Dose Ranging Study of Celivarone With Amiodarone as Calibrator for the Prevention of Implantable Cardioverter Defibrillator (ICD) Interventions or Death

Study Overview
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Brief Summary
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The Primary objective was to assess the efficacy of Celivarone for the prevention of Implantable Cardioverter Defibrillator (ICD) interventions or death. Secondary objectives were: To assess the tolerability and safety of the different dose regimens of Celivarone in the selected population. To document Celivarone plasma levels during the study.

Detailed Description
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The study included a one week screening period, followed by a treatment period ranging between 6 and 19 months. The treatment was to be continued until the End of Treatment visit scheduled 10-15 days prior to the common Scheduled Study End Date (SSED). The SSED was defined as about 190 days after the last patient randomization date. The expected recruitment duration was about 14 months and thus the total duration of the study about 20 months. Visits were planned to be performed at baseline, after 5 days, after 14 days, every month for 6 months and then, every three months after 6 months until the end of the study.

Official Title
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Double Blind Placebo Controlled Dose Ranging Study of the Efficacy and Safety of Celivarone at 50, 100 or 300 mg OD With Amiodarone as Calibrator for the Prevention of ICD Interventions or Death

Conditions
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Arrhythmia Prophylaxis, Ventricular Arrhythmia

Intervention / Treatment
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* Drug: Celivarone
* Drug: Amiodarone
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Implantable Cardioverter Defibrillator (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 Exclusion criteria : Patients of either sex aged below 21 years (or the age of legal consent of the country), Women of childbearing potential without adequate birth control or pregnant or breastfeeding women Patients with known ICD lead problem (lead dislodgement) ICD without the following characteristics : data logging function with cumulative counting of device intervention (shocks and anti-tachycardia pacing [ATP]) electrogram storage capabilities ventricular demand pacing. Recent unstable angina pectoris or myocardial infarction (< 4 weeks), History of torsades de pointes, Genetic channelopathies including congenital long QT syndrome, Wolff-Parkinson-White syndrome, Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with intravenous pressor agents; patients on respirator; congestive heart failure of stage New York Heart Association (NYHA) IV within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardiomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization, Incessant sustained VT/VF (VT/VF that recurs promptly despite termination attempts) during the three days preceding randomization. Patients with inappropriate (not triggered by VT nor VF) shocks during the month preceding randomization. Clinically relevant haematologic, hepatobiliary (ALT, AST > 3 times the upper limit of normal at randomization), gastro-intestinal, renal (serum creatinine > 221 µmol/l (2.5 mg/dl) at randomization), pulmonary, endocrinologic or psychiatric disease. Patients treated with oral amiodarone (more than 20 tablets during the 2 months preceding randomization) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Celivarone 50 mg<br>Celivarone, 50 mg once daily up to 10-15 days before the common study end date | Drug: Celivarone<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SSR149744;Drug: Matching placebo<br>* Pharmaceutical form: capsule Route of administration: oral Matching placebo added to active drug if any for a total of 3 capsules per intake<br>|
| Experimental: Celivarone 100 mg<br>Celivarone, 100 mg once daily up to 10-15 days before the common study end date | Drug: Celivarone<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SSR149744;Drug: Matching placebo<br>* Pharmaceutical form: capsule Route of administration: oral Matching placebo added to active drug if any for a total of 3 capsules per intake<br>|
| Experimental: Celivarone 300 mg<br>Celivarone, 300 mg once daily up to 10-15 days before the common study end date | Drug: Celivarone<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: SSR149744;Drug: Matching placebo<br>* Pharmaceutical form: capsule Route of administration: oral Matching placebo added to active drug if any for a total of 3 capsules per intake<br>|
| Active Comparator: Amiodarone<br>Amiodarone, 600 mg once daily for 10 days (loading dose) then 200 mg once daily up to 10-15 days before the common study end date | Drug: Amiodarone<br>* Pharmaceutical form: capsule Route of administration: oral<br>* Other names: Cordarone;Drug: Matching placebo<br>* Pharmaceutical form: capsule Route of administration: oral Matching placebo added to active drug if any for a total of 3 capsules per intake<br>|
| Placebo Comparator: Placebo<br>Matching placebo once daily up to 10-15 days before the common study end date | Drug: Matching placebo<br>* Pharmaceutical form: capsule Route of administration: oral Matching placebo added to active drug if any for a total of 3 capsules per intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Ventricular Tachycardia or Ventricular Fibrillation (VT/VF) triggered ICD interventions or sudden death | The presence of VT or VF was documented by ICD interrogation leading to any ICD interventions (shocks or anti-tachycardia pacing). The 10 first ICD interventions for each patient were centrally and blindly adjudicated by an Adjudication Committee. | up to 20 months (median follow-up of 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ICD shocks (appropriate or inappropriate) or death from any cause |  | up to 20 months (median follow-up of 12 months) | 
| Time to Cardiovascular hospitalization or death |  | up to 20 months (median follow-up of 12 months) |