Accepted Manuscript EMPIRE-CF: A phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis – Study design and patient demographics
J. Stuart Elborn, Sanjeev Ahuja, Eric Springman, John Mershon, Ralph Grosswald, Steven M. Rowe PII: DOI: Reference:
S1551-7144(18)30192-7 doi:10.1016/j.cct.2018.07.014 CONCLI 5650
To appear in:
Contemporary Clinical Trials
Received date: Revised date: Accepted date:
10 April 2018 23 July 2018 23 July 2018
Please cite this article as: J. Stuart Elborn, Sanjeev Ahuja, Eric Springman, John Mershon, Ralph Grosswald, Steven M. Rowe , EMPIRE-CF: A phase II randomized placebocontrolled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis – Study design and patient demographics. Concli (2018), doi:10.1016/j.cct.2018.07.014
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ACCEPTED MANUSCRIPT EMPIRE-CF: A Phase II randomized placebo-controlled trial of once-daily, oral acebilustat in adult patients with cystic fibrosis – study design and patient demographics J. Stuart Elborna, *, Sanjeev Ahujab, Eric Springmanc , John Mershond, Ralph Grosswalde, Steven M. Rowef
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*Corresponding author National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, South
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Parade, London, SW3 6LL, UK
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National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London,
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UK; email
[email protected] b
Celtaxsys, Inc., 201 17th St NW #530, Atlanta, Georgia, USA; email
[email protected] Celtaxsys, Inc., 201 17th St NW #530, Atlanta, Georgia, USA; email
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c
[email protected] d
[email protected] e
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Celtaxsys, Inc., 201 17th St NW #530, Atlanta, Georgia, USA; email
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Celtaxsys, Inc., 201 17th St NW #530, Atlanta, Georgia, USA; email
[email protected] f
Departments of Medicine, Pediatrics, Cell Developmental, and Integrative Biology,
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University of Alabama at Birmingham, Birmingham, Alabama, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA; email:
[email protected]
ACCEPTED MANUSCRIPT Abstract Inflammation causes irreparable damage in the cystic fibrosis (CF) lung. Despite high standards of care and the advent of new therapies, inflammation continues to cause significant loss of lung function and morbidity. Acebilustat is a once-daily, oral molecule with anti-inflammatory activity through the inhibition of LTA4 hydrolase and modulation of LTB4. It has potential to reduce lung function decline
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and pulmonary exacerbations in patients with CF and is currently being tested in a Phase II multicenter, randomized, double-blind, placebo-controlled, parallel-group study (EMPIRE-
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CF).
Strict inclusion criteria based on modeling of the Cystic Fibrosis Foundation Patient Registry
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data were selected to enrich the trial with patients most likely to benefit from chronic antiinflammatory therapy that reduces lung function decline. 200 patients between 18–30 years
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of age, with an FEV1 percent predicted (pp) ≥50%, and ≥1 exacerbation in the past year have been enrolled. Patients are randomized 1:1:1 to placebo, acebilustat 50 mg or 100 mg for 48 weeks, taken concomitantly with their current standard of care, and stratified based on
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concomitant CFTR modulator use, baseline FEV1pp (50% to 75% and >75%), and number of exacerbations in the past year (1 or >1). The primary endpoints are absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints include rate of pulmonary
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exacerbations and time to first pulmonary exacerbation. Biomarkers of inflammation will also be assessed.
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EMPIRE-CF is expected to identify the optimal patient population, dose, duration and endpoints for future acebilustat trials, and widen understanding of the drug’s efficacy in
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patients with CF.
Keywords: acebilustat, anti-inflammatory, clinical trial, cystic fibrosis, novel therapy, trial design
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Abbreviations: AE, Adverse events; ANOVA, Analysis of variance; BMI, Body mass index; CF, Cystic fibrosis; CFF, Cystic Fibrosis Foundation; CFFPR, Cystic Fibrosis Foundation Patient Registry; CFQ- R, Cystic Fibrosis Questionnaire – Revised; CFTR, Cystic fibrosis transmembrane conductance regulator; DSMB, Data safety monitoring board; ECG, Electrocardiogram; FAP, Full analysis population; FEF25–75%, Forced expiratory flow during the middle portion of the forced vital capacity; FEV, Forced expiratory volume; FEV1pp, Forced expiratory volume in 1 second percent predicted; FVCpp, Forced vital capacity percent predicted; HbsAg, Hepatitis B surface antigen; HCV, Hepatitis C virus; hs -CRP, High-sensitivity C-reactive protein; ICS, Inhaled corticosteroids; IP, Investigational product; IWRS, Interactive web-based randomization system; LTA4, leukotriene A4. LTA4H. leukotriene A4 hydrolase; LTB4, leukotriene B4; NSAID, Non-steroidal anti-inflammatory drug; P25, 25th percentile; P50, 50th percentile; P75, 75th percentile; PP, Per-protocol; ULN, Upper limit of normal.
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1
Introduction
Pulmonary pathology in the cystic fibrosis (CF) lung is characterized by high levels of inflammation that contribute to lung function decline and are strongly associated with more frequent pulmonary exacerbations and associated morbidity. Inflammatory lung damage is evident early in life, with increased neutrophil elastase in bronchoalveolar lavage fluid clearly linked to the risk of developing bronchiectasis as early as 3 months of age in children with
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CF [1]. Inflammation-induced damage can occur even in the absence of detectable infection [2,3]. Inflammation also persists despite high standards of care and novel therapies such as
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cystic fibrosis transmembrane conductance regulator (CFTR) modulators [4]. Chronic inflammation in the CF lung is driven by the persistent recruitment of immune cells,
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principally neutrophils, into the airways [5]. Modulation of the inflammatory mediators that drive neutrophil influx may provide a viable therapeutic pathway to reduce inflammation in
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the lung [6].
Leukotriene B4 (LTB4) is an immune cell chemoattractant and activator implicated in the
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initiation of cytokines and chemokine cascades that amplify and perpetuate inflammation [7,8,9]. It is generated from leukotriene A4 (LTA4) by the enzyme leukotriene A4 hydrolase (LTA4H). (Fig. 1) Inhibition of LTA4H has the potential to reduce LTB4 production, thus
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reducing neutrophil influx and the release of neutrophil-derived enzymes such as neutrophil elastase. The potential of LTB4 as a therapeutic target for reducing inflammation in the CF
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lung was first recognized with the use of high-dose ibuprofen [10], where the clinical effect is related in part to LTB4 modulation. High-dose ibuprofen has been used for many years in CF and has demonstrated efficacy in reducing lung function decline, reducing mortality and associated neutrophil influx in the lung [11,12; 13] . It is not, however, used widely due to the
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high doses (up to 3200 mg per day) required to reduce LTB4, the potential for gastrointestinal bleeding, and the requirement for individual pharmacokinetic profiling [14]. The investigational agent BIIL 284, a leukotriene B4 receptor 1 (BLT1) antagonist, showed promise in a range of inflammatory conditions however, the Phase II trial in patients with CF was terminated prematurely due to an excess of pulmonary-related SAEs in the adult cohort. [15]. Therefore, an unmet need remains for a safe and effective anti-inflammatory treatment in CF. Acebilustat is a novel, synthetic, small-molecule LTA4H inhibitor in development as a oncedaily oral therapy that modulates LTB4 production and targets the inflammatory process in CF [14]. In two Phase I trials, acebilustat reduced LTB4 production and other inflammatory markers in healthy volunteers and patients with CF [14,16]. Based on these promising data,
ACCEPTED MANUSCRIPT a Phase IIb study, EMPIRE-CF (Evaluation of the modulation of the pulmonary inflammatory response in CF) has been designed and initiated to determine the dose, duration and endpoints for future clinical trial(s). It is hoped that the study will provide the first proof of concept for a novel anti-inflammatory therapy designed to prevent loss of lung function and reduce pulmonary exacerbations in CF patients. This paper describes the design and rationale of the study. The demographics of the study population are also presented, and
2.1
Methods Design considerations
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their importance to the study outcomes is discussed.
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Previous short-term trials (12 weeks’ treatment or less) have shown that anti-inflammatory medications may not lead to acute changes in forced expiratory volume in 1 second percent predicted (FEV1pp) or even changes in biomarkers of inflammation, despite the potential for
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effective therapy [17,18,19]. A longer-term study is more likely to show an attenuation in the annual rate of lung function, as well as reductions in exacerbations. For example, the 4-year
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high-dose ibuprofen study demonstrated a decreased rate of FEV1 decline in a general CF population, without demonstrating more rapid evidence of benefit [11]. Such a duration is not feasible for current Phase II trials. On this basis, a treatment period of 48 weeks was
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considered for the current study, with use of a larger sample size to detect changes over a
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shorter period of observation (see section 2.2). Measuring significant changes in lung function decline and exacerbation frequency is only possible if the correct patient population is enrolled. We hypothesized that certain subsets of the general CF population may be at greater risk for rapid lung function decline, and that this
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subset may provide a study population that is affected by active inflammation, and that also experiences a decline of adequate magnitude to detect clinical benefit over a 48-week interval. Such a subset was identified through research of the Cystic Fibrosis Patient Registry (CFFPR) by analyzing the projected rate of decline of FEV1pp and the frequency of pulmonary exacerbations in different subpopulations. In addition, prior pulmonary exacerbations are one of the strongest predictors of a future pulmonary exacerbation [20,21]. Furthermore, it has been estimated that up to half of lung function decline is related to pulmonary exacerbations [22] and that exacerbations are a clear indicator of active neutrophil-driven inflammation. Susceptibility to annual decline in lung function is greatest from adolescence to early adulthood and attenuates after patients reach approximately 30 years of age [23]. Additionally, patients with a higher baseline lung function may also be more susceptible to greater declines in FEV1pp [24].
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Based on these published observations, data from the CFFPR [25] were analyzed for different age ranges (12–17 years, 18–30 years, 31–35 years, or 36–39 years); baseline FEV1pp (50–59%, 60–79%, 80–99%, or ≥100%); and number of pulmonary exacerbations requiring use of an intravenous antibiotic in the prior year (0 or ≥1). The registry data (see Supplementary Tables) provided strong support for the concept that patients between 12–30 years old who had had at least one pulmonary exacerbation in the prior year were at highest
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risk for rapid lung function decline. Within this subgroup, the registry data provided further evidence that patients with a higher FEV1pp at baseline were likely to have the most rapid
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decline in FEV1pp. Within the subgroup of 18−30 years’ old, CF patients who had had at least one pulmonary exacerbation in the prior year, the present year rate of decline is
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estimated to be −3.47 percentage points per year. Detection of differences in rate of FEV1pp decline versus placebo in the order of three percentage points per year requires observation
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over at least 48 weeks. Thus, the patient population for the current study is enriched based on optimal patient age, FEV1pp and exacerbation history, in order to detect a change in rate of FEV1 decline and change in exacerbation rate over 48 weeks in a Phase II study (see
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section 2.4 and Supplementary Tables). This population and study duration is in line with published guidance from the Cystic Fibrosis Foundation (CFF) [26].
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This Phase II study will be used as an important test of the study design, while also establishing proof of concept that LTA4H is a therapeutic target in CF. A priori baseline
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stratification based on lung function (FEV1pp), number of exacerbations in the prior year and concomitant CFTR use ensures that patient characteristics are balanced between treatment arms and will allow identification of the optimal patient population for future trials. The inclusion of CFTR modulator use as a stratification criterion is also important given the
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evolving standard of care, which may soon include use of a CFTR modulator regimen across a broad spectrum of the CF population. 2.2
Overall study design
EMPIRE-CF is a Phase II multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of acebilustat in adult patients with CF (NCT02443688). The study consists of a 48-week treatment period and follow-up visit 4 weeks after treatment completion. Screening visits occur up to 21 days prior to the first study drug dose (Fig. 2).
ACCEPTED MANUSCRIPT 2.3
Ethics and governance
Documented approval from independent ethics committees and institutional review boards was obtained from all participating centers/countries before the start of the study at a clinical site, according to Good Clinical Practice and local laws and regulations. Written informed consent was obtained from all participants.
2.4
Patients
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Patients were enrolled from 69 centers in the USA, Canada, and Europe. All centers were experienced in CF care and the conduct of clinical trials. Inclusion and exclusion criteria are
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shown in Table 1. In brief, adult women and men 18–30 years old with a documented
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diagnosis of CF, an FEV1pp ≥50% at screening and at least one pulmonary exacerbation in the previous year were enrolled. The prior pulmonary exacerbation as determined by the investigator must have been documented in the patient’s medical record and no specific
Interventions
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2.5
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treatment was required by the protocol. Baseline demographics are presented in section 3.
Patients are randomized 1:1:1 to receive either once-daily oral acebilustat 50 mg or 100 mg (Celtaxsys, Atlanta, GA, USA), or placebo supplied as capsules. Patients are instructed to
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take their treatment with breakfast and a full glass of water at approximately the same time every day. The two acebilustat doses were selected based on the levels of reduction of serum LTB4 production seen in Phase I studies. The 100 mg dose resulted in near-
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maximum LTB4 reduction (86% reduction) while the 50 mg dose showed a peak reduction in LTB4 production of ~75% [16]. Outcomes
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2.6
The primary endpoints are absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints include rate of pulmonary exacerbations and time to first pulmonary exacerbation, and the effects on biomarkers of lung and systemic inflammation (Table 2). Analyses are described in section 2.10. Pulmonary exacerbations are defined as the requirement for oral, inhaled or intravenous antibiotics for four or more signs or symptoms according to the modified Fuch’s criteria (change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue or lethargy; temperature >38°C; anorexia or weight loss; sinus pain or tenderness; change in sinus discharge; change in physical examination of the chest; ≥10% absolute decrease in FEV1pp from the previously recorded value; radiographic changes
ACCEPTED MANUSCRIPT indicative of pulmonary infection) [27]. The date the pulmonary exacerbation began was defined as the first day of antibiotic use. 2.7
Assessments
2.7.1 Patient medical status Patient assessments conducted at each visit are shown in Table 3. At the screening visit investigators record a full medical history and perform a complete physical examination and
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laboratory tests to determine eligibility for the study. Demographics and disease characteristics, concomitant CF medications (including use of CFTR modulators such as
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ivacaftor or ivacaftor+lumacaftor, use of dornase alfa and chronic azithromycin), history of Pseudomonas aeruginosa colonization and CFTR genotype (if known) are recorded. The
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number of pulmonary exacerbations in the last 12 months and the date of last pulmonary
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exacerbation are also recorded at screening. 2.7.2 Spirometry
Spirometry data are recorded at screening and baseline; all spirometric measurements at
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subsequent visits are ideally recorded within ±1 h of the time of day of the baseline visit measurement. All tests should meet American Thoracic Society/European Respiratory Society criteria for quality (acceptability, reproducibility, and end-of-test criteria) [28]. To
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ensure consistency of measurement, spirometry measurements are ideally performed by the same researcher and the patient coached to use maximum effort at every attempt. Patients
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are able to take all of their concomitant medications according to their regular schedule; however, they are to refrain from using short-acting bronchodilators within 4 h of the scheduled spirometry time, and long-acting bronchodilators within 12–24 h of the scheduled
2.7.3
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spirometry time. Safety
Treatment-emergent adverse events (TEAEs), including SAEs and deaths, are collected at each visit, and summarized by Medical Dictionary for Regulatory Activities system organ class and preferred term, severity, and relatedness to the study drug. A data safety monitoring board (DSMB) is monitoring the safety and study conduct at approximately 8week intervals.
ACCEPTED MANUSCRIPT 2.7.4 Treatment adherence Assessment of adherence to treatment with the study drug is based on a capsule count by investigators at visits 3, 5–9, 11, 13, and 15. Patients are asked whether any capsules have been lost or destroyed to ensure accuracy of the adherence assessment. 2.8 Sample size determination It was assumed that a sample size of 156 patients in the full analysis population (FAP, n=52
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acebilustat 50 mg: n=52 acebilustat 100 mg: n=52 placebo) would be required for the primary endpoint to be met. However, to ensure an adequate sample size for a per-protocol
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(PP) analysis (based on 80% of patients being included in the PP population), the number of
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randomized patients in the FAP was 195, i.e. n=65 in each treatment arm. Sample size calculations were based on the primary efficacy endpoint of absolute change
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from baseline in FEV1pp. Assumptions in the calculation are that: there is a 1:1:1 ratio of patients receiving 50 mg acebilustat vs 100 mg acebilustat vs placebo; the difference in average treatment effect for active treatment (both doses of acebilustat) vs placebo is at
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least 3.5 units at 48 weeks. With a standard deviation of 7 units the study has a power of at least 90% with one-sided alpha of 0.05 to detect the difference in average treatment effect of 3.5 units at 48 weeks.
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(change from baseline in FEV1pp) for active treatment (both doses of acebilustat) vs placebo
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2.9 Randomization and blinding
Eligible patients are randomized to active treatment by an interactive web-based randomization system (IWRS). Randomization is stratified by baseline FEV1pp (50 to 75%
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and >75%), number of pulmonary exacerbations in the 12 months before screening (1 or >1), and use of the CFTR-modulating therapy ivacaftor or ivacaftor+lumacaftor (yes/no). All patients, investigators and others in direct contact with patients are blinded to treatment assignment as are the sponsor and contract research organization staff. Blinding will only be broken due to medical necessity or safety reasons and can be carried out in cases of medical emergency via the IWRS. 2.10 Analysis 2.10.1 Primary endpoint The primary analysis will be based upon an analysis of variance (ANOVA) in which the average of the Week 48 change from baseline in FEV1pp for the two acebilustat doses is compared with that in the placebo group. The ANOVA model will contain a separate term for
ACCEPTED MANUSCRIPT each dose group with the average over the two acebilustat doses created by averaging the parameter estimates from the ANOVA model. In addition to terms for treatment group, the ANOVA will include stratification for the factors used for randomization. If the primary analysis (aggregate acebilustat effect) reaches the 0.05 level of significance (one-sided), the individual acebilustat doses will be compared with the placebo arm using Dunnett's
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procedure at the 0.05 (two-sided) alpha level.
2.10.2 Secondary endpoints
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Pulmonary exacerbations will be analyzed both as the time to first pulmonary exacerbation and the rate of pulmonary exacerbations. The time to first protocol-defined pulmonary
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exacerbation will be analyzed using a Cox proportional hazards model. The number of protocol-defined pulmonary exacerbations will be annualized (where 1 year is defined as 52 weeks) and analyzed using a negative binomial regression. Spirometry-based endpoints will
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be analyzed using the same methods as the primary endpoint. Analyses of sputum DNA and elastase and serum high-sensitivity C-reactive protein will be based upon descriptive
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statistics by treatment group. 2.10.3 Exploratory endpoints
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Analyses of sputum bacterial density (total density and density for each of the following species: P. aeruginosa, Burkholderia cepacia complex, Achromobacter xylosoxidans,
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Stenotrophomonas maltophilia, and Staphylococcus aureus [including methicillin-resistant S. aureus and small colony variants of S. aureus)] and health-related quality of life (using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) quality-of-life measure [29]) will be based
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upon descriptive statistics by treatment group.
Baseline characteristics
A total of 200 patients were enrolled in the study. Baseline demographics are shown in Table 4. Patients had a mean age of 23.7 years, and mean FEV1pp of 70.6% overall at baseline. Nearly one-third of patients were using concomitant CFTR modulators. The mean number of exacerbations in the prior year was two. Nearly half of all patients had experienced one exacerbation in the prior year; while 28.5% experienced two, and 25% experienced three or more exacerbations. At the time of writing, data remain blinded but stratified randomization based on baseline lung function, frequency of pulmonary exacerbations in the prior year, and
ACCEPTED MANUSCRIPT concomitant CFTR modulator use should ensure balanced characteristics across the three study arms.
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Safety monitoring
At approximately 8-week intervals the study data will be submitted to the DSMB, which will be able to review these with a focus toward monitoring subject safety, including pulmonary exacerbations. The DSMB will be unblinded to the study arms. Additionally, the DSMB chair
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will be notified of all SAEs and pulmonary exacerbations within 1 business day of notification of the study sponsor. This information will be blinded but unblinding may be done for DSMB
Discussion
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purposes, if requested.
The damaging impact of chronic inflammation is well recognized in CF. Although CFTR
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mutations have been implicated in some aspects of inflammation [30,31], CFTR modulators do not fully address chronic lung inflammation [4], making treatments in this area of
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modulation of inflammation a significant unmet need [26]. Studies of anti-inflammatory agents for CF have shown equivocal results. High-dose
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ibuprofen is recommended for children 6–17 years of age [32] and can reduce lung function decline and mortality while attenuating neutrophil influx in the lung [11,12]. Although the
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benefits of high-dose ibuprofen appear to outweigh the risks of use, persisting safety concerns limit its use in CF [33]. The need for a 3-hour pharmacokinetic study both prior to and during treatment provides an additional barrier to use [13].
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The macrolide antibiotic azithromycin has improved respiratory function and/or decreased pulmonary exacerbations in some – but not all – studies (reviewed in Southern et al., 2012 [34]); and is recommended in patients with CF with chronic P. aeruginosa infection. Notably, studies enrolling patients with poorer vs better lung function were more likely to show a clinical benefit [34], pointing to the importance of identifying the most appropriate patient population based on therapeutic approach. While azithromycin also reduced the frequency of pulmonary exacerbations [34], the significant heterogeneity in outcomes across trials indicates a need for robust, well-controlled studies of adequate duration [34] to assess its effectiveness. It has been demonstrated that azithromycin may interfere with the benefits of inhaled tobramycin. Additionally, the emergence of resistance in non-tuberculosis mycobacteria remains a concern with chronic azithromycin therapy [32].
ACCEPTED MANUSCRIPT Oral or inhaled corticosteroids (ICS) interrupt several points in the inflammatory pathway [36] but their use is controversial and not recommended in patients without asthma or allergic bronchopulmonary aspergillosis [32]. In an analysis of three trials published in 1999, Cheng et al. [37] described that alternate daily dosing of 1–2 mg/kg prednisolone slowed the progression of lung disease but was also associated with a high risk of adverse effects. A later review of 13 trials concluded that there is insufficient evidence to establish an efficacy benefit of ICS [38]. As oral corticosteroids slow disease progression but also cause side
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effects, including cataracts, glucose intolerance, and growth retardation [38,39], chronic use
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requires a thorough risk/benefit assessment for individual patients.
Dornase alfa has an indirect anti-inflammatory effect via the facilitation of mucus clearance
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[40]. A meta-analysis of the effects of dornase alfa suggests that it can decrease the rate of lung function decline; however, its use has historically been reserved for more severely ill
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patients [40], despite recommendations for its use in patients across the disease severity spectrum [32]. However, although patients on dornase alfa (as with other CF treatments) experience initial improvement in lung function, they subsequently continue to experience
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lung function decline and pulmonary exacerbations.
The investigational agent BIIL 284 was developed for use in a range of inflammatory
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conditions [15] and showed potent LTB4 antagonist effects in vitro and in vivo through binding to the BLT1 receptor [41]. This did not, however, translate to clinical benefits. Indeed,
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the Phase II trial of BIIL 284 in patients with CF was terminated prematurely due to an excess of pulmonary-related SAEs in the adult cohort. Most adult patients also experienced elevated circulating neutrophil levels [15]. The adverse effects of BIIL 284 were likely related to the high drug doses used in the trial. Human and animal pharmacodynamic studies of BIIL
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284 suggested that, although a 150 mg dose provided faster and more durable inhibition albeit with higher AE rates, a human dose of 25 mg (or ≥0.3 mg/kg) would be sufficient for near-complete inhibition of BLT1 signaling over the course of 24 hours [41,42]. However, doses of 75 mg and 150 mg were tested in the CF trial, in both cases representing doses that would likely completely block this pathway. Further studies in the CF mouse lung model showed that high doses of BIIL 284 were associated with increased cytokine and chemokine levels and increased P. aeruginosa colony-forming units in the lungs in the presence of decreased lung neutrophil counts [43]. The clinical program was discontinued and an unmet need remains for effective, well-tolerated anti-inflammatory therapies in CF.
ACCEPTED MANUSCRIPT The LTA4 inhibitor acebilustat is in development as an anti-inflammatory therapy in CF and has shown promising results in Phase I studies. In a study of once-daily acebilustat in adult patients with CF, the drug significantly reduced sputum neutrophil levels by up to 65% and sputum elastase levels by up to 58%. There was a reduction in C-reactive protein (CRP) in the acebilustat-treated groups of -1.2 ± 6.2 mg/L (mean ± SD, n=12) whereas the placebo CRP had an increase from baseline of +2.7 ± 5.3 mg/L (mean ± SD, n=4). This difference was not statistically significant and there was no clear dose dependence. [14]. Investigators
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also showed that sputum LTB4 levels decreased significantly in acebilustat- vs placebotreated patients [16]. These Phase I studies highlighted several important pharmacokinetic
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and pharmacodynamic aspects of acebilustat. Data confirmed that once-daily oral dosing is appropriate [16]. No significant differences occurred between healthy volunteers and
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patients with CF in the Cmax or AUC0–24 of acebilustat. Given the high burden of CF therapies [45], a simple dosing regimen for any additional therapies is important. Furthermore, no
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differences occurred in the AUC0–2 4 at steady state in fed vs fasting patients [16]. This is relevant given the potential for compromised absorption from the gut in patients with CF and their complex dietary needs [45]. Based on results from preclinical and clinical studies,
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acebilustat did not inhibit or induce CYP3A4, a key enzyme in metabolism of the CFTR modulators ivacaftor and tezacaftor, indicating that acebilustat and these CFTR modulators
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could be taken concomitantly [16].
The AE profile of acebilustat was closely monitored in the Phase I studies. Reassuringly, acebilustat was well tolerated in these trials, with the majority of TEAEs being mild or
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moderate in severity and no drug-related SAEs reported [14,16]. The promising data from the Phase I studies led to the progression of acebilustat into the
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Phase IIb trial described here. The trial has been robustly designed, taking into account guidance from the CFF, including recommendations from the 2014 CFF Anti-inflammatory Strategy Group (CFF-ASG) [26]. The study endpoints examine both change from baseline in lung function and rate of exacerbations, both of which have real-life clinical impacts. Lung function decline is a powerful predictor of morbidity [46], while exacerbation frequency is associated with a nonrecoverable loss in lung function and decline in health status in many patients [47]. Choosing a study duration appropriate to the drug being tested is important. While CFTR modulators can lead to a relatively rapid improvement in lung function [4], longer-term trials are required to show benefits from anti-inflammatory therapies that aim to stem the decline
ACCEPTED MANUSCRIPT in lung function and/or decreasing pulmonary exacerbation rate. The CFF-ASG recommended that Phase II trials should be at least 3–6 months [26], but, for more conclusive data on anti-inflammatory effects, a 12-month study may be preferred. The current study has a 48-week treatment period. Enrolling the most appropriate patient phenotype is key to assessing clinical outcomes in a trial for a novel potential therapy. Patients for EMPIRE-CF were selected based on stringent
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inclusion criteria (age 18–30 years, FEV1pp ≥50, and at least one exacerbation in the past year). This enriches the study population with patients who are most susceptible to
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pulmonary exacerbations and annual lung function decline. The enrolled patients experienced a mean of two exacerbations in the prior year. Modeling FEV1pp decline from a
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similar patient group in the CFFPR [48] suggests that patients eligible for this study may have an annual decline in FEV1pp of 3.5 (standard deviation [SD] 7.9), ranging from 2.7 (SD
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7.6) for those with one exacerbation in the prior year, to 3.7 (SD 7.9) for those with two exacerbations, and 5.1 (SD 8.4) for those with three or more exacerbations [49]. Importantly, the total population size has been calculated to ensure that the trial is sufficiently powered to
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show a change in lung function decline. There is also the potential that change in the pulmonary exacerbation rate may be detectable in this population. This assumption is based on the fact that an estimated 388 total events of pulmonary exacerbations are feasible
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(assuming the same rate of exacerbation as prior year) over 48 weeks of observation.
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Ensuring treatment arms are well balanced with respect to patient characteristics will help identify any specific patient groups that are more likely to benefit from acebilustat and could be included in future clinical trials. Randomization has, therefore, been stratified by baseline FEV1pp, number of pulmonary exacerbations in the prior 12 months, and use of CFTR-
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modulating therapy (ivacaftor or ivacaftor+lumacaftor). Stratification based on concomitant CFTR modulator use is important as neutrophil elastase is shown to downregulate CFTR [50]; an anti-inflammatory agent, such as acebilustat, that reduces neutrophil elastase could have synergistic effects with CFTR modulators. Finally, safety is being monitored closely throughout the trial. In light of the concerns raised over BIIL284, a DSMB reviews a full report of unblinded data approximately every 8 weeks. Unlike BIIL284, acebilustat is not a receptor antagonist, and the dosing is designed to modulate LTB4 levels rather than completely inhibit its activity. Hence, safety events similar to those seen with BIIL284 are not anticipated. Additionally, in the Phase 1 study in CF patients there was no change in sputum microbiology despite the patients being ‘off’ their inhaled antibiotics [16].
ACCEPTED MANUSCRIPT
It is expected that the unique and rigorous design elements of the EMPIRE-CF trial will help identify the optimal patient population, dose, duration and endpoints for future trials, and widen our understanding of the efficacy of acebilustat in patients with CF.
Funding
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The EMPIRE-CF study was funded by the Cystic Fibrosis Foundation and Celtaxsys.
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Author contributions
All authors made substantial contributions to this manuscript. All authors were involved in
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drafting the manuscript and critically revising it for intellectual content and accuracy. All
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authors have approved the final version of the manuscript for publication.
Disclosures and acknowledgments
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SA, ES, JM and RG are employees of Celtaxsys Inc. SE and SR have received fees from Celtaxsys for consultancy work on design and conduct of CF clinical trials. The authors thank Sonya Heltshe, PhD, Director of Biostatisics at the CF Foundation’s
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Therapeutic (CFFT) Development Network for consultation advice on analyses of the CF Patient Registry (CFFPR) data to help select the patient population for the trial ; and the CF
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Foundation for access to the CFFPR, advice on the design of the study, and funding. The authors acknowledge highfield:communication, Oxford, UK for the provision of medical
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writing and editorial services with funding from Celtaxsys Inc.
Appendix A. Supplementary data Supplementary data to this article can be found online.
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ACCEPTED MANUSCRIPT Tables Table 1. Inclusion and exclusion criteria. Inclusion criteria
18 to 30 years of age inclusive at the time of screening
Documented, confirmed diagnosis of pulmonary CF (defined as follows): CF signs and symptoms AND either two CFTR mutations on genetic testing OR sweat chloride
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≥60 mEq/L Medically stable, in the investigator’s opinion
At least one pulmonary exacerbation, based on the investigator’s judgment, in the 12
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months before screening
Resolution of any pulmonary exacerbation of CF at least 14 days before screening, in
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the investigator’s opinion
On a stable regimen of CF treatments with no change for at least 14 days before
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screening and between screening and baseline
If on ivacaftor or ivacaftor+lumacaftor combination, on a stable regimen for at least 8
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weeks before baseline
No clinical or radiological evidence, per the investigator’s site procedures, of clinically significant lung abnormalities (e.g. major atelectasis, pneumothorax) FEV1pp ≥50% at screening
Resting oxygen saturation >92% on room air
Body mass index ≥17.0 kg/m 2
No smoking (including electronic cigarettes) for at least 6 months before screening
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and agreement not to use such products for the duration of the study Females of childbearing potential must have a negative pregnancy test at screening
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(unless surgically sterile) and use an effective contraception method from screening throughout the study
Able to perform spirometry according to European Respiratory Society/American Thoracic Society guidance
Able to swallow acebilustat or placebo tablets whole
Able to comply with the study procedures, in the opinion of the investigator
Has provided informed consent to participate in the study
ACCEPTED MANUSCRIPT Exclusion criteria
In the opinion of the investigator, any significant clinical/laboratory/radiological/ spirometric sign of unstable or unexpectedly deteriorating respiratory disease within 14 days before screening or between screening and baseline (these clinical/laboratory/radiological/ spirometric signs include, but are not limited to, features suggestive of a pulmonary exacerbation as suggested by the modified Fuchs’ criteria)
A medical condition that is unstable, could be adversely impacted by participation in the
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study, or could impact assessment of the study results, in the opinion of the investigator History of organ transplantation
History of either alcoholism or drug abuse in the opinion of the investigator
Clinically significant hemoptysis (e.g., > approximately 30 cc per episode, or clinically
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significant in the investigator’s opinion) within 180 days before screening Colonization with organisms associated with a more rapid decline in respiratory function
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in CF patients (e.g. all Burkholderia species, Mycobacterium abscessus); patients with a history of a positive culture could be considered free of colonization if she/he has had six subsequent respiratory tract cultures negative for these bacteria within the past 24
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months prior to screening, with one of these cultures obtained within 6 months prior to screening
Active allergic bronchopulmonary aspergillosis at screening or at baseline
Any clinically significant electrocardiogram abnormality, in the investigator’s opinion
Positive serology for HIV-1 or HIV-2 antibody, hepatitis C virus antibody, or hepatitis B
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surface antigen at screening
Aspartate aminotransferase or alanine aminotransferase >2 ULN at screening
Bilirubin >1.25 ULN at screening (patients with known Gilbert’s syndrome can be
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included with bilirubin >1.25 ULN)
Any patient with cirrhosis of the liver
Any patient with portal hypertension
Neutrophil count 1.6 g ibuprofen/day) within 60 days before screening or between screening and baseline
Participation in a clinical trial for any medical/device product within 30 days before screening (participation in a non-interventional or observational study is permitted)
Current pregnancy or breastfeeding
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CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; FEV1pp, forced expiratory volume in 1 second percent predicted; NSAID, non-steroidal anti-
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inflammatory drug; ULN, upper limit of normal.
ACCEPTED MANUSCRIPT Table 2. Primary and secondary endpoints. Primary endpoints
Absolute change from baseline to Week 48 in FEV1pp
Safety and tolerability
Secondary endpoints Number of pulmonary exacerbations
Time to first pulmonary exacerbation
Relative change from baseline in FEV1pp
Change from baseline in FVCpp and FEF25–75%pp
Biomarker levels (sputum DNA and elastase, serum hs-CRP)
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Exploratory endpoints
Sputum bacterial density [total density and the following species: P. aeruginosa,
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Burkholderia cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas
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maltophilia, and Staphylococcus aureus (including methicillin-resistant S. aureus and small colony variants of S. aureus)]
Change from baseline in health-related quality of life as measured by the CFQ-R
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CFQ-R, Cystic Fibrosis Questionnaire – Revised; FEF25–75%, forced expiratory flow during the middle portion of the forced vital capacity; FEV1pp, forced expiratory volume in 1 second
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C-reactive protein
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percent predicted; FVCpp, forced vital capacity percent predicted; hs-CRP, high-sensitivity
ACCEPTED MANUSCRIPT Table 3. Assessments. Visit no.
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
Visit name/weeka,
Screeni ng
Baselin e
4
6
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 2
Informed consent Demographi cs and disease characteristi cs Medical history Physical exam c 12-lead ECG Height, calculation of BMI Weight Vital signs Pulse oximetry CFQ-Re Spirometry Pulmonary exacerbation checklist Sputum sample f Hematology Serum chemistry hs-CRP Serum pregnancy g test HIV and HCV antibodies, HBsAg Urinalysis Urine pregnancy testg Urine alcohol and drug screen Randomizati on IP dispensing IP collection and capsule count AE and concomitant medication recording
b
Early terminati on
c
d
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c
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h
h
h
ACCEPTED MANUSCRIPT AE, adverse event; BMI, body mass index; CFQ-R, Cystic Fibrosis Questionnaire – Revised; ECG, electrocardiogram; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; IP, investigational product. a
Baseline visit within 21 days of Screening, window for other visits: ±5 days Visits 10, 12, and 14 will be conducted via phone call c Complete physical exam at Screening and Week 48, focused physical exam at all other visits d Predose and before discharge e To be administered before spirometry and sample collection f After spirometry g For women of childbearing potential h Two bottles of the IP must be dispensed Table 4. Baseline demographics (overall population). Value
Total number of patients enrolled
200
Mean age (years)
23.7
62 (31)
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Mean FEV1pp
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Current use of CFTR modulators, n (%)
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Characteristic
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b
Overall
70.6
In CFTR modulator users
72.6
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In CFTR modulator non-users
69.7
Overall, n 1, n (%) 2, n (%)
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≥3, n (%)
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Mean exacerbations in the prior year
2 93 (46.5) 57 (28.5) 50 (25.0)
CFTR, cystic fibrosis transmembrane conductance regulator, FEV1pp, forced expiratory volume in 1 second percent predicted.
ACCEPTED MANUSCRIPT Figures
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Fig. 1 Leukotriene Pathway
In many inflammatory diseases, the neutrophil signaling pathway governed by the potent inflammation mediator leukotriene B4 (LTB4) and the recovery mediator lipoxin A4 (LXA4) becomes imbalanced, leading to over-activation of neutrophils with sustained inflammation
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and tissue damage. Acebilustat tunes down the over-active neutrophil response [51,52].
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Fig. 2. Study design.
*Visits 10, 12, 14 conducted via telephone.
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CFTR, cystic fibrosis transmembrane conductance regulator; FEV1pp, forced expiratory volume in 1 second percent predicted.
