

Investigator reported causes of deaths by primary system organ class and preferred term

•

Adjudicated primary causes of deaths

In addition, to account for the treatment administered during each run-in period the time of onset of an adverse event will be categorized according to the start dates of the run-in doses for the run-in dose level 2 and run-in dose level 3. Denominators will be the number of patients who received at least one dose of the respective run-in dose level. If a specific AE occurs multiple times or increases in severity within a patient during a run-in period it will be counted for each run-in step interval where it newly starts or increases in severity. The annualized exposure duration adjusted event rates will also provided. Double blind period The following summaries will be generated for AEs during the double blind period: •

All adverse events

•


•





•

Adverse events requiring dose adjustment or study-drug interruption

•


•

Adjudicated primary causes of deaths.

In addition to above standard analyses, for double blind phase, analysis for time-to-first selected AEs by treatment group will be performed using Kaplan-Meier estimate. The annualized exposure duration adjusted event rates will also provided.

10.4

Laboratory data

10.4.1

General laboratory data

Laboratory data will be summarized for each reporting phase as described before: Run-ins based on the ERS and LRS and double blind period based on the SAF. The summary of laboratory evaluations will be presented for three groups of laboratory tests: hematology, serum chemistry and urinalysis, which include hemoglobin, hematocrit, RBC count, WBC count, platelet count, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus, total protein, albumin, and uric acid. The eGFR is calculated according to the formula: eGFR (mL/min/1.73 m2) = 175 x (Serum creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if black), where serum creatinine is in µmol/L (SI unit) and age is non-rounded at the time of the laboratory sample in years. Descriptive summary statistics (mean, median, standard deviation, min and max) for the change from baseline to each study visit will be presented. These descriptive summaries will be presented by laboratory test and treatment group. Change from baseline will only be summarized for subjects with both baseline and post baseline values and will be calculated as: • change from baseline = post baseline value – baseline value Note that baselines (run-in and double blind period) are defined in Section 4. In addition, shift tables will be provided for all parameters to compare a subject’s baseline laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, low, or high for each visit value relative to whether or not the baseline value was normal, low, or high. These summaries will be presented by laboratory test and treatment group. The number and percentage of subjects with clinically notable laboratory results after baseline will be presented. Clinically notable laboratory results, for those parameters where ranges are available, are given in Table 10-4 below. For the calculation the denominator are based on the




evaluable post-baseline subjects who did not have the notable abnormality at baseline from the central laboratory. The following clinical laboratory values will be summarized graphically by treatment group and visit using mean plot with 95% CIs: creatinine, estimated glomerular filtration rate (eGFR), sodium, and potassium. For all laboratory evaluation scheduled and unscheduled laboratory measurements will be taken into account. Table 10-4

Clinical notable criteria for selected laboratory tests

Hematology RBC count Hemoglobin Hematocrit WBC count Platelet count Blood Chemistry ALT (SGOT) AST (SGPT) BUN Creatinine Total bilirubin CPK Alkaline phosphatase Sodium Potassium

Chloride Calcium Uric acid

>50% increase, >20% decrease >50% increase, >20% decrease >50% increase, >20% decrease >50% increase, >50% decrease >75% increase, >50% decrease >150% increase >150% increase >50% increase >14.28 mmol/L >50% increase >136.8 µmol/L >100% increase >300% increase >100% increase >5% decrease >20% increase, >20% decrease ≥6.0 mmol/L >5.0 mmol/L 10% increase, >10% decrease >10% increase, >10% decrease >50% increase

In the above table increase and decrease are defined as compared to the baseline value. Here baseline is defined as the run-in baseline for the run-in phases and the double blind baseline for the double blind phase. 10.4.2

Specific laboratory data

Liver function test (LFT) data will be analyzed according to what specified in hepatotoxicity in Table 10-3 in Section 10.3. Laboratory data related to renal impairment (serum creatinine, eGFR) will be analyzed according to what specified in renal impairment in Table 10-3 in Section 10.3.


10.5



Vital signs

Sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse rate and body weight will be summarized by treatment group and visit with standard summary statistics (mean, median, standard deviation, min, max), including changes from baseline. Baselines (run-in and double blind period) are defined in Section 4. Graphical mean plots with 95% CIs for these vital signs will also be provided. The descriptive summaries will be presented by vital sign and treatment group and visit. Change from baseline will only be summarized for subjects with both baseline and postbaseline values and will be calculated as: • change from baseline = post-baseline value – baseline value The number and percentage of subjects with clinically notable vital signs changes from baseline will be presented. Clinically notable vital sign results are provided in Table 10-5 below. Table 10-5

Clinically notable changes in vital signs

Vital Sign (unit) Weight (kg) Sitting systolic blood pressure (mmHg) Sitting diastolic blood pressure (mmHg) Pulse (bpm)

10.6

Clinically notable criteria decrease > 7% from Baseline increase > 7% from Baseline 20 >180 and increase from baseline of >20 15 >105 and increase from baseline of >15 15 >120 and increase from baseline of >15


The following quantitative variables will be summarized: heart rate and QRS duration. Summary statistics (n, mean, SD, min .Q1, median, Q3, max) for the change from baseline (Visit 5) in ECG intervals by visit and treatment will be provided. In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, total) with the maximum on-study result (normal, clinical significant, not available, total) will be provided for each variable. Clinical significant is defined if at least one abnormality: “atrial fibrillation, atrial flutter, LBB block, RBB block, pathological Q-waves, left ventricular hypertrophy, paced rhythm or other” is answered “yes”.

11


Data relating to resource utilization will be used to describe medical resources used by the study participants. Mainly descriptive statistics of resources utilization data will be provided by treatment group. However some analyses on resource utilization are already provided as part of the exploratory analyses described above.


12



Interim analyses

It is planned to have three formal interim efficacy analyses. The cutoff dates for the interim analyses are planned to be approximately at 1/3, 1/2 and 2/3 of information time (i.e. approximately 804, 1205, and 1607 patients, respectively, with a primary event of either CV death or HF hospitalization). However, some adjustment to the frequency and time for interim analyses may be made to coincide with the DMC meetings. One-sided testing will be performed and appropriate statistical adjustments for the interim analyses actually performed will be made to control the overall type-I error of 0.025. For each interim analysis, the analysis dataset will comprise all patients who were randomized before the cutoff date. The Haybittle-Peto type of boundary will be used for the interim efficacy analyses to assess superiority. The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (one-sided) at the first interim analysis and 0.001 (one-sided and nominal) at the second and third interim analyses. In case additional interim efficacy analysis is required, another 0.001 may be spent for the interim analysis and the alpha for the final analysis will be adjusted with Bonferroni method. In addition to the primary composite endpoint, the CV mortality component will also be analyzed at each interim efficacy analysis. When 1/3, 1/2, and 2/3 of the total number of primary patient events occur, approximately 410, 614 and 819 CV deaths, respectively, are also expected. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the above planned boundary are obtained for both primary composite endpoint and CV death component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment for the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. The proposed futility boundaries are: -1.312, 0, and 0.5 in Z-scale, which corresponds to 1.100, 1.000, and 0.975 in hazard ratio scale (LCZ696 versus enalapril). These boundaries will not be the sole consideration in the futility analyses; futility will also require that there is no observed benefit on biomarkers such as change from baseline vs. enalapril in NT-proBNP. Furthermore, these two considerations will be used only as a guideline for triggering discussion of stopping for futility. If the study is stopped early for claiming superiority efficacy due to statistically significant results for both primary endpoint and the CV death component at an interim analysis, the secondary endpoints will be tested using the same testing procedure as described in Section 9.3.2 for the final analysis at the overall alpha level equal to the one used for the interim analysis of the primary endpoint. Interim safety assessments are planned to be performed twice a year. As discussed in Section 4.2.6 of the protocol, in order to identify potential safety signals earlier, a formal blinded review of selected safety assessments is planned to will be performed when the first 200 patients have completed the first 4 weeks of double-blind randomized treatment. Additionally, reviews of selected safety assessments will be reviewed are planned when approximately the first 100, 300, and 600 patients completing who have completed (or discontinued) the run-in period. Summary of the selected safety assessments during the run-in period will be provided




for enalapril and LCZ696 separately. No further alpha adjustment will be made due to these interim safety assessments. Interim analyses will be performed by an independent statistician who will not be involved in the trial conduct. The results will be reviewed by the independent DMC. Investigators, Novartis employees, and others who are involved in the conduct of the trial will remain blinded to the treatment codes and IA results until all monitoring decisions have been made and the database has been locked for final analysis.

13

Power and sample size considerations

13.1

Power for primary endpoint

The sample size estimation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the efficacy interim analyses currently planned (Section 12). The targeted sample size mainly is driven by the CV mortality component of the primary composite endpoint. With a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril for CV mortality, using the log-rank test. Assuming an annual CV death rate of 7% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months, a total sample size of 7,980 patients will be required to obtain 1,229 CV deaths. By randomizing 7,980 patients in the study, assuming the same enrollment period, follow-up duration same as above, 15% reduction in hazard, and an annual primary event rate of 14.5% in the enalapril group, it is expected to attain greater than 97% power to detect a difference between treatments for the primary composite endpoint. This, in turn, corresponds to a total number of at least 2,410 patients with primary events during the course of the trial. The assumption of 14.5% annual event rate for the primary composite endpoint is based on the CHARM-Added trial (CHARM Investigators and Committees 2003). In that study the reported annual event rate was 14.1% in the candesartan group and 16.6% in the placebo group. In CHARM-Added all patients received ACEIs, such as enalapril, as background therapy, although the ACEIs may not have been administered at their top doses. Hence, an estimate of the annual primary event rate between the candesartan and placebo group in CHARM-Added would provide a reasonable estimate for event rate for the active comparator enalapril in the current study. Assuming further improvement in underlying HF therapy within the past 5 years since CHARM-Added was conducted, a more conservative annual rate of 14.5% was chosen for sample size calculation. The 7% CV mortality annual event rate is estimated from the CHARM-Added trial in a similar manner.

13.2

Power for secondary endpoints

The tests of secondary variables are part of the global testing strategy.




For the change from baseline to Month 8 in clinical summary score assessed by KCCQ, the above sample size will provide 96~99% individual power to detect a treatment difference of 2 points at the one-sided significance level of 0.00463 (i.e., 0.02314 × 0.2), assuming a standard deviation between 15 and 20. A standard deviation of 15 was observed in the published literature (Flynn et al 2009). For time to all-cause mortality, the above sample size will provide approximately 87% individual power to detect a 15% reduction in hazard at one-sided significance level of 0.0185 (i.e. 0.02314 × 0.8), assuming an annual event of 9% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months. The numbers in the assumption are estimated based on the CHARM-low LVEF trial (Young et al 2004). For time to composite renal endpoint, the above sample size will provide about 80% power to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.02314 and 0.004628 (i.e., 0.02314 × 0.2), respectively. It is assumed for the annual rate to be 0.021 based on the CHARM trials and AASK trial (Wright, Jr 2002).

14

Reference

1. Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially rejective multiple test procedures. Statist Med; 28:586-604. 2. CHARM Investigators and Committees (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: the CHARM-Added trial. Lancet; 362: 767-771. 3. Cook, RJ, Lawless, JF (1997) Marginal analysis of recurrent events and a terminating event. Stat in Medicine; 16:911-924. 4. Cowling BJ, Hutton JL, Shaw JEH (2006) Joint modeling of event counts and survival times. Appl. Statist; 55(Part 1):31-39. 5. Fleiss J, Statistical methods for rates and proportions. 2nd ed. 1981: John Wiley and Sons, Inc, New York 6. Flynn KE, Pina IL, Whellan DJ, et al (2009) Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA; 301: 1451-1459. 7. Ghosh, D, Lin, DY (2000) Nonparametric analysis of recurrent events and death. Biometrics; 56:554–562. 8. Kalbfleisch JD, Prentice RL (2002). The Statistical Analysis of Failure Time Data. 2nd ed. New York: Wiley 9. Lin DY, Wei LJ, Ying Z, Yang I (2000) Semiparametric regression for the mean and rate functions of recurrent events. J R Stat Soc; B, 62:711–730. 10. McCullagh P, Nelder JA. (1989) Generalized Linear Models, 2nd ed. London: Chapman and Hall. 11. SAS/STAT User’s Guide, version 9.3, SAS Institute, Inc., Cary, North Carolina.




12. Wei LJ, Lin DY, Weissfeld L (1989). Regression Analysis of Multivariate Incomplete Failure Time Data by Modeling Marginal Distribution. Journal of the American Statistical Association; 84, 1065–1073. 13. Wright, Jr JT, Bakris G, Greene T, et al (2002) Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA; 288:2421-2431. 14. Young JB, Dunlap ME, Pfeffer MA, et al (2004) Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction, results of the CHARM low-left ventricular ejection fraction trials. Circulation; 110:26182626. 15. Zeng D, and Lin DY (2009). Semiparametric Transformation Models with Random Effects for Joint Analysis of Recurrent and Terminal Events. Biometrics; 65:746-752.

Clinical Development

LCZ696B

Protocol number CLCZ696B2314


RAP Module 3 – Detailed Statistical Methodology

Author:

Jim Gong, Trial Statistician

Document type:

RAP Documentation

Document status:

Final version 1.0; Amendment 1

Release date:

April 8, 2014

Number of pages:

53

Property of Novartis Confidential May not be used, divulged, published or otherwise disclosed without the consent of Novartis


Confidential 9-Apr-2014 (1:16)

Page 2 CLCZ696B2314

Table of contents Table of contents ............................................................................................................. 2 List of tables ................................................................................................................... 4 List of figures .................................................................................................................. 4 GENERAL INSTRUCTIONS................................................................................................ 5 Statistical and analytical plans ................................................................................................ 5 1 Introduction .................................................................................................................... 5 2 Analysis sets ................................................................................................................... 5 3 Subgroup definitions and subgroup analyses ................................................................... 9 3.1 Subgroups ............................................................................................................ 9 3.2 Subgroup analyses ............................................................................................. 10 4 Definitions of baseline, post baseline, close-out and analysis cut-off ............................. 10 5 Missing date handling ................................................................................................... 13 5.1.1 Visit date missing .............................................................................. 13 5.1.2 Event date missing or partially missing .............................................. 13 5.1.3 Medication stop date missing ............................................................. 13 6 Subject Disposition, background and demographic characteristics ................................. 14 6.1 Subject disposition ............................................................................................. 14 6.2 Background and demographic characteristics ..................................................... 15 6.3 Medical history .................................................................................................. 16 7 Study medication .......................................................................................................... 16 7.1 Run-in phase ...................................................................................................... 16 7.1.1 Duration of treatment exposure .......................................................... 16 7.1.2 Dose levels ........................................................................................ 18 7.2 Double blind phase ............................................................................................ 18 7.2.1 Duration of treatment exposure .......................................................... 18 7.2.2 Dose levels ........................................................................................ 19 7.2.3 Other exposure analyses ..................................................................... 20 7.2.4 Treatment exposure in subgroups ....................................................... 20 7.3 Study exposure .................................................................................................. 21 8 Concomitant medication................................................................................................ 21 8.1 Run-in phase ...................................................................................................... 22 8.2 Double blind phase ............................................................................................ 22 9 Efficacy evaluation ....................................................................................................... 23 9.1 Event counting for efficacy ................................................................................ 26 9.2 Variables ........................................................................................................... 26 9.3 Statistical hypothesis, model, and method of analysis......................................... 29


10

11 12 13

14


Page 3 CLCZ696B2314

9.3.1 Primary analysis ................................................................................ 29 9.3.2 Secondary analysis ............................................................................. 30 9.3.3 Exploratory analysis........................................................................... 33 9.3.4 Missing data handling in efficacy analysis ......................................... 38 9.4 Efficacy measurements in run-in ........................................................................ 41 Safety evaluation ........................................................................................................... 41 10.1 Allocation of AEs .............................................................................................. 43 10.2 Analysis for the identified and potential risks in the risk management plan ........ 44 10.3 Adverse events (AEs) ........................................................................................ 45 10.4 Laboratory data .................................................................................................. 47 10.4.1 General laboratory data ...................................................................... 47 10.4.2 Specific laboratory data...................................................................... 48 10.5 Vital signs .......................................................................................................... 48 10.6 Electrocardiogram (ECG) .................................................................................. 49 Resource utilization....................................................................................................... 49 Interim analyses ............................................................................................................ 49 Power and sample size considerations ........................................................................... 51 13.1 Power for primary endpoint ............................................................................... 51 13.2 Power for secondary endpoints .......................................................................... 51 Reference ...................................................................................................................... 52



Page 4 CLCZ696B2314

List of tables Document History – Changes compared to previous version of RAP module 3. ..................... 5 Table 2-1 Rules for subject classification in the analysis sets based on protocol deviations and non-protocol deviation classification criteria ................................................................................................. 7 Table 2-2 Specification of protocol deviations which lead to exclusion from analysis sets ......................................................................................... 8 Table 3-1 Specification of subgroups ................................................................... 9 Table 9-1 Sketch of efficacy analyses ................................................................ 23 Table 10-1 Sketch of safety evaluation ................................................................ 42 Table 10-2 Allocation of AEs .............................................................................. 43 Table 10-3 Identified and potential risks .............................................................. 44 Table 10-5 Clinically notable changes in vital signs ............................................. 49

List of figures Figure 2-1 Figure 6-1

Analysis sets ........................................................................................ 6 Definition of study completer ............................................................. 14



Page 5 CLCZ696B2314

Document History – Changes compared to previous version of RAP module 3. Version Final 1.1

Date Nov. 5, 2013

Changes All changes are based on 1) FDA’s comments, including sensitivity analysis when MAR is not valid; 2) The protocol amendment of adding a new secondary endpoint of new onset of AF; 3) The internal reviewers’ comments on too many subgroups for subgroup analyses; (4) Between group comparison for EQ-5D based on index is deleted due to there exists no adequate weights for all countries in the study.

GENERAL INSTRUCTIONS To ensure consistency across studies within the project, the RAP refers to the CSU harmonization MAP for heart failure (version number Final 1.0) and can be found in Novartis Clinical Research Documentation and Information system (CREDI) under: Cabinets/CREDI Projects/L/LCZ696B/Administrative files /CIS (Clinical Information Sciences)/ Biostatistics/ MAP module 3 OR MAP module 3 amendment 1.

Statistical and analytical plans 1

Introduction

Data will be analyzed according to the data analysis section 10 of the study protocol which will be available in Appendix 16.1.1 of the CSR. Important information is given in the following sections 9 (Efficacy evaluation), 10 (Safety evaluation), 12 (Interim analysis) and 13 (Powers and sample size considerations).

2

Analysis sets

The following analysis populations will be defined for statistical analysis: • Screened set (SCR) – All patients who signed the informed consent. The screened set includes only unique screened patients, i.e., in the case of re-screened patients only the chronologically last screening data is counted. • Enrolled set (ENR) (run-in phase) – All patients who received at least one dose of run-in study drug. • Enalapril run-in set (ERS) – All patients who are in the ENR and received at least one dose of run-in enalpril. • LCZ696 run-in set (LRS) – All patients who are the ERS and received at least one dose of run-in LCZ696.



Page 6 CLCZ696B2314

• Randomized set (RAN) – All patients who received a randomization number, regardless of receiving trial medication. • Full analysis set (FAS) – All randomized patients. This is the primary efficacy population applied in efficacy analyses for all efficacy endpoints. Following the intentto-treat principle, patients are analyzed according to the treatment they have been assigned to at randomization. However, patients who did not qualify for randomization but were inadvertently randomized into the study and did not receive study medication may be excluded from FAS. Further exclusions from the FAS may only be justified in exceptional circumstances (e.g., serious GCP violations). These potential incidences imply the possibility that the FAS may be smaller than the RAN. • Per protocol set (PPS) – A subset of the FAS, consists of all randomized patients in FAS who received at least one dose of study drug during the double blind period of the study and have no major protocol deviations. Major protocol deviations are those affecting the primary endpoint analyses, which will be identified prior to the final database lock. • Safety set (SAF) – All randomized patients who received at least one dose of study drug during the double blind period of the study. Patients will be analyzed according to treatment received. Treatment received will be considered identical to the randomized treatment if the patient has received at least one dose of the randomized treatment. A graphic display of the defined analysis sets is illustrated in the following figure. Figure 2-1

Analysis sets

PPS FAS SAF RAN

ERS SCR

LRS ENR

All cases of prospectively defined protocol deviations will be identified prior to clinical database lock/unblinding and entered into a dedicated data panel as part of the locked



Page 7 CLCZ696B2314

database. Certain deviations may stipulate that only data up to the time of infraction will be included in the per-protocol analysis, i.e. for analyses of the PPS data beyond this time-point will be ignored. This supplemental efficacy population is used to assess robustness of the primary analysis results for study to claim superiority. All exceptional cases and problems and the final decisions on the allocation of patients to populations will be fully defined and documented before database lock (in particular before breaking the blind where applicable) and will be fully identified and summarized in the clinical study report according to ICH E9. Criteria defining protocol deviations are referenced in the EDC VAP module 3--data processing document. Protocol deviations severity codes defined in VAP module 3 that lead to subject classification into the analysis populations as follows: Severity Codes

Actions

0

Exclude from all efficacy analyses (FAS, PPS)

1

Exclude from Per-Protocol analysis (PPS)

5

Exclude from Main safety analyses (SAF)

6

Exclude from Main Analysis Set (RAN, FAS, PPS)

8

Exclude from all analysis

Table 2-1

Rules for subject classification in the analysis sets based on protocol deviations and non-protocol deviation classification criteria

Analysis set Screened Enrolled Randomized

PD severity codes that cause a subject to be excluded NA NA 6

Safety

5, 8*

Full Analysis Set (FAS)

0, 6, 8*

Non-PD criteria that cause a subject to be excluded NA NA - Patient without a randomization number - Patients not receiving any dose of double-blind study medication

- Patient without a randomization number Per Protocol set (PPS) 0, 1, 6, 8 * - Patient without a randomization number * E.g.: Patient randomized twice with full parallel administration of double blind (DB) medication with severity code. With the severity code the data is kept into the database and no elimination of the efficacy data due to questionable GCP adherence is necessary. The team can re-evaluate patients post CDBL and after unblinding. E.g. it could happen that the patient is randomized to exactly the same treatment group or randomized to placebo in the one center and active medication in the other one. In both cases the patient could be eligible for further sensitivity analysis. For the latter one the patient can be considered as randomized to one active medication group.



Page 8 CLCZ696B2314

The following Table 2-2 contains a sample of current study specific important protocol violations that lead to exclusion from analysis sets in the study. The final list may be different from this and will be signed before DBL. Table 2-2

Specification of protocol deviations which lead to exclusion from analysis sets

Category

Description of Protocol Deviation

Inclusion / Exclusion in analyses

Identificati on method

General

GCP issue present at site

Excluded from PPS,FAS Excluded from PPS Excluded from PPS Excluded from SAF

Manual

Blind broken locally Wrong treatment allocation Study treatment

Exclusion criteria

Inclusion criteria

Patient enrolled in Run-in period but no study medication taken. Patient was misrandomized (patient randomized in error and no DB study medication taken). Diagnosis of peripartum or chemotherapy induced cardiomyopathy within 12 months prior to Visit 1. History of severe pulmonary disease. LVEF > 40% at Visit 1 (Original Protocol). LVEF >35% at Visit 1 (Amendment 1) Heart transplant or ventricular assistance device (VAD) or intent to transplant (on transplant list) or implant a VAD Current acute decompensated heart failure. Informed consent missing

NYHA Class I or no heart failure at Visit 1

Manual

Person responsible for identification Field monitor (FM) FM

Manual

FM

Programma ble

TDM

Excluded from PPS, FAS, SAF, RAN

Manual

FM

Excluded from PPS

Manual

FM

Excluded from PPS Excluded from PPS

Manual

FM

Programma ble

TDM

Excluded from PPS

Manual

FM

Excluded from PPS

Manual

FM

Excluded from PPS,FAS, SAF, RAN Excluded from PPS

Manual

FM

Manual

FM



Page 9 CLCZ696B2314

3

Subgroup definitions and subgroup analyses

3.1

Subgroups

Subgroups will be formed for the analyses for the FAS or SAF depending on the parameters under consideration to explore the consistency of treatment effects and safety profiling between the subgroups and the overall population. In general, subgroups will be defined based on baseline information. In this study, since we have a run-in phase to test patients’ tolerability to the study drugs before they can enter the double blind phase, we have defined two baselines (Section 4): the run-in baseline and the double blind baseline. Subgroups will be formed using one of these baselines according to their analysis purposes. In Table 3-1, we have listed all subgroups defined for this study and the ways to derive them. In different analysis, such as efficacy analysis or safety analysis, a different subset of them will be selected. Also note that only important parameters or variables in these analyses will have sub-group analyses. The details about the parameters having subgroup analyses will be presented in the corresponding sections below. Also, additional subgroups may be formed later for regional or country-wise analyses. Table 3-1

Specification of subgroups

Subgroup

Method of Derivation

Disposition /Background & demo. /Exposures

Efficacy (Primary and secondar y)

Age groups: median Baseline LVEF ≤35% vs. >35%

Randomization

x

Randomization (Derived) Randomization (Derived) Screening

x

Screening

x x x

x

Health economic s (KCCQ and EQ5D only)

x

Safety

x

Novartis RAP Module 3 Atrial Fibrillation at baseline based on ECG at V5: yes/no Baseline NTproBNP**: ≤ median and > median Hypertension at baseline: yes/no Prior use of ACEi Prior use of ARB Use of Aldosterone antagonist at baseline: yes/no Time since diagnosis of HF: ≤ 1 year, 1-5 years, > 5 years Prior heart failure hospitalization UK***



Randomization

x

Screening

x

Screening

x

Screening

x

x

Screening Randomization (Derived)

x x

x

Screening

x

x

Screening

x x

* North America: USA, Canada Latin America (including Central America): Argentina, Brazil, Chile, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Panama, Peru, Venezuela Western Europe: Belgium, Denmark, Finland, France, Germany, Iceland , Italy, Netherlands, Portugal, Spain, Sweden, UK, Israel, South Africa Central Europe: Bulgaria, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Rep. of Slovakia, Romania, Russia, Turkey Asia/Pacific and other: China, Hong Kong, India, Rep of Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand. ** It is not pre-specified in the protocol; ***It is not pre-specified in the protocol and it will be performed only for limited analyses.

3.2

Subgroup analyses

Subgroup analyses will be performed depending on the analysis purposes. Subgroups selected and types of analyses are specified in Table 3-1 and will be detailed later in the sequel sections. In principle, there will be no adjustment for multiple comparisons for subgroup analyses.

4

Definitions of baseline, post baseline, close-out and analysis cut-off

Single-blind run-in phase (run-in phase) The run-in phase is defined as the period between start of study drug and prior to randomization. The run-in phase will be divided further into the enalapril run-in phase and the LCZ696 run-in phase. The start of enalapril phase is the date the patient receives the run-in dose of enalapril. In principle, the day before a patient receives the first dose of LCZ696 (any




dose level) will be the end of the enalapril run-in phase and the day patient receives the first dose of LCZ696 will be the start day for the LCZ696 run-in phase for that patient. If the date of the start day of receiving LCZ696 is missing, then the date of Visit 3, which is the protocol specified run-in drug switching day, will be used as the start date for the LCZ696 phase. If the date of the last dose of enalapril run-in medication falls on the same day of the first dose of LCZ696 run-in medication, this day will be considered the end of the enalapril run-in phase and the following day will be considered as the start of the LCZ696 run-in phase. The LCZ696 run-in phase ends at the time when the patient receives the randomization drug. During these two run-in phases, patients will be on the run-in drugs in a single blind manner. Randomized treatment phase The randomized treatment phase begins at the time of randomization and ends with the last study drug intake or the death of the patient, whichever is earlier. During the randomized treatment phase, subjects will return for scheduled clinic visits. For all related safety analyses randomized treatment starts with the first intake of randomized, double-blind study medication. Temporary discontinuation of the study drug will not be counted as treatment phase discontinuation. Post-randomized treatment phase Post-randomized treatment phase (after unscheduled drug discontinuation) begins after last study drug intake + 1 day and ends up on the date last seen (or vital status confirmed by indirect contact). Double-blind (DB) phase Combined on-randomized treatment and post-randomized treatment phase. Baseline for run-in phase The run-in baseline is defined as the last available measurement prior to or at time of Visit 2 or Visit 2A, whichever is earlier. Baseline for double blind phase Baseline for the double blind phase is defined depending on the parameter considered. In general, based on the principle described in the protocol, the baseline for the double blind phase is defined as the last available measurement during the LCZ696 run-in phase including the time of randomization (general Visit 5/Randomization). For the parameters that were not designated to have measurements collected during the LCZ696 run-in or at randomization, the run-in baseline may be used as the baseline for the double blind phase. The following parameters will have the double blind phase baseline at randomization visit: NYHA class, HF signs and symptoms, vital signs, waist/hip circumference, plasma BNP/NTproBNP, biomarkers (sub-study patients only), eGFR, safety laboratory values, endpoints, 1st morning urine (sub-study patients only), lab assessments, ECG, patient global assessment (it is assumed that patients will assess their status comparing to that at randomization), KCCQ scores and EQ-5D assessments.




The following parameters will have their double blind phase baseline measured at screening phase, i.e., prior or at visit 2 or 2A: Height/weight, heart failure and CV medications, histories (CV disease, HF, and medical), demography, and incl/excl criteria. Note that since the values of patient characteristics will change during run-in, the double blind phase baselines for some parameters will be derived based on the data collected at randomization, such as diabetes status and atrial fibrillation status. Post-baseline definition Any measurements taken after baseline will be considered as post-baseline measurements. In analysis, this will be further classified according to run-in phase and double blind phase: runin post-baseline and double blind post-baseline. Unscheduled visit Only for the analysis of safety laboratory evaluation unscheduled measurements will be taken into account. For efficacy evaluations, measurements from unscheduled visits will generally not be used for analysis, unless specifically specified, such as eGFR. Analysis cut-off date (Study endpoint for analysis) The trial was designed to be terminated when 2410 patients have experienced a confirmed primary composite event. The analysis cut-off date is a predicted date when either the targeted number of 2410 patients experienced a primary composite event has met with confidence based on available data or a study termination date has been decided based on other study termination decisions. Final visit Final visit will be the last time a patient’s study record has been taken. For a patient who is still alive and in the study the final visit will be his/her last clinical visit. For a patient who died or is determined to be lost to follow-up (see Figure 6-1 for the illustration of lost-tofollow-up) before the analysis cut-off date, the final visit will be his/her death/lost-to-followup day. For a patient who is alive but no longer has regularly scheduled clinic visits and whose study records only can be obtained by telephone or indirect contact, the final visit will be the day the study records being taken. Close-out date The close-out date will be the date when the study sites are informed to schedule patients’ final visits for those patients who are still alive. It is expected to occur within three months before the analysis cut-off date, depending on the timing the final visits can be scheduled in each site.



5

Missing date handling

5.1.1

Visit date missing


In any analysis or evaluation, if the visit date(s) is used but is missing, then the date(s) calculated base on the planned date(s) in the schedule specified in the protocol should be used to impute the missing date(s). 5.1.2

Event date missing or partially missing

If the date of an event is not known or is incomplete, the imputation rules are: a) If the day of the event is unknown, then the 15th day of this month will be imputed for a missing day; b) If only the month is unknown, then July will be used for imputation of the missing; c) If only the year of the event is known, then the 1st of July will be imputed for a missing day and month; d) The above rules are only for general case. If there is additional information available for the missing date, then the information should be used and the imputation of missing date should be treated differently. For example, if an event occurs between two visits and its date is missing, then the date in the middle of these visits may be used. 5.1.3

Medication stop date missing

If medication stop date is unknown or is incomplete, the imputation rules are: a) If only the day field of the drug stop is missing, then the missing date is imputed by using the 15th of the month; b) If year and month are missing, then use the next scheduled visit date (using the protocol specified visit schedule) from the previous last non-missing visit date to replace the missing drug stop date; c) If the drug stop date is completely missing, then: a. If patient had fatal AEs (identified as either start or end date is equal to the date of death and the AE is flagged as an SAE), handling rules are (in the specified order): i. AE end date is not missing: use the AE end date to replace the missing drug stop date; ii. AE end date is completely missing but AE onset date not missing: use the AE onset date to replace the missing drug stop date; iii. AE end date is partially missing (only day field is missing): use Novartis standard procedure to impute the AE end date, and then use the imputed AE end date to replace the missing drug stop date; iv. AE end date is completely missing and AE onset date is partial missing (missing the date field only): impute the AE onset date using Novartis




standard procedure, and then use the imputed AE onset date to replace the missing drug stop date; v. If both the AE onset and end dates are completely missing, then use the last previous non-missing visit date plus 35 days to replace the missing drug stop date. b. If patients had no fatal AEs, handling rules are the same with the case that year and month are missing.

6

Subject Disposition, background and demographic characteristics

6.1

Subject disposition

The number and percentage of patients successfully screened will be presented. In addition, the reasons for screen failures will be provided. For patient who was screened more than once, the information from the last screen will be used in the summary. The analysis set is the SCR. The number and percentage of subjects enrolled, completed, and failed in run-in will be summarized for the enalapril run-in and LCZ696 run-in separately. The reasons for run-in failures will be provided. The analysis set is the ENR. The same information for the ERS and LRS will also be provided. The number of subjects randomized (RAN) and included in the full analysis set (FAS) will be presented by treatment group. The number and percentage as well as the reasons that subjects had been excluded from the RAN will be summarized by treatment group. The number and percentage of subjects in the FAS who completed the study (“Study completer” see also Figure 6-1), who discontinued the study and the reasons for discontinuation will be presented for each treatment group. The number and percentage of subjects with protocol deviations as well as the criteria leading to exclusion from analysis sets will be presented in separate tables for the FAS. Study completer is defined as the one died or having vital status available after the close-out date. Furthermore, the number of subjects enrolled and randomized per region and per country will be presented descriptively for the ENR and the FAS, respectively. Figure 6-1

Definition of study completer Last visit after start of close-out = completer Died before close-out = completer Died during close-out = completer Follow-up* obtained during close-out w/o office visit = completer No follow-up* at least to start of close-out = lost to follow-up



Run-in

Page 15 CLCZ696B2314 Close-out

Randomization

Start of close-out

CDBL

Analysis cut-off

*: Follow-up means patient’s vital/medical status information. It may be obtained through indirect contact.

As described in Section 3, the disposition analysis will be repeated for the following subgroups: •

Age group 30 mL/min/1.73 m2 decline in eGFR relative to baseline to a value below 60 mL/min/1.73 m2, or (3) reaching ESRD

Exploratory variables •

Time to first occurrence of a composite event of CV death, hospitalization for HF, non-fatal MI, non-fatal stroke or resuscitated sudden death o Time to first occurrence of a composite event of CV death, non-fatal MI, nonfatal stroke or resuscitated sudden death o Time to first occurrence of a composite event of CV death, non-fatal MI, and non-fatal stroke




o Time to first occurrence of MI and stroke o Time to first occurrence of MI o Time to first occurrence of stroke o Time to first occurrence of resuscitated sudden death •

Time to first all-cause hospitalization

•

Time to first cause-specific hospitalization, such as cardiovascular hospitalization

•

Number of hospitalization admissions (all-cause and cause-specific)

•

Number of days alive out of the hospital at Month 12

•

Rate of change in eGFR from baseline to last available value

•

Time to study treatment failure defined as: addition of a new drug for treatment of worsening HF, IV treatment requirement, or increase of diuretic dose (e.g., more than 80 mg furosemide) for persistent use for more than one month

•

Change in the clinical composite assessment at Month 8

•

Time to new onset diabetes mellitus (NODM)

•

Changes in health-related quality of life (assessed by total score and individual scores of the sub-domains from the KCCQ and assessments of the EQ-5D for health status)

•

Time to first coronary revascularization procedures

•

Changes from baseline to pre-defined time-point in pre-selected biomarkers (e.g., vascular, renal, collagen, metabolism, and inflammatory biomarkers)

•

Number of days/stays in ICU, number of re-hospitalizations, and number of ER visits for heart failure

•

Variables for measuring the PK parameters of valsartan, AHU377, and LBQ657 at steady-state in patients receiving LCZ696 using population modeling and/or noncompartmental based methods

•

Number of recurrent HF hospitalization; number of recurrent composite events of CV mortality and HF hospitalization; number of recurrent composite events of CV death, HF hospitalization, MI, stroke, and resuscitated sudden death; number of recurrent composite events of CV mortality, MI, and stroke; number of recurrent composite events of MI, and stroke; number of recurrent events of MI; number of recurrent events of stroke (This item is not specified in the protocol.)

•

Indicator of re-hospitalization within 30 days (This item is not specified in the protocol.)

Among the variables above, some of them or their components need to be adjudicated to confirm the reported types and occurrences based on the unified criteria for analyses. The adjudication of these events is based on an adjudication process through an independent Endpoint Adjudication Committee. The following events will be assessed by the Endpoint Adjudication Committee during the study:




•

All death events

•

Unplanned hospitalization for HF

•

MI

•

Stroke

•

Resuscitated sudden death (successful resuscitation following cardiac arrest)

•

Renal dysfunction (including occurrence of end stage renal disease)

•

Others (NOAF, NODM)

In the analysis, unless specified specifically, only adjudicated events will be utilized if the events included in the analysis are required to be adjudicated. Note that in the sensitivity analysis, the reported events may be used for the analysis. As specified before, all events and endpoints occurred or measured prior to or at the specified analysis time-points (such as Month 8, Month 12, etc.), including the analysis cut-off date, will be counted. Censoring variables Number of events and time-to-event variables are usually subject to censoring. The censoring can be caused by withdrawal of consent, lost to follow-up, other competing events, or administrative reasons (interim or final analysis cut off date). Below are the rules for deriving censoring variables in the analyses (primary, secondary, exploratory) except for the perprotocol analysis: •

For all-cause death, the censoring will occur at minimum (date of withdrawal of consent, last known alive date, analysis cut off date)

•

For CV death, the censoring will occur at minimum(date of withdrawal of consent, last known alive date, analysis cut off date, date when patient died for non-CV causes)

•

For non-mortality and non-composite endpoint, the censoring will occur at minimum(date of withdrawal of consent, date of lost to follow-up, analysis cut off date, date when patient died)

•


On-treatment analysis is referring to the sensitivity analysis for the primary endpoint based on the FAS and with events censored after premature discontinuation of study drug. The events occurred after having major protocol deviations need to be censored. The censoring variables for the on-treatment analysis are: •

For CV death, the censoring will occur at minimum(date of withdrawal of consent, last known alive date, analysis cut off date, date patient died for non-CV causes, date of premature discontinuation of study drug (end of on-treatment phase))

•

For non-mortality and non-composite endpoint, the censoring will occur at minimum(date of withdrawal of consent, date of lost to follow-up, analysis cut off date, date patient died, date of premature discontinuation of study drug)


•




Per-protocol analysis is referring to the sensitivity analysis for the primary endpoint based on the PPS. The events occurred after having major protocol deviations need to be censored. The censoring variables for the per-protocol analysis are: •

Minimum(the censoring time defined for the primary, secondary, exploratory analyses, date of the first major protocol deviation).

9.3

Statistical hypothesis, model, and method of analysis

9.3.1

Primary analysis

All primary events occurred between randomization and the analysis cut-off date will be included in the primary analysis. 9.3.1.1

Analysis for primary endpoint

The primary hypothesis to be tested is H10: λ2 / λ1 ≥ 1 versus H1a: λ2 / λ1 < 1, where λ1 and λ2 are hazards for enalapril treatment and LCZ696 treatment, respectively. The primary efficacy variable will be analyzed using Cox’s proportional hazards model with treatment and region as fixed-effect factors. The overall type I error rate will be controlled at 2.5% (one-sided). Thus one-sided significance level of α will be used for the final analysis, which has been adjusted for the interim efficacy analyses and will be decided after the last interim analysis. The estimated hazards ratio and the corresponding two-sided (1- α)100%-confidence interval will be provided. The FAS will be used for the primary analysis. 9.3.1.2

Supportive analyses

In addition to the primary analysis, the primary efficacy variable will also be analyzed using the same primary analysis model for the PPS and for the on-treatment analysis. A supplemental log-rank test will be performed for all the analyses. Survival function for each treatment group will be estimated by Kaplan-Meier method and the Kaplan-Meier curves will be presented in all the analyses. The frequency and percentage of patients who reach the primary composite endpoint will be provided by treatment group for all the analyses. Additionally, similar analyses will be performed for each of the components of the composite endpoint with all events for that component that occurred during the double blind period of the study to quantify the strength of the effect for each component in the primary composite endpoint. The estimated hazards ratios and the corresponding two-sided 95%-confidence intervals will be provided. Their Kaplan-Meier curve estimates will also be provided. The FAS will be used for the analysis. Time to first investigator reported composite event of CV death and heart failure hospitalizations will also be performed using the Cox regression model with treatment a factor and stratified by region. Effect size based on hazard ratio, its confidence interval, and KMestimates will also be provided.




Note that when there is a difference in CV death between treatment groups in favor of LCZ696, the estimated reduction in hazard ratio for non-CV mortality endpoint will be smaller than its actual size. However when the difference is not in favor of LCZ696, then the estimated reduction for non-CV mortality endpoint may be greater than its actual size. Further analysis that can model the impact on non-CV mortality endpoints from the CV mortality may be needed. The joint-frailty modeling method (Zeng and Lin 2009; Cowling, Hutton, Shaw 2006) will be utilized for this analysis. 9.3.1.3

Subgroup analysis

A full set of subgroups will be looked at for subgroup analysis for the primary endpoint and its components, as outlined at Section 3. Subgroup analyses will be performed for the FAS. To explore beneficial effects in subgroups or homogeneity of beneficial effects among subgroups, the estimated hazard ratio, two-sided 95% confidence interval, and within subgroup p-value and p-value for the test for the treatment-by-subgroup interaction will be provided for each of the subgroups based on the Cox’s proportional hazards model in which treatment, subgroup, and treatment-by-subgroup are included as fixed-effect factors. It should be aware that positive findings from these subgroup analyses have to be interpreted with caution since there is a non-negligible chance of false positives. Kaplan-Meier estimates will be provided for each subgroup. Additionally, the frequency and percentage of patients reaching primary composite endpoint will be presented by treatment group for each of the subgroups. The Kaplan-Meier curves and hazards ratios from each subgroup will be graphically displayed using forest plot. 9.3.1.4

Model checking

The assumption of proportionality between treatment groups in the Cox proportional hazards model used for the primary analysis will be checked graphically. If a critical departure from the proportionality assumption is observed, further investigation on the adequacy of the primary analysis results, such as estimated effect size, will be granted. 9.3.2

Secondary analysis

9.3.2.1

Multiplicity adjustment among secondary comparisons

The secondary null hypotheses will be tested and statistical inferences will be made only if the primary null hypothesis is rejected. The three secondary efficacy variables will be tested for superiority of LCZ696 to enalapril for the FAS. For each secondary variable, the null hypothesis of no treatment difference between LCZ696 and enalapril will be tested against the alternative hypothesis that LCZ696 is more effective than enalapril. The sequentially rejective multiple test procedure (Bretz et al 2009) will be used for the secondary efficacy comparisons in order to control the alpha level which is the same as the adjusted alpha for the final analysis of the primary efficacy variable. As indicated in Figure 9-1, after rejection of the primary null hypothesis (H10), the sequentially rejective multiple test procedure for the secondary variables is illustrated below: • The initial allocation of significance levels are 0.2α, 0.8α, 0α, and 0α for the comparisons of KCCQ clinical summary score (noted as H210), all-cause mortality


•

•

•



(noted as H220), new onset AF (noted by H230), and the composite renal endpoint (noted as H240), respectively. If both of the hypotheses H210 and H220 are rejected at the initially assigned alpha levels, then H230 (the new onset AF endpoint) will be tested at the level of alpha. o If H230 is rejected at this level, then full α will be passed to test H240. o If H230 is not rejected at this α level, then no further hypothesis will be formally tested. If the hypothesis H220 is rejected and H210 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.8α. o If H230 is rejected at this 0.8α level, then 0.8α will be passed to test H240. If H240 is rejected at 0.8α level, then 0.4α (1/2 of 0.8α) will be passed to H210. Subsequently H210 will be re-tested at 0.6α level (0.2α + 0.4α). o If H230 is not rejected at this 0.8α level, then no further hypothesis will be formally tested. If the hypothesis H210 is rejected and H220 is not rejected at the initially assigned alpha levels, then H230 will be tested at the level of 0.2α. o If H230 is rejected at this 0.2α level, then 0.2α will be passed to test H240. If H240 is rejected at 0.2α level, then 0.1α (1/2 of 0.2α) will be passed to H220. Subsequently H220 will be re-tested at 0.9α level (0.8α + 0.1α). o If H230 is not rejected at this 0.2α level, then no further hypothesis will be formally tested.

Figure 9-1 Illustration of weights for alpha relocation in the sequentially rejective multiple test procedure for the secondary hypotheses 0.2α 0.8α H210

H220 0α

1

1

H230 1/2

0α

1

1/2

H240 H210 denotes the null hypothesis for the comparison of KCCQ clinical summary score. H220 denotes the null hypothesis for the comparison of all-cause mortality. H230 denotes the null hypothesis for the comparison of new onset AF. H240 denotes the null hypothesis for the composite renal endpoint.

For publications, these secondary variables may be further assessed using full level of alpha without consideration of multiplicity adjustment.


9.3.2.2



Analysis of KCCQ clinical summary score at 8 months

The KCCQ instrument includes several domains. Only the domains that address HF symptoms and physical limitations will be analyzed. The clinical summary score of KCCQ is computed as the mean of the following available domain scores: • Physical limitation score • Total HF symptom score Change from baseline in the clinical summary score of KCCQ will be analyzed based on a repeated measures ANCOVA model in which treatment, region, visit (Month 4, and Month 8), and treatment-by-visit interaction will be included as fixed-effect factors and baseline value as a covariate, with a common unstructured covariance matrix among visits for each treatment group. The treatment comparison between LCZ696 and enalapril for the secondary objective is to be made at Month 8. The analysis will be performed based on all available data up to 8 months in the FAS and based on likelihood method with an assumption of missing at random (MAR) for missing data. The estimated between and within treatment effects with the associated two-sided 95% confidence intervals at Month 8 will be provided. Missing data handling in forming the KCCQ scores follows the algorithms defined in Section 9.3.4.2. To investigate the sensitivity of the analysis results based on the MAR assumption, we will perform an analysis using a pattern mixture model approach which assumes, besides the imputation with 0 for the KCCQ scores after death, that missing KCCQ scores after HF hospitalizations were missing not at random (MNAR). This sensitivity analysis would first create multiple (100) imputations of missing KCCQ values under a MAR assumption, resulting in multiple (100) complete data sets. The imputation model assumes a multivariate normal model for the 3 KCCQ measurements at baseline, Month 4 and Month 8. This model will be estimated separately within each treatment by region stratum. For each completed data set, the imputed values at a given visit of patients who had a HF hospitalization since the preceding visit, a penalty factor ( 5 years.

9.3.4

Missing data handling in efficacy analysis

9.3.4.1

Time to event variables

For time-to-event variables, the censoring rules are presented in Section 9.2. 9.3.4.2

KCCQ clinical summary score

The clinical summary score is a mean of the physical limitation and total symptom scores. The total symptom score is the mean of the symptom frequency and symptom burden scores. Each scale score (the physical limitation, symptom frequency or symptom burden) is calculated as the mean of its item scores and transformed to a 0–100 scale, with higher score indicating higher level of functioning. A score of 100 represents perfect health whereas a score of 0 represents dead. For patients who die, a worst score (score of 0) will be imputed for the clinical summary score at all subsequent scheduled visits after the date of death where the clinical summary score would have been assessed. Below are the rules each scale score being calculated: 1. Physical Limitation •

Code responses to each of Questions 1a-f as follows:




Extremely limited = 1 Quite a bit limited = 2 Moderately limited = 3 Slightly limited = 4 Not at all limited = 5 •

Limited for other reasons or did not do =

If at least three of Questions 1a-f are not missing, then compute •

Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4

Note: references to “means of questions actually answered” imply the following. If there are n questions in a scale, and the subject must answer m to score the scale, but the subject answers only n-i, where n-i >= m, calculate the mean of those questions as (sum of the responses to those n-i questions) / (n-i) not (sum of the responses to those n-i questions) / n 2. Symptom Frequency Code responses to Questions 3, 5, 7 and 9 as follows: Question 3 •

Every morning = 1

•


•


•


•


Questions 5 and 7 •

All of the time = 1

•

Several times a day = 2

•

At least once a day = 3

•


•


•


•


Question 9 •

Every night = 1



•


•


•


•



If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: •

S3 = [(Question 3) – 1]/4

•

S5 = [(Question 5) – 1]/6

•

S7 = [(Question 7) – 1]/6

•

S9 = [(Question 9) – 1]/4

Symptom frequency score = 100*(mean of S3, S5, S7 and S9) 3. Symptom burden Code responses to each of Questions 4, 6 and 8 as follows: •

Extremely bothersome = 1

•

Quite a bit bothersome = 2

•

Moderately bothersome = 3

•

Slightly bothersome = 4

•

Not at all bothersome = 5

•

I’ve had no swelling/fatigue/shortness of breath = 5

If at least one of Questions 4, 6 and 8 is not missing, then compute Symptom burden score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4 4. Total symptom score = mean of the following available summary scores: Symptom frequency score Symptom burden score 5. Clinical summary score = mean of the following available summary scores: •

Physical limitation score

•

Total symptom score

9.3.4.3

Other variables

For the variables other than those mentioned above, double blind post-baseline LOCF will be utilized for imputing missing data unless specific rules are mentioned in the analysis sections. If it deems necessary, multiple imputations method may be used in addition to the available




data analysis for each variable when the missing at random assumption is considered reasonable.

9.4

Efficacy measurements in run-in

Because of the different lengths of durations and sequential follow-up nature for the two subrun-in phases, the analysis results for the two sub-run-ins must be interpreted with caution. Percentage without adjusting exposure duration is apparently not meaning for comparison between the two phases. Even the exposure adjusted rates will not be adequate for treatment comparisons due to the sequential follow-up nature of the two sub-run-ins. Many efficacy parameters discussed above are also measured during run-in phase, such as the information of endpoints, new onset of diabetes mellitus, new onset of atrial fibrillation, and NYHA classification and heart failure signs/symptoms. Since all patients will take the same study drugs during run-in, the focus of our efficacy analysis for the run-in data will be on checking balances of efficacy profiles between the two treatment groups assigned at randomization based on the FAS, though the total summary will also be provided sequentially based on the ERS and LRS for providing the information over time prior to randomization. The frequency of patients with endpoint events, including the composite endpoints (first event), occurred during run-in will be summarized separately for the enalapril and LCZ696 run-ins and the treatment exposure adjusted event rates (annualized incidence rates) will be provided, based on the ERS and LRS. Similar summaries will also be provided for all patients in the FAS and for each treatment group as assigned at randomization in the FAS. The frequency and percentage of patients in each NYHA classification or HF signs/symptoms category will be summarized similarly for the FAS and for each visit where data were collected during run-in. The endpoint information summary will be provided for both investigator reported and CEC adjudicated.

10

Safety evaluation

Safety will always be evaluated based on the ERS and LRS for run-in phase and the SAF for double blind phase. For the purpose of simplifying the description of the analysis methods, in the following, the terms “by treatment group” in the safety analysis will always mean in sequential order of enalapril (ERS) then LCZ696 (LRS) for the two run-in periods. The safety evaluation will include: •

Specific identified and potential risk and safety factors evaluation

•

Adverse events

•


•

Vital signs

•

Electrocardiogram




The following subgroups will be evaluated for safety, except for the specific identified and potential risk analysis: •

Age group 6.0 mEq/L and >6.5 mEq/L by treatment. 1. Blood pressure summary (mean, standard deviation, median, and range) including measurement at each visit and change from baseline will be provided by treatment 2. Summary with frequency and percentage by treatment for patients with: a. systolic blood pressure (SBP) 50%, and >30 mL/min/1.73 m2; b. Serum creatinine increase by >50%; c. Serum creatinine level >0.5 mg/dL, >2.0 mg/dL, >2.5 mg/dL, >3.0 mg/dL 3. Subgroup analyses on the relationship between eGFR < 60 and >60 mL/min/1.73 m2 at baseline and incidence rate/severity of AEs/laboratory parameters indicating newly occurred/worsening of renal impairment.

Hypotension

Angioedema Renal impairment



Risks

Analysis

Gastric lesions Hypersensitivity reaction (excluding angioedema) Hepatotoxicity

Standard statistical analysis Standard statistical analysis

Change in bone growth/bone mineral density Stimulation of lipolysis Change in cognitive function QT-Prolongation (Routine risk)

10.3


1. Summary with frequency and percentage by treatment for patients with: a. ALT or AST >3x ULN; b. ALT or AST >5x ULN; c. ALT or AST >8x ULN; d. ALT or AST >3x ULN and TB >2x ULN; e. TB >3x ULN and AST or ALT are ≤3 x ULN and alkaline phosphatase ≤1.5x ULN; f. AP >3x ULN and AST, ALT, TB are within normal range. 2. A cross-tabulation of baseline and worst post-baseline values by below, within and above normal range categories will be provided. Shift tables will be provided for the parameters AST, ALT, TB and AP. Standard statistical analysis

Standard statistical analysis Standard statistical analysis Standard statistical analysis

Adverse events (AEs)

Any AE occurred during the study period will be included in AE summary tables as described in Section 10.1, i.e., AEs occurred in run-ins, double blind period, and SAEs up to one-month after the study completion. The incidence of treatment-emergent adverse events (new or worsened) will be summarized by primary system organ class, preferred term, severity, and relationship to study drug according to the Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used for reporting the study will be described in a footnote. Within each reporting phase (run-ins or double blind, see Table 10-2), the following rules are applicable. If a subject reported more than one adverse event with the same preferred term, the adverse event with the greatest severity will be presented. If a subject reported more than one adverse event within the same primary system organ class, the subject will be counted only once with the greatest severity at the system organ class level, where applicable. Statistical analyses, which will only be performed for the double blind or later phase, will include all post-baseline AEs up to and including the analysis cut-off (AEs up to the final visit and SAEs up to 30 days after the final visit for each patient) irrespective of how long after the last day of study treatment they occurred. The number and percentage of subjects reporting any adverse event during each reporting phase will be summarized by primary system organ class, preferred term and treatment. The most common adverse events reported (‡ 1 % in any group for each preferred term in the




SOC-PT table) will be presented in descending frequency according to its incidence in the LCZ696 group starting from the most common event. Separate summaries, for each reporting phase (run-ins and double blind), will be provided for study medication related adverse events, death, serious adverse event, other significant adverse events leading to study discontinuation and adverse events leading to dose adjustment. Specific interested AEs will be summarized separately in addition to the above analysis. These specific interested AEs are: angioedema, hyperkalemia, hypotension, renal dysfunction, liver. Due to the different durations in the two sub-run-in phases, besides providing percentages, the annualized exposure duration adjusted event rates will also be provided. In summary, we will have: Run-ins The following summaries will be generated for AEs during the enalapril and LCZ696 run-ins: •

All adverse events

•


•


•


•

Adjudicated primary causes of deaths

In addition, to account for the treatment administered during each run-in period the time of onset of an adverse event will be categorized according to the start dates of the run-in doses for the run-in dose level 2 and run-in dose level 3. Denominators will be the number of patients who received at least one dose of the respective run-in dose level. If a specific AE occurs multiple times or increases in severity within a patient during a run-in period it will be counted for each run-in step interval where it newly starts or increases in severity. The annualized exposure duration adjusted event rates will also be provided. Double blind period The following summaries will be generated for AEs during the double blind period: •

All adverse events

•


•


•

Adverse events requiring dose adjustment or study-drug interruption

•


•

Adjudicated primary causes of deaths.




In addition to above standard analyses, for double blind phase, analysis for time-to-first selected AEs by treatment group will be performed using Kaplan-Meier estimate. The annualized exposure duration adjusted event rates will also be provided.

10.4

Laboratory data

10.4.1

General laboratory data

Laboratory data will be summarized for each reporting phase as described before: Run-ins based on the ERS and LRS and double blind period based on the SAF. The summary of laboratory evaluations will be presented for three groups of laboratory tests: hematology, serum chemistry and urinalysis, which include hemoglobin, hematocrit, RBC count, WBC count, platelet count, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus, total protein, albumin, and uric acid. The eGFR is calculated according to the formula: eGFR (mL/min/1.73 m2) = 175 x (Serum creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if black), where serum creatinine is in µmol/L (SI unit) and age is non-rounded at the time of the laboratory sample in years. Descriptive summary statistics (mean, median, standard deviation, min and max) for the change from baseline to each study visit will be presented. These descriptive summaries will be presented by laboratory test and treatment group. Change from baseline will only be summarized for subjects with both baseline and post baseline values and will be calculated as: • change from baseline = post baseline value – baseline value Note that baselines (run-in and double blind period) are defined in Section 4. In addition, shift tables will be provided for all parameters to compare a subject’s baseline laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, low, or high for each visit value relative to whether or not the baseline value was normal, low, or high. These summaries will be presented by laboratory test and treatment group. The number and percentage of subjects with clinically notable laboratory results after baseline will be presented. Clinically notable laboratory results, for those parameters where ranges are available, are given in Table 10-4 below. For the calculation the denominator are based on the evaluable post-baseline subjects who did not have the notable abnormality at baseline from the central laboratory. The following clinical laboratory values will be summarized graphically by treatment group and visit using mean plot with 95% CIs: creatinine, estimated glomerular filtration rate (eGFR), sodium, and potassium.




For all laboratory evaluation scheduled and unscheduled laboratory measurements will be taken into account. Table 10-4

Clinical notable criteria for selected laboratory tests

Hematology RBC count Hemoglobin Hematocrit WBC count Platelet count Blood Chemistry ALT (SGOT) AST (SGPT) BUN Creatinine Total bilirubin CPK Alkaline phosphatase Sodium Potassium

Chloride Calcium Uric acid

>50% increase, >20% decrease >50% increase, >20% decrease >50% increase, >20% decrease >50% increase, >50% decrease >75% increase, >50% decrease >150% increase >150% increase >50% increase >14.28 mmol/L >50% increase >136.8 µmol/L >100% increase >300% increase >100% increase >5% decrease >20% increase, >20% decrease ≥6.0 mmol/L >5.0 mmol/L 10% increase, >10% decrease >10% increase, >10% decrease >50% increase

In the above table increase and decrease are defined as compared to the baseline value. Here baseline is defined as the run-in baseline for the run-in phases and the double blind baseline for the double blind phase. 10.4.2

Specific laboratory data

Liver function test (LFT) data will be analyzed according to what specified in hepatotoxicity in Table 10-3 in Section 10.2. Laboratory data related to renal impairment (serum creatinine, eGFR) will be analyzed according to what specified in renal impairment in Table 10-3 in Section 10.2.

10.5

Vital signs

Sitting systolic blood pressure, sitting diastolic blood pressure, sitting pulse rate and body weight will be summarized by treatment group and visit with standard summary statistics (mean, median, standard deviation, min, max), including changes from baseline. Baselines




(run-in and double blind period) are defined in Section 4. Graphical mean plots with 95% CIs for these vital signs will also be provided. The descriptive summaries will be presented by vital sign and treatment group and visit. Change from baseline will only be summarized for subjects with both baseline and postbaseline values and will be calculated as: • change from baseline = post-baseline value – baseline value The number and percentage of subjects with clinically notable vital signs changes from baseline will be presented. Clinically notable vital sign results are provided in Table 10-5 below. Table 10-5

Clinically notable changes in vital signs

Vital Sign (unit)

Clinically notable criteria

Weight (kg)

decrease > 7% from Baseline increase > 7% from Baseline 20 >180 and increase from baseline of >20 15 >105 and increase from baseline of >15 15 >120 and increase from baseline of >15

Sitting systolic blood pressure (mmHg) Sitting diastolic blood pressure (mmHg) Pulse (bpm)

10.6


The following quantitative variables will be summarized: heart rate and QRS duration. Summary statistics (n, mean, SD, min .Q1, median, Q3, max) for the change from baseline (Visit 5) in ECG intervals by visit and treatment will be provided. In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, total) with the maximum on-study result (normal, clinical significant, not available, total) will be provided for each variable. Clinical significant is defined if at least one abnormality: “atrial fibrillation, atrial flutter, LBB block, RBB block, pathological Q-waves, left ventricular hypertrophy, paced rhythm or other” is answered “yes”.

11


Data relating to resource utilization will be used to describe medical resources used by the study participants. Mainly descriptive statistics of resources utilization data will be provided by treatment group. However some analyses on resource utilization are already provided as part of the exploratory analyses described above.

12

Interim analyses

It is planned to have three formal interim efficacy analyses. The cutoff dates for the interim analyses are planned to be approximately at 1/3, 1/2 and 2/3 of information time (i.e. approximately 804, 1205, and 1607 patients, respectively, with a primary event of either CV death or HF hospitalization). However, some adjustment to the frequency and time for interim




analyses may be made to coincide with the DMC meetings. One-sided testing will be performed and appropriate statistical adjustments for the interim analyses actually performed will be made to control the overall type-I error of 0.025. For each interim analysis, the analysis dataset will comprise all patients who were randomized before the cutoff date. The Haybittle-Peto type of boundary will be used for the interim efficacy analyses to assess superiority. The interim efficacy analysis with the boundary will spend approximately an alpha of 0.0001 (one-sided) at the first interim analysis and 0.001 (one-sided and nominal) at the second and third interim analyses. In case additional interim efficacy analysis is required, another 0.001 may be spent for the interim analysis and the alpha for the final analysis will be adjusted with Bonferroni method. In addition to the primary composite endpoint, the CV mortality component will also be analyzed at each interim efficacy analysis. When 1/3, 1/2, and 2/3 of the total number of primary patient events occur, approximately 410, 614 and 819 CV deaths, respectively, are also expected. The study may be concluded early with a claim of efficacy superiority for LCZ696 versus enalapril if statistically significant results per the above planned boundary are obtained for both primary composite endpoint and CV death component at an interim efficacy analysis. In addition to the interim efficacy analysis for a potential superiority claim, interim futility assessment for the primary composite endpoint will also be performed at each interim efficacy analysis to provide a potential opportunity for early study termination due to lack of efficacy. The proposed futility boundaries are: -1.312, 0, and 0.5 in Z-scale, which corresponds to 1.100, 1.000, and 0.975 in hazard ratio scale (LCZ696 versus enalapril). These boundaries will not be the sole consideration in the futility analyses; futility will also require that there is no observed benefit on biomarkers such as change from baseline vs. enalapril in NT-proBNP. Furthermore, these two considerations will be used only as a guideline for triggering discussion of stopping for futility. If the study is stopped early for claiming superiority efficacy due to statistically significant results for both primary endpoint and the CV death component at an interim analysis, the secondary endpoints will be tested using the same testing procedure as described in Section 9.3.2 for the final analysis at the overall alpha level equal to the one used for the interim analysis of the primary endpoint. Interim safety assessments are planned to be performed twice a year. As discussed in Section 4.2.6 of the protocol, in order to identify potential safety signals earlier, a formal blinded review of selected safety assessments is planned to will be performed when the first 200 patients have completed the first 4 weeks of double-blind randomized treatment. Additionally, reviews of selected safety assessments will be reviewed are planned when approximately the first 100, 300, and 600 patients completing who have completed (or discontinued) the run-in period. Summary of the selected safety assessments during the run-in period will be provided for enalapril and LCZ696 separately. No further alpha adjustment will be made due to these interim safety assessments. Interim analyses will be performed by an independent statistician who will not be involved in the trial conduct. The results will be reviewed by the independent DMC.




Investigators, Novartis employees, and others who are involved in the conduct of the trial will remain blinded to the treatment codes and IA results until all monitoring decisions have been made and the database has been locked for final analysis.

13

Power and sample size considerations

13.1

Power for primary endpoint

The sample size estimation below is based on a 1:1 randomization and a one-sided significance level of 0.02314, which has been adjusted for the efficacy interim analyses currently planned (Section 12). The targeted sample size mainly is driven by the CV mortality component of the primary composite endpoint. With a hazard reduction of 15%, a power of 80% will require a total of 1,229 events when comparing LCZ696 to enalapril for CV mortality, using the log-rank test. Assuming an annual CV death rate of 7% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months, a total sample size of 7,980 patients will be required to obtain 1,229 CV deaths. By randomizing 7,980 patients in the study, assuming the same enrollment period, follow-up duration same as above, 15% reduction in hazard, and an annual primary event rate of 14.5% in the enalapril group, it is expected to attain greater than 97% power to detect a difference between treatments for the primary composite endpoint. This, in turn, corresponds to a total number of at least 2,410 patients with primary events during the course of the trial. The assumption of 14.5% annual event rate for the primary composite endpoint is based on the CHARM-Added trial (CHARM Investigators and Committees 2003). In that study the reported annual event rate was 14.1% in the candesartan group and 16.6% in the placebo group. In CHARM-Added all patients received ACEIs, such as enalapril, as background therapy, although the ACEIs may not have been administered at their top doses. Hence, an estimate of the annual primary event rate between the candesartan and placebo group in CHARM-Added would provide a reasonable estimate for event rate for the active comparator enalapril in the current study. Assuming further improvement in underlying HF therapy within the past 5 years since CHARM-Added was conducted, a more conservative annual rate of 14.5% was chosen for sample size calculation. The 7% CV mortality annual event rate is estimated from the CHARM-Added trial in a similar manner.

13.2

Power for secondary endpoints

The tests of secondary variables are part of the global testing strategy. For the change from baseline to Month 8 in clinical summary score assessed by KCCQ, the above sample size will provide 96~99% individual power to detect a treatment difference of 2 points at the one-sided significance level of 0.00463 (i.e., 0.02314 × 0.2), assuming a standard deviation between 15 and 20. A standard deviation of 15 was observed in the published literature (Flynn et al 2009).




For time to all-cause mortality, the above sample size will provide approximately 87% individual power to detect a 15% reduction in hazard at one-sided significance level of 0.0185 (i.e. 0.02314 × 0.8), assuming an annual event of 9% in the enalapril group, an enrollment period of 18 to 22 months and a minimum follow-up of 21 months. The numbers in the assumption are estimated based on the CHARM-low LVEF trial (Young et al 2004). For time to new onset of AF, the results from the previous published studies suggest that the annual event rate of the comparator group will be around 4%. There is an enrollment period of 18 to 22 months and a minimum follow-up of 21 months. It is expected that two-thirds of patient population will have no AF history, therefore about 5320 patients (2660 per treatment group) will be included in the analysis of NOAF. Based on these assumptions, at one-sided significance levels of 0.004628 (i.e., 0.02314 × 0.2), 0.0185 (i.e., 0.02314 × 0.8) and 0.02314, the above sample size will provide about 87%, 95% and 96% power, respectively, to detect a reduction of 30% in hazard. The numbers in the assumption are estimated based on the EMPHASIS-HF and Val-HeFT trials (Swedberg et al 2012, Maggioni et al 2005). For time to composite renal endpoint, the above sample size will provide about 80% power to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.02314 and 0.004628 (i.e., 0.02314 × 0.2), respectively. Also, the above sample size will provide about 75% and 90% power, respectively, to detect 25% and 30% reductions in hazard at one-sided significance levels of 0.0185 (i.e., 0.02314 × 0.8). It is assumed for the annual rate to be 0.021 based on the CHARM trials and AASK trial (Wright, Jr 2002).

14

Reference

1. Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially rejective multiple test procedures. Statist Med; 28:586-604. 2. CHARM Investigators and Committees (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: the CHARM-Added trial. Lancet; 362: 767-771. 3. Cook RJ, Lawless JF (1997) Marginal analysis of recurrent events and a terminating event. Stat in Medicine; 16:911-924. 4. Cowling BJ, Hutton JL, Shaw JEH (2006) Joint modeling of event counts and survival times. Appl. Statist; 55(Part 1):31-39. 5. Fleiss J, Statistical methods for rates and proportions. 2nd ed. 1981: John Wiley and Sons, Inc, New York 6. Flynn KE, Pina IL, Whellan DJ, et al (2009) Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA; 301: 1451-1459. 7. Ghosh D, Lin DY (2000) Nonparametric analysis of recurrent events and death. Biometrics; 56:554–562. 8. Kalbfleisch JD, Prentice RL (2002). The Statistical Analysis of Failure Time Data. 2nd ed. New York: Wiley




9. Lin DY, Wei LJ, Ying Z, Yang I (2000) Semiparametric regression for the mean and rate functions of recurrent events. J R Stat Soc; B, 62:711–730. 10. Maggioni AP, Latini R, Carson P, et al (2005) Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J; 149:548-557. 11. McCullagh P, Nelder JA. (1989) Generalized Linear Models, 2nd ed. London: Chapman and Hall. 12. SAS/STAT User’s Guide, version 9.3, SAS Institute, Inc., Cary, North Carolina. 13. Swedberg K, Zannad F, McMurray JJV, et al (2012) Eplerenone and atrial fibrillation in mild systolic heart failure. Results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) Study. J Am Coll Cardiol; 59:15981603. 14. Wei LJ, Lin DY, Weissfeld L (1989). Regression Analysis of Multivariate Incomplete Failure Time Data by Modeling Marginal Distribution. Journal of the American Statistical Association; 84, 1065–1073. 15. Wright, Jr JT, Bakris G, Greene T, et al (2002) Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA; 288:2421-2431. 16. Young JB, Dunlap ME, Pfeffer MA, et al (2004) Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction, results of the CHARM low-left ventricular ejection fraction trials. Circulation; 110:26182626. 17. Zeng D, and Lin DY (2009). Semiparametric Transformation Models with Random Effects for Joint Analysis of Recurrent and Terminal Events. Biometrics; 65:746-752.

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