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

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

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.

Study Overview

• Status: Completed
• Conditions: Ventricular Arrhythmia; Arrhythmia Prophylaxis
• Intervention / Treatment: Drug: Celivarone; Drug: Matching placebo; Drug: Amiodarone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 486
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma De Bs.As, Argentina, 1428
    • Investigational Site Number 032002
  • Corrientes, Argentina, 3400
    • Investigational Site Number 032003
  • San Miguel De Tucuman, Argentina, T4000NIL
    • Investigational Site Number 032004
• Australia
  • Adelaide, Australia, 5000
    • Investigational Site Number 036012
  • Auchenflower, Australia, 4066
    • Investigational Site Number 036006
  • Bedford Park, Australia, 5042
    • Investigational Site Number 036004
  • Camperdown, Australia, 2050
    • Investigational Site Number 036014
  • Garran, Australia, 2605
    • Investigational Site Number 036013
  • Gosford, Australia, 2250
    • Investigational Site Number 036010
  • Herston, Australia, 4029
    • Investigational Site Number 036005
  • Nedlands, Australia, 6009
    • Investigational Site Number 036008
  • New Lambton, Australia, 2305
    • Investigational Site Number 036009
  • Perth, Australia, 6000
    • Investigational Site Number 036007
  • Woolloongabba, Australia, 4102
    • Investigational Site Number 036003
• Belgium
  • Aalst, Belgium, 9300
    • Investigational Site Number 056005
  • Brugge, Belgium, 8000
    • Investigational Site Number 056007
  • Brussel, Belgium, 1090
    • Investigational Site Number 056001
  • Gilly, Belgium, 6060
    • Investigational Site Number 056002
  • Hasselt, Belgium, 3500
    • Investigational Site Number 056004
  • Roeselare, Belgium, 8800
    • Investigational Site Number 056003
• Canada
  • Calgary, Canada, T2N 2T9
    • Investigational Site Number 124009
  • Hamilton, Canada, L8L 2X2
    • Investigational Site Number 124010
  • London, Canada, N6A 5A5
    • Investigational Site Number 124004
  • Montreal, Canada, H1T 1C8
    • Investigational Site Number 124008
  • Montreal, Canada, H2W 1T8
    • Investigational Site Number 124001
  • Ste-Foy, Canada, G1V 4G5
    • Investigational Site Number 124005
  • Toronto, Canada, M5B 1W8
    • Investigational Site Number 124002
  • Vancouver, Canada, V6E 1M9
    • Investigational Site Number 124006
  • Victoria, Canada, V8R 4R2
    • Investigational Site Number 124007
• Chile
  • Santiago, Chile, 8380456
    • Investigational Site Number 152001
• Czech Republic
  • Brno, Czech Republic, 65691
    • Investigational Site Number 203004
  • Ceske Budejovice, Czech Republic, 37087
    • Investigational Site Number 203002
  • Hradec Kralove, Czech Republic, 50005
    • Investigational Site Number 203005
  • Liberec, Czech Republic, 46063
    • Investigational Site Number 203001
  • Olomouc, Czech Republic, 77520
    • Investigational Site Number 203003
  • Praha 5, Czech Republic, 15030
    • Investigational Site Number 203006
• Denmark
  • Aarhus, Denmark, 8200
    • Investigational Site Number 208002
  • Hellerup, Denmark, 2900
    • Investigational Site Number 208004
  • København Ø, Denmark, 2100
    • Investigational Site Number 208005
  • Odense C, Denmark, 5000
    • Investigational Site Number 208001
• Finland
  • Helsinki, Finland, 00290
    • Investigational Site Number 246001
  • Tampere, Finland, 33520
    • Investigational Site Number 246004
• France
  • Brest, France, 29609
    • Investigational Site Number 250004
  • Grenoble, France, 38043
    • Investigational Site Number 250006
  • Lille, France, 59037
    • Investigational Site Number 250005
  • Montpellier, France, 34295
    • Investigational Site Number 250002
  • Paris Cedex 15, France, 75908
    • Investigational Site Number 250001
  • Rennes, France, 35033
    • Investigational Site Number 250007
  • Vandoeuvre Les Nancy Cedex, France, 54511
    • Investigational Site Number 250003
• Germany
  • Bad Neustadt, Germany, 97616
    • Investigational Site Number 276005
  • Bernau, Germany, 16321
    • Investigational Site Number 276002
  • Dresden, Germany, 01099
    • Investigational Site Number 276003
  • Frankfurt Am Main, Germany, 60590
    • Investigational Site Number 276001
  • Hamburg, Germany, 20246
    • Investigational Site Number 276006
• Hungary
  • Balatonfüred, Hungary, 8230
    • Investigational Site Number 348001
  • Budapest, Hungary, 1027
    • Investigational Site Number 348004
  • Pécs, Hungary, 7624
    • Investigational Site Number 348005
  • Zalaegerszeg, Hungary, 8900
    • Investigational Site Number 348003
• Israel
  • Afula, Israel, 18101
    • Investigational Site Number 376002
  • Ashkelon, Israel, 78278
    • Investigational Site Number 376003
  • Haifa, Israel, 31048
    • Investigational Site Number 376004
  • Tel Aviv, Israel, 64239
    • Investigational Site Number 376001
• Italy
  • Bari, Italy, 70124
    • Investigational Site Number 380004
  • Bergamo, Italy, 24125
    • Investigational Site Number 380008
  • Como, Italy, 22100
    • Investigational Site Number 380002
  • Firenze, Italy, 50141
    • Investigational Site Number 380001
  • Roma, Italy, 00169
    • Investigational Site Number 380007
• Japan
  • Meguro-Ku, Japan
    • Investigational Site Number 392004
  • Niigata-Shi, Japan
    • Investigational Site Number 392005
  • Osaka Sayama-Shi, Japan
    • Investigational Site Number 392001
  • Osaka-Shi, Japan
    • Investigational Site Number 392006
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392003
  • Suita-Shi, Japan
    • Investigational Site Number 392002
• Mexico
  • Mexico City, Mexico, 14080
    • Investigational Site Number 484002
• Netherlands
  • Alkmaar, Netherlands, 1815 JD
    • Investigational Site Number 528001
  • Amsterdam, Netherlands, 1091 AC
    • Investigational Site Number 528005
  • Breda, Netherlands, 4818 CK
    • Investigational Site Number 528002
  • Maastricht, Netherlands, 6229 HX
    • Investigational Site Number 528003
  • Rotterdam, Netherlands, 3015 CE
    • Investigational Site Number 528007
  • Zwolle, Netherlands, 8011 JW
    • Investigational Site Number 528004
• Norway
  • Drammen, Norway, 3004
    • Investigational Site Number 578003
• Poland
  • Bydgoszcz, Poland, 85-094
    • Investigational Site Number 616007
  • Gdynia, Poland, 81-348
    • Investigational Site Number 616011
  • Lodz, Poland, 90-548
    • Investigational Site Number 616006
  • Lodz, Poland, 91-425
    • Investigational Site Number 616003
  • Szczecin, Poland, 70-111
    • Investigational Site Number 616002
  • Warszawa, Poland, 02-097
    • Investigational Site Number 616008
  • Warszawa, Poland, 04-073
    • Investigational Site Number 616001
• Portugal
  • Coimbra, Portugal, 3000-075
    • Investigational Site Number 620004
  • Lisboa, Portugal, 1169-024
    • Investigational Site Number 620003
  • Vila Nova De Gaia, Portugal, 4430-502
    • Investigational Site Number 620005
• Russian Federation
  • Ekaterinburg, Russian Federation, 620102
    • Investigational Site Number 643006
  • Moscow, Russian Federation, 650002
    • Investigational Site Number 643005
  • Samara, Russian Federation, 443070
    • Investigational Site Number 643008
  • St-Petersburg, Russian Federation, 197110
    • Investigational Site Number 643003
  • St-Petersburg, Russian Federation, 199106
    • Investigational Site Number 643011
  • Tomsk, Russian Federation, 634012
    • Investigational Site Number 643004
  • Tyumen, Russian Federation, 625023
    • Investigational Site Number 643007
• Slovakia
  • Bratislava, Slovakia, 81104
    • Investigational Site Number 703001
  • Kosice, Slovakia, 04011
    • Investigational Site Number 703002
• South Africa
  • Pretoria, South Africa, 181
    • Investigational Site Number 710002
• Spain
  • Barcelona, Spain, 08036
    • Investigational Site Number 724001
  • Barcelona, Spain, 08907
    • Investigational Site Number 724002
  • Madrid, Spain, 28046
    • Investigational Site Number 724003
  • Madrid, Spain, 28035
    • Investigational Site Number 724004
  • Santiago De Compostela, Spain, 15706
    • Investigational Site Number 724006
  • Sevilla, Spain, 41008
    • Investigational Site Number 724009
  • Valencia, Spain, 46026
    • Investigational Site Number 724007
• Sweden
  • Stockholm, Sweden, 118 83
    • Investigational Site Number 752002
  • Umeå, Sweden, 901 85
    • Investigational Site Number 752003
  • Uppsala, Sweden, 751 85
    • Investigational Site Number 752001
• Turkey
  • Ankara, Turkey, 06490
    • Investigational Site Number 792001
  • Istanbul, Turkey, 34304
    • Investigational Site Number 792003
  • Istanbul, Turkey, 34390
    • Investigational Site Number 792002
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Investigational Site Number 840006
    • Mobile, Alabama, United States, 36608
      • Investigational Site Number 840042
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Investigational Site Number 840014
    • Phoenix, Arizona, United States, 85006
      • Investigational Site Number 840032
    • Tucson, Arizona, United States, 85723
      • Investigational Site Number 840033
  • California
    • Redondo Beach, California, United States, 90277
      • Investigational Site Number 840054
    • Redwood City, California, United States, 94062
      • Investigational Site Number 840007
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Investigational Site Number 840039
  • Florida
    • Fort Myers, Florida, United States, 33908
      • Investigational Site Number 840002
    • Orlando, Florida, United States, 32806
      • Investigational Site Number 840010
    • Port Charlotte, Florida, United States, 33952-8008
      • Investigational Site Number 840005
    • St. Petersburg, Florida, United States, 33707
      • Investigational Site Number 840013
    • St. Petersburg, Florida, United States, 33707
      • Investigational Site Number 840043
  • Georgia
    • Augusta, Georgia, United States, 30901
      • Investigational Site Number 840004
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Investigational Site Number 840045
    • Lombard, Illinois, United States, 60148
      • Investigational Site Number 840035
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Investigational Site Number 840017
  • Maine
    • Scarborough, Maine, United States, 04074
      • Investigational Site Number 840022
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0759
      • Investigational Site Number 840009
    • Detroit, Michigan, United States, 48236
      • Investigational Site Number 840026
    • Petoskey, Michigan, United States, 49770
      • Investigational Site Number 840003
    • Ypsilanti, Michigan, United States, 48197
      • Investigational Site Number 840015
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Investigational Site Number 840049
    • Kansas City, Missouri, United States, 64114
      • Investigational Site Number 840019
  • New York
    • New York, New York, United States, 10001
      • Investigational Site Number 840031
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Investigational Site Number 840029
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • Investigational Site Number 840037
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Investigational Site Number 840024
    • Doylestown, Pennsylvania, United States, 18901
      • Investigational Site Number 840030
    • Upland, Pennsylvania, United States, 19013
      • Investigational Site Number 840034
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Investigational Site Number 840020
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Investigational Site Number 840048
  • Tennessee
    • Tullahoma, Tennessee, United States, 37388
      • Investigational Site Number 840011
  • Virginia
    • Chesapeake, Virginia, United States, 23320
      • Investigational Site Number 840025
    • Norfolk, Virginia, United States, 23507
      • Investigational Site Number 840012
    • Richmond, Virginia, United States, 23225
      • Investigational Site Number 840038
  • Washington
    • Spokane, Washington, United States, 99204
      • Investigational Site Number 840016

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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	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)

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Chair: Peter KOWEY, Pr, Steering Committee Chair Person

Publications and helpful links

General Publications

• Kowey PR, Crijns HJ, Aliot EM, Capucci A, Kulakowski P, Radzik D, Roy D, Connolly SJ, Hohnloser SH; 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. 2011 Dec 13;124(24):2649-60. doi: 10.1161/CIRCULATIONAHA.111.072561. Epub 2011 Nov 14.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): May 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: October 9, 2009
• First Submitted That Met QC Criteria: October 9, 2009
• First Posted (Estimate): October 12, 2009

Study Record Updates

• Last Update Posted (Estimate): May 30, 2016
• Last Update Submitted That Met QC Criteria: May 2, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: DRI10936; 2008-008412-47 (EudraCT Number)