Journal of Cardiac Failure Vol. 23 No. 1 2017
Clinical Trials: Methods and Design
Evaluating the Efficacy, Safety, and Tolerability of Serelaxin When Added to Standard Therapy in Asian Patients With Acute Heart Failure: Design and Rationale of RELAX-AHF-ASIA Trial NAOKI SATO, MD, PhD,1 CAROLYN S. P. LAM, MBBS, MRCP, MS,2 JOHN R. TEERLINK, MD,3 BARRY H. GREENBERG, MD,4 HIROYUKI TSUTSUI, MD, PhD,5 BYUNG-HEE OH, MD, PhD,6 JIAN ZHANG, MD, PhD,7 MARTIN LEFKOWITZ, MD,8 TSUSHUNG A. HUA, PhD,8 THOMAS HOLBRO, PhD,9 MIRIAM MARSHOOD, PhD,8 XING LI WANG, MD, PhD,8 AND JUNBO GE, MD10 Kawasaki and Fukuoka, Japan; Singapore; Los Angeles and La Jolla, California; Seoul, South Korea; Beijing, People’s Republic of China; East Hanover, New Jersey; Basel, Switzerland; and Shanghai, China
ABSTRACT Background: Acute heart failure (AHF), a common and growing health concern worldwide, is associated with high risk of post-discharge rehospitalization and mortality. Existing evidence indicates potential therapeutic benefits of serelaxin in Caucasian AHF patients, but corresponding data in Asians remain scarce. RELAX-AHF-ASIA, a multinational, randomized, double-blind, placebo-controlled, phase III trial, will evaluate the effects of serelaxin on symptom relief and clinical outcomes in Asian AHF patients, with the use of novel assessments. Methods and Results: Patients with AHF, systolic blood pressure ≥125 mm Hg, and mild to moderate renal dysfunction will be randomized within 16 hours of presentation to receive 48-hour intravenous infusion of 30 μg · kg−1 · d−1 serelaxin or placebo in addition to standard therapy. The composite primary end point includes: (1) treatment success (moderate/marked improvement in patient-reported dyspnea and physician-assessed signs of congestion on day 2); (2) treatment failure (in-hospital worsening of signs and/ or symptoms of heart failure [HF] requiring intensification of intravenous HF therapy or mechanical ventilation, renal/circulatory support, rehospitalization due to HF/renal-failure, or death through day 5); and (3) unchanged status. Secondary end points include time to in-hospital worsening HF through day 5 and allcause and cardiovascular deaths through day 180. Conclusions: RELAX-AHF-ASIA, the largest randomized clinical trial in Asian AHF patients to date, has a novel composite primary end point and the potential to become a hallmark of AHF trials. (J Cardiac Fail 2017;23:63–71) Key Words: Serelaxin, efficacy, Asian, acute heart failur.
From the 1Cardiology and Intensive Care Unit, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Japan; 2National Heart Centre Singapore and Duke-NUS, Singapore; 3University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, Los Angeles, California; 4Division of Cardiology, University of California, San Diego, La Jolla, California; 5Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; 6Department of Internal Medicine, Seoul National University, College of Medicine, Seoul, South Korea; 7 Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 8Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; 9Novartis Pharma, Basel, Switzerland and 10Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Manuscript received August 15, 2016; revised manuscript received October 10, 2016; revised manuscript accepted October 28, 2016. Reprint requests: Naoki Sato, MD, PhD, Cardiology and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, 1-396 Kosugi-cho Nakahara-ku Kawasaki-shi, Kanagawa 211-8533, Japan. Tel: +81 44 733 5181; Fax: +81 44 711 8333. E-mail:
[email protected] Funding: This study is sponsored by Novartis Pharma. See page 69 for disclosure information. 1071-9164/$ - see front matter © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.cardfail.2016.10.016
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64 Journal of Cardiac Failure Vol. 23 No. 1 January 2017 Heart failure (HF) is a global public health concern affecting ~26 million patients worldwide.1 In the United States, the prevalence of HF exceeds 5.8 million, with its incidence approaching 10 in 1000 among individuals aged ≥65 years.2 In Europe, there are ≥15 million patients with HF.3 Acute heart failure (AHF) is the leading cause of hospitalization in the United States and Europe.1 In Asia, the overall prevalence of HF is ~1.2%–6.7%, depending on the population studied.4–7 In China alone, ~4.2 million individuals have HF,8 and there are ~1 million individuals with HF in Japan.9 The ADHERE–Asia Pacific registry showed that Asian patients with AHF were younger and had more severe symptoms and signs of congestion at presentation compared with similar cohorts from the United States and Europe.10 AHF is typically characterized by the rapid onset of or changes in the symptoms of HF and has a complex heterogeneous pathophysiology.11 The occurrence of an AHF episode augurs a new phase of the disease characterized by recurrent hospitalizations and a high rate of mortality, neither of which have yet been addressed by the current therapies.11 Moreover, recently completed international phase III clinical trials of AHF therapies have failed to show an improvement in the rates of rehospitalization and mortality, both of which are unacceptably high.12 Therefore, the development of novel, effective, and safe therapies, as well as appropriate strategies for the management of AHF, is urgently required. Patients with AHF may have varied clinical presentations; although dyspnea is the most common presenting symptom (present in 90% of emergency room cases), jugular venous distention, ascites, hepatomegaly, and peripheral edema are common physician-assessed signs of systemic congestion. In addition, the signs and symptoms of AHF may present with varying degrees of severity.13,14 A secondary analysis of the EVEREST trial showed that patients discharged with persistent clinical congestion despite minimal resting symptoms and signs experienced worse post-discharge outcomes, such as high mortality and readmission rates, compared with those discharged without any congestion signs.15 Based on these considerations, the present trial is uniquely designed and includes a bidirectional assessment of congestion, ie, patientreported dyspnea and physician-assessed signs of congestion. Serelaxin, a recombinant human relaxin-2 hormone, has a unique mechanism of action that may address the complex pathophysiology of AHF16 and provide clinical benefits in patients with AHF. In Pre-RELAX-AHF, a phase II dosefinding study, the 30 μg · kg−1 · d−1 dose of serelaxin (when added to standard therapy) resulted in an improvement in dyspnea compared with placebo.17 That study also showed that serelaxin was well tolerated with favorable effects on the long-term clinical outcomes. In addition, RELAX-AHF, a phase III trial in 1161 patients with AHF, showed that serelaxin added to standard therapy significantly improved dyspnea, which was measured with the use of the visual analog scale through day 5 (a co–primary end point), reduced worsening of HF episodes through day 5, and significantly reduced allcause and cardiovascular (CV) deaths by 37% through day 180. However, serelaxin had no demonstrable benefits for re-
hospitalization due to HF or renal failure (RF) through day 60.17 Although the data from Pre-RELAX-AHF and RELAXAHF trials are encouraging, those trials predominantly enrolled Caucasian patients with AHF.17 To date, data regarding the efficacy and safety of serelaxin in Asian patients with AHF are limited.18 A double-blind, placebo-controlled, parallelgroup trial in healthy Japanese and Caucasian volunteers showed no apparent differences in the pharmacokinetics, safety, and tolerability of serelaxin between these 2 populations.19 Given the differences in populations worldwide and even among countries within Asia itself regarding ethnicity, sociocultural factors, and management of HF, additional evidence for the efficacy of serelaxin in Asian patients with AHF is required. Therefore, we initiated a multinational, randomized, double-blind, placebo-controlled, phase III clinical trial with a novel composite end point to evaluate the safety and efficacy of serelaxin in primarily Asian patients with AHF. Methods Study Design
The RELAX-AHF-ASIA trial (RLX030A2302; ClinicalTrials.gov identifier: NCT02007720) aims to recruit and randomize a total of 1520 patients with AHF who meet the eligibility criteria, primarily in Asian countries including, but not limited to, China, Japan, India, Jordan, Korea, Lebanon, Malaysia, the Philippines, Singapore, Taiwan, and Thailand (Fig. 1). This clinical trial was designed and will be conducted and reported in accordance with the International Conference on Harmonization Harmonized Tripartite Guidelines for Good Clinical Practice (with applicable local regulations) and the Declaration of Helsinki. Study Population
Male and female patients with AHF (≥18 years of age) who meet the eligibility criteria (Table 1) and provide written informed consent may be enrolled in the trial. Patients will be included in the trial if they (1) present with AHF requiring hospitalization, where AHF is defined as including all of the following, measured at any time between presentation (including the emergency department and outpatient clinic) and the end of screening: (a) persistent dyspnea at rest or with minimal exertion at screening and at the time of randomization, (b) pulmonary congestion on chest X-ray, and (c) B-type natriuretic peptide (BNP) ≥500 pg/mL or N-terminal proBNP ≥2000 pg/mL; (2) have systolic blood pressure (SBP) ≥125 mm Hg at the start and end of screening; (3) have received ≥40 mg of intravenous (IV) furosemide or its equivalent before the start of screening; and (4) have impaired renal function (defined as an estimated glomerular filtration rate of ≥25 and ≤75 mL • min−1 • 1.73 m−2 between presentation and randomization) estimated using the simplified Modification of Diet in Renal Disease (sMDRD) formula or modified sMDRD
Serelaxin in Asian Patients With AHF
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Fig. 1. The RELAX-AHF-ASIA participating countries. China, Japan, India, Jordan, Korea, Lebanon, Malaysia, the Philippines, Singapore, Taiwan, and Thailand, shown in yellow, are participating in RELAX-AHF-ASIA trial.
formula (modified according to specific ethnic groups and local practice guidelines).20–22 The key exclusion criteria are as follows: (1) dyspnea primarily due to noncardiac causes, such as acute or chronic respiratory disorders or infections (namely severe chronic obstructive pulmonary disease, bronchitis, and pneumonia), or primary pulmonary hypertension sufficient to cause dyspnea at rest, which may interfere with the ability to interpret the primary cause of dyspnea; (2) treatment with any IV vasoactive drugs within 2 hours before randomization, except IV furosemide (or equivalent), or IV nitrates at a dose of ≤0.1 mg · kg−1 · h−1 if the patient has an SBP >150 mm Hg at screening; (3) AHF due to significant arrhythmias which include any of the following: sustained ventricular tachycardia, bradycardia with a sustained ventricular rate 130 beats/min; (4) SBP >180 mm Hg at the end of screening; (5) clinical evidence of acute coronary syndrome (either at present or within 30 days before enrollment); and (6) hepatic disease unrelated to HF etiology and as determined by any of the following: aspartate transaminase and/ or alanine transaminase values exceeding 3× the upper limit of normal (ULN) and/or bilirubin >1.5× ULN at screening, history of hepatic encephalopathy, esophageal varices, or portacaval shunt, diagnosis of cirrhosis, or chronic hepatitis B or hepatitis C infection. Eligible patients will be randomized to receive serelaxin or placebo within 16 hours of presentation to the hospital (emergency department and outpatient clinic). The standard therapy for AHF will be maintained throughout the trial period in all patients.
Study Treatment
The enrolled patients will be randomized (1:1) to a continuous IV infusion for 48 hours with either serelaxin 30 μg · kg−1 · d−1 or placebo in addition to the standard therapy defined according to the American Heart Association/ American College of Cardiology and European Society of Cardiology guidelines, which are followed in most Asian countries.23,24 Each study site will receive blinded kits containing placebo and the active study drug, serelaxin. Appropriately diluted study drug will be administered continuously as an IV infusion (in a 5% dextrose solution) through a dedicated IV line for up to 48 hours. If the patient’s SBP decreases by >40 mm Hg from the pretreatment value but remains at >100 mm Hg, the study drug infusion rate will be halved for the remainder of the infusion period. However, the study drug will be permanently discontinued if the SBP falls to 38.5°C, sepsis, active and clinically significant infection requiring IV antimicrobial treatment, or known presence or evidence of infection with human immunodeficiency virus (based on history and/or clinical findings, including laboratory results obtained during screening period). 3. Clinical evidence of acute coronary syndrome currently or within 30 days of enrollment. 4. AHF due to significant arrhythmias including sustained ventricular tachycardia or bradycardia with ventricular rate 130 beats/min. 5. Hematocrit 150 mm Hg at screening. 9. Any major solid organ transplant recipient—or planned/anticipated organ transplantation within 1 year. 10. Major surgery, including implantable devices (eg, ICD and CRT), or major neurologic event, including cerebrovascular events, within 30 days before screening. 11. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a life expectancy 1 for treatment success and an odds ratio of
