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Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - Celivarone Version Number: 1 (Electronic 1.0)

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Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - Celivarone Version Number: 1 (Electronic 1.0) Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - celivarone Version number: 1 (electronic 1.0) SYNOPSIS Title of the study: Double blind placebo controlled dose ranging study of the efficacy and safety of celivarone 50, 100 or 300 mg OD with amiodarone as calibrator for the prevention of ICD interventions or death (DRI10936 – ALPHEE) Investigator(s): Study centers: 151 active centers in 26 countries across Europe (Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Slovakia, Spain, Sweden), Argentina, Australia, Canada, Chile, Israel, Japan, Mexico, Norway, Russian Federation, South Africa, Turkey, and the USA. Publications (reference): Kowey PR, Crijns HJGM, Aliot EM, Capucci A, Kulakowski P, Radzik D, et al, on behalf of the ALPHEE study Investigators. Efficacy and safety of celivarone, with amiodarone as calibrator, in patients with an implantable cardioverter- defibrillator for prevention of implantable cardioverter-defibrillator interventions or death: The ALPHEE study. Circulation, published online November 14, 2011. Study period: Date first patient enrolled: 21 September 2009 Date last patient completed: 12 May 2011 Phase of development: 2b Objectives: Primary: To assess the efficacy of celivarone for the prevention of implantable cardioverter defibrillator (ICD) interventions or death. Secondary: To assess the tolerability and safety of the different dose regimens of celivarone in the selected population. To document SSR149744 plasma levels during the study. Methodology: This was a dose-finding, multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-arm study including a positive control calibrator arm. Eligible patients were randomized (2:2:2:2:1) via an interactive voice response system (IVRS) to placebo, celivarone 50 mg, celivarone 100 mg, celivarone 300 mg, or amiodarone group. The randomization was non-adaptative, centralized, and stratified by the timing of ICD implantation (less or more than 30 days) and by country. A summary of the study design is provided in the figure below. Post Treatment Pl n = 108 Follow-up 10 -1 5 da ys C1 n = 10 8 C2 n = 10 8 RR* C 3 n= 108 A n=54 Screening 1 clinicalexam (Cs) Treatment period 2 Labtest D-7 D1 See Study Flowchart EOT SSE D 1 Co n fi rm el igi b ilit y for visits 2 Informed consent available 3 Randomization 4 First studydrug dosing D: day R: R andomizat ion C1= Celivarone 50 mg OD C2= Celivarone 100 mg OD C3= Celivarone 300 mg OD A= Amiodarone 600 mg OD for 10 days then 200 mg OD Pl= Placebo EOT: End Of Treatment Visit SSED: Scheduled Study End Date (190 days [up to +14days] after the randomization of the last patient) Property of sanofi-aventis Page 1 Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - celivarone Version number: 1 (electronic 1.0) Number of patients: Planned: 486 patients (108 in the placebo group and in each of the 3 celivarone groups, and 54 in the amiodarone group) Randomized and treated: 486 randomized and 481 treated patients (109 in the placebo group, 107 in the celivarone 50 mg group, 101 in the celivarone 100 mg group, 113 in the celivarone 300 mg group, and 51 in the amiodarone group) Evaluated: Efficacy: 486 patients (109 in the placebo and celivarone 50 mg groups, 102 in the celivarone 100 mg group, 113 in the celivarone 300 mg group, and 53 in the amiodarone group) Safety: 481 patients (109 in the placebo group, 107 in the celivarone 50 mg group, 101 in the celivarone 100 mg group, 113 in the celivarone 300 mg group, and 51 in the amiodarone group) Pharmacokinetics: 372 patients (107 in the celivarone 50 mg group, 101 in the celivarone 100 mg group, 113 in the celivarone 300 mg group, and 51 in the amiodarone group) Diagnosis and criteria for inclusion: ICD patients with a left ventricular ejection fraction (LVEF) of 40% or less and one of the following criteria: at least one ICD therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) in the previous month, or ICD implantation in the previous month for documented VT/VF. Study treatments Investigational product Celivarone (SSR149744C) Amiodarone (as calibrator) Placebo (as comparator) Formulation 50-mg capsule 200-mg capsule capsule 100-mg capsule Route of administration Oral, in fed conditions Oral, in fed conditions Oral, in fed conditions (breakfast, lunch, or dinner (breakfast, lunch, or dinner (breakfast, lunch, or dinner depending on the patient’s depending on the patient’s depending on the patient’s habits) habits) habits) Dose regimen 50, 100, or 300 mg once daily 600 mg once daily (loading 3 capsules once daily dose) from Day 1 to Day 10, then 200 mg once daily Batch numbers 50 mg: 100 mg: Duration of treatment: 6 months minimum Duration of observation: 19 months for the 1st patient enrolled in the study: 1-week screening, treatment period going from the 1st day of treatment to the end-of-treatment (EOT) visit to be done 10-15 days prior to the scheduled study end date (SSED) defined as last patient randomization date + 190 days (up to +14 days). Property of sanofi-aventis Page 2 Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - celivarone Version number: 1 (electronic 1.0) Criteria for evaluation: Efficacy: Primary endpoint: The primary efficacy variable was defined as VT/VF triggered ICD interventions or sudden death (whichever occurred first). The presence of VT or VF leading to any ICD interventions (shocks or antitachycardia pacing [ATPs]) was documented by ICD interrogation. The Central Adjudication Committee adjudicated the 10 first episodes of VT/VF leading to an ICD intervention for a patient. Only adjudicated data occurred between the randomization and the SSED were analyzed. Sudden death data came from the central review of fatal events performed by a subset of Steering Committee members. The main analytical approach was the time in days elapsed between the randomization and the first occurrence of primary endpoint. The second analytical approach was the time in days elapsed between the randomization and each of first 10 occurrences of primary endpoint. Secondary endpoint: The secondary efficacy variable was defined as time to first ICD shock or death from any cause. Tertiary and other endpoint: The tertiary efficacy variable was defined as time to first cardiovascular hospitalization (Investigator’s judgement with preprinted form) or death from any cause. Other efficacy variables were inappropriate shocks and supraventricular arrhythmia. Safety: Safety variables were defined as adverse events (AEs) reported by the patient or noted by the Investigator, clinical laboratory data (hematology and clinical chemistry), vital signs (blood pressure), and electrocardiogram (ECG) parameters. The main safety criterion was the incidence of treatment-emergent adverse events (TEAEs) classified as deaths, serious adverse events (SAEs), AEs leading to treatment discontinuation, and all AEs (including AEs of special interest [AESI] defined as alanine aminotransferase [ALT] ≥3 upper limit of normal [ULN] or ≥2 times the baseline value if baseline ALT ≥ ULN). Pharmacokinetics: Celivarone, amiodarone, and desethylamiodarone plasma concentrations (concentration observed just before treatment administration during repeated dosing [Ctrough] and maximum concentration observed [Cmax]) were assessed. Plasma concentrations obtained from patients in the celivarone or amiodarone groups were classified as Ctrough if time interval between last dose before sampling and sampling was less than 2 hours or between 16 and 24 hours, and as Cmax if time interval between last dose before sampling and sampling was between 2 and 8 hours. Pharmacokinetic sampling times and bioanalytical methods: Investigators were recommended to collect blood samples for pharmacokinetic (PK) assay within 1 hour predose on Day 5 ± 2 days, within 2 to 6 hours postdose in Month 1 ± 5 days, within 8 to 16 hours postdose in Month 2 ± 5 days, within 1 hour predose in Month 3 ± 14 days, within 2 to 6 hours postdose in Month 6 ± 14 days, and any time in Month 12 ± 14 days. Celivarone plasma concentrations were determined using a validated liquid chromatography with tandem mass spectrometry method with a limit of quantification (LOQ) of 5 ng/mL. Amiodarone and its metabolite desethylamiodarone plasma concentrations were determined using a validated high performance liquid chromatography method with UV detection, with a LOQ of 5 ng/mL. Statistical methods: Analysis populations: Efficacy populations: The main efficacy population was the intent-to-treat (ITT) population defined as all randomized patients analyzed according to the treatment group allocated by IVRS randomization. The secondary population for efficacy analysis was the per-protocol population defined as a subset of the ITT population containing patients without a major efficacy-related protocol deviation. Safety population: The safety population included all randomized patients who did actually receive at least 1 dose or partial of a dose of investigational product (IP) analyzed according to the treatment actually received. If a patient had taken more than one treatment, the treatment actually received was the treatment taken for the longest period during the study. Pharmacokinetic population: The PK population corresponded to the safety population. Property of sanofi-aventis Page 3 Synopsis Style Clinical Study Report 18-Nov-2011 SSR149744 - DRI10936 - celivarone Version number: 1 (electronic 1.0) Efficacy analyses: The primary analysis of the primary endpoint was the time from randomization to first VT/VF triggering ICD intervention or sudden death. The comparison of each celivarone dose group versus the placebo group was performed using a stratified two-sided Log-rank asymptotic test according to stratum of randomization (timing of ICD implantation ≤30 days / >30 days). Hazard ratio with 95% confidence interval (each celivarone dose versus placebo) was estimated using the Cox model. The secondary efficacy analysis of the primary endpoint was the comparison between placebo and each celivarone dose performed on recurrent episodes. The maximum number of episodes was limited to 10 per patient.
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