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

• Time to ICD shocks (appropriate or inappropriate) or death from any cause [ Time Frame: up to 20 months (median follow-up of 12 months) ] [ Designated as safety issue: No ]
• Time to Cardiovascular hospitalization or death [ Time Frame: up to 20 months (median follow-up of 12 months) ] [ Designated as safety issue: No ]

• Time to ICD shocks or deaths [ Time Frame: up to 20 months ] [ Designated as safety issue: No ]
• Time to Cardiovascular hospitalization or death [ Time Frame: up to 20 months ] [ Designated as safety issue: No ]

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 SSR149744 plasma levels during the study.

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.

• Arrhythmia Prophylaxis
• Ventricular Arrhythmia

• Drug: Celivarone (SSR149744)

  50 or 100 mg capsules

  oral administration with a meal

• Drug: amiodarone

  200 mg capsules

  oral administration with a meal

• Drug: placebo

  Matching capsules

  oral administration with a meal

• Experimental: celivarone 50 mg
  Celivarone 50 mg capsule once daily up to 10-15 days before the common study end date
  Interventions:

  • Drug: Celivarone (SSR149744)
  • Drug: placebo
• Experimental: celivarone 100 mg
  Celivarone 100 mg once daily up to 10-15 days before the common study end date
  Interventions:

  • Drug: Celivarone (SSR149744)
  • Drug: placebo
• Experimental: celivarone 300 mg
  Celivarone 300 mg once daily up to 10-15 days before the common study end date
  Intervention: Drug: Celivarone (SSR149744)
• Active Comparator: amiodarone 200 mg
  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
  Interventions:

  • Drug: amiodarone
  • Drug: placebo
• Placebo Comparator: placebo
  Placebo once daily up to 10-15 days before the common study end date
  Intervention: Drug: placebo

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 antitachycardia 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.