Effects of Dronedarone on Atrial Fibrillation Burden in Subjects With Permanent Pacemakers (HESTIA)

A Placebo-Controlled, Double-Blind, Randomized, Multi-Center Study to Assess the Effects of Dronedarone 400 mg BID for 12 Weeks on Atrial Fibrillation Burden in Subjects With Permanent Pacemakers

Primary objective was to evaluate the effects of dronedarone on Atrial Fibrillation (AF) burden (i.e. percent time in AF) as measured on electrogram (EGM) in subjects with a permanent pacemaker.

Secondary objectives were to evaluate:

• the effects of dronedarone on AF pattern characteristics i.e. ventricular rate during AF;
• the effects of dronedarone on subject-perceived AF burden and symptom severity as reported by subjects using the Atrial Fibrillation Severity Scale (AFSS);
• the incidence of electrical cardioversion (or overdrive pacing) during treatment;
• the safety of dronedarone.

Study Overview

• Status: Terminated
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Dronedarone; Drug: Placebo (for Dronedarone)

Detailed Description

The maximum duration of the study period for a participant was 18 weeks (approximatively 4.5 months) including up to 4 weeks screening, 12-week Treatment period and a post-treatment follow-up of 2 weeks.

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35235
      • Investigational Site Number 840015
    • Huntsville, Alabama, United States, 35801
      • Investigational Site Number 840087
    • Mobile, Alabama, United States, 36608
      • Investigational Site Number 840018
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Investigational Site Number 840030
    • Phoenix, Arizona, United States, 85006
      • Investigational Site Number 840048
    • Phoenix, Arizona, United States, 85032
      • Investigational Site Number 840072
    • Tucson, Arizona, United States, 85723
      • Investigational Site Number 840013
  • Arkansas
    • Hot Springs, Arkansas, United States, 71913
      • Investigational Site Number 840069
  • California
    • Beverly Hills, California, United States, 90211
      • Investigational Site Number 840121
    • Laguna Hills, California, United States, 92653
      • Investigational Site Number 840090
    • Los Angeles, California, United States, 90048
      • Investigational Site Number 840068
    • Mission Hills, California, United States, 91345
      • Investigational Site Number 840062
    • Orange, California, United States, 92868
      • Investigational Site Number 840070
    • Riverside, California, United States, 92501
      • Investigational Site Number 840021
    • San Diego, California, United States, 92103
      • Investigational Site Number 840024
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Investigational Site Number 840001
    • Littleton, Colorado, United States, 80120
      • Investigational Site Number 840089
    • Loveland, Colorado, United States, 80538
      • Investigational Site Number 840029
  • Delaware
    • Newark, Delaware, United States, 19713
      • Investigational Site Number 840108
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2975
      • Investigational Site Number 840045
    • Washington, District of Columbia, United States, 20037
      • Investigational Site Number 840106
  • Florida
    • Clearwater, Florida, United States, 33756
      • Investigational Site Number 840010
    • Ft. Myers, Florida, United States, 33908
      • Investigational Site Number 840020
    • Inverness, Florida, United States, 34452
      • Investigational Site Number 840058
    • Jacksonville, Florida, United States, 32204
      • Investigational Site Number 840043
    • Jacksonville, Florida, United States, 32216
      • Investigational Site Number 840066
    • Jacksonville, Florida, United States, 32216
      • Investigational Site Number 840128
    • Jacksonville Beach, Florida, United States, 32250
      • Investigational Site Number 840044
    • Orlando, Florida, United States, 32803
      • Investigational Site Number 840042
    • Port Charlotte, Florida, United States, 33952
      • Investigational Site Number 840016
    • Wellington, Florida, United States, 33449
      • Investigational Site Number 840080
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Investigational Site Number 840056
  • Illinois
    • Normal, Illinois, United States, 61761
      • Investigational Site Number 840092
    • Oak Lawn, Illinois, United States, 60453
      • Investigational Site Number 840032
    • Rockford, Illinois, United States, 61107
      • Investigational Site Number 840046
  • Indiana
    • Bloomington, Indiana, United States, 47403
      • Investigational Site Number 840051
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Investigational Site Number 840053
  • Kentucky
    • Owensboro, Kentucky, United States, 42303
      • Investigational Site Number 840110
  • Maryland
    • Columbia, Maryland, United States, 21044
      • Investigational Site Number 840102
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Investigational Site Number 840017
    • Lapeer, Michigan, United States, 48446
      • Investigational Site Number 840081
    • Petoskey, Michigan, United States, 49770
      • Investigational Site Number 840075
    • Troy, Michigan, United States, 48085
      • Investigational Site Number 840027
  • Minnesota
    • St Cloud, Minnesota, United States, 56301
      • Investigational Site Number 840104
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • Investigational Site Number 840097
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Investigational Site Number 840037
    • Kansas City, Missouri, United States, 64111
      • Investigational Site Number 840035
    • St Louis, Missouri, United States, 63122
      • Investigational Site Number 840060
    • St. Louis, Missouri, United States, 63141
      • Investigational Site Number 840055
  • Montana
    • Missoula, Montana, United States, 59802
      • Investigational Site Number 840067
  • Nevada
    • Reno, Nevada, United States, 89502
      • Investigational Site Number 840049
    • Reno, Nevada, United States, 89502
      • Investigational Site Number 840054
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Investigational Site Number 840026
    • Englewood, New Jersey, United States, 07631
      • Investigational Site Number 840093
  • New York
    • Bronx, New York, United States, 10467
      • Investigational Site Number 840036
    • Buffalo, New York, United States, 14215
      • Investigational Site Number 840006
    • Kingston, New York, United States, 12401
      • Investigational Site Number 840077
    • Mineola, New York, United States, 11501
      • Investigational Site Number 840096
    • Syracuse, New York, United States, 13202
      • Investigational Site Number 840041
    • Troy, New York, United States, 12180
      • Investigational Site Number 840086
    • Williamsville, New York, United States, 14221
      • Investigational Site Number 840007
  • North Carolina
    • Raleigh, North Carolina, United States, 27610
      • Investigational Site Number 840084
    • Wilmington, North Carolina, United States, 28401
      • Investigational Site Number 840061
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Investigational Site Number 840065
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Investigational Site Number 840008
    • Doylestown, Pennsylvania, United States, 18901
      • Investigational Site Number 840009
    • Philadelphia, Pennsylvania, United States, 19111
      • Investigational Site Number 840004
    • Phoenixville, Pennsylvania, United States, 19460
      • Investigational Site Number 840078
    • Pittsburgh, Pennsylvania, United States, 15236
      • Investigational Site Number 840105
    • Scranton, Pennsylvania, United States, 18510
      • Investigational Site Number 840130
    • Unionville, Pennsylvania, United States, 15401
      • Investigational Site Number 840019
    • Wyomissing, Pennsylvania, United States, 19610
      • Investigational Site Number 840023
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Investigational Site Number 840119
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Investigational Site Number 840002
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Investigational Site Number 840114
  • Texas
    • Corpus Christi, Texas, United States, 78404
      • Investigational Site Number 840118
    • Dallas, Texas, United States, 75390-8858
      • Investigational Site Number 840014
    • San Antonio, Texas, United States, 78229
      • Investigational Site Number 840012
    • Tyler, Texas, United States, 75701
      • Investigational Site Number 840125
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Investigational Site Number 840083
  • Virginia
    • Danville, Virginia, United States, 24541
      • Investigational Site Number 840113
    • Lynchburg, Virginia, United States, 24501
      • Investigational Site Number 840082
    • Manassas, Virginia, United States, 20109
      • Investigational Site Number 840088
    • Richmond, Virginia, United States, 23219
      • Investigational Site Number 840099
    • Richmond, Virginia, United States, 23230
      • Investigational Site Number 840112
  • Washington
    • Tacoma, Washington, United States, 98405
      • Investigational Site Number 840003
    • Tacoma, Washington, United States, 98405
      • Investigational Site Number 840107
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301-3505
      • Investigational Site Number 840123
    • Madison, Wisconsin, United States, 53713
      • Investigational Site Number 840022
    • Milwaukee, Wisconsin, United States, 53215
      • Investigational Site Number 840033
    • Milwaukee, Wisconsin, United States, 53215
      • Investigational Site Number 840047
    • Milwaukee, Wisconsin, United States, 53226
      • Investigational Site Number 840076

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:

• Paroxysmal AF or atrial flutter (AFL) documented by evidence of AF/AFL and sinus rhythm within the prior 6 months;
• AF burden ≥1% on pacemaker EGM interrogation at screening, with at least one episode of AF within the previous 28 days;
• Programmable dual chamber pacemaker with lead placement no less than 3 months before screening, a minimum capability of storing 3 months or more of EGM data, and an expected remaining battery life of 1 year or more.

Exclusion criteria:

• AF burden <1% on pacemaker EGM interrogation at screening;
• None of the following cardiovascular risk factors: Age ≥70 years, hypertension, diabetes mellitus, prior cardiovascular accident or systemic embolism, left atrium diameter ≥50 mm by M-mode or 2D echocardiography, or left ventricular ejection fraction ≤0.40 by M-mode or 2D echocardiography, cardiac catheterization, or nuclear cardiac imaging;
• Permanent AF;
• Evidence of persistent AF (continuous AF activity lasting longer than 7 days);
• Electrical cardioversion (or overdrive pacing) within 4 weeks prior to screening;
• Cardiac ablation procedure within 3 months prior to screening;
• Evidence of uncorrected atrial undersensing or oversensing documented in routine pacemaker evaluation at screening;
• Pacemaker programming requirements for the study not clinically feasible, contraindicated, or could have posed risk;
• Ongoing potentially dangerous symptoms when in AF/AFL such as angina pectoris, transient ischemic attacks, stroke, or syncope;
• New York Heart Association (NYHA) Class IV heart failure or NYHA Class II or III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic within 4 weeks prior to screening;
• Evidence of clinical instability including hypotension, unstable angina and hemodynamically significant obstructive valvular disease, hemodynamically significant obstructive cardiomyopathy, a cardiac operation, or revascularization procedure within 4 weeks prior to screening;
• Noncardiovascular illness or disorder that could have precluded participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression;
• Planned noncardiac or cardiac surgery or procedures including surgery for valvular heart disease, coronary artery bypass graft, percutaneous coronary intervention, cardiac transplantation or electrical cardioversion for AF/AFL;
• Need for concomitant medication that were prohibited in this trial: Antiarrhythmics, drugs or products that are strong inhibitors of CYP3A, CYP3A inducers;
• Chronic use of amiodarone within the 4 weeks prior to screening;
• Use of Class I or Class III antiarrhythmics (other than amiodarone) within 5-half lives prior to screening;
• Use of St John's wort, grapefruit juice, or drugs that prolong the QT interval and might have increased the risk of torsade de pointes;
• Inability or unwillingness to comply with oral anticoagulation therapy, if indicated;
• Bazett corrected QT interval interval ≥500 msec at screening (if in sinus rhythm);
• Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥ 100mmHg) at screening;
• Uncorrected hypokalemia (serum potassium <3.5 mEq/L)
• Severe hepatic impairment (ie, Child-Pugh Class C), abnormal liver function test defined as alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin >2 X upper limit of normal (ULN), or renal impairment defined as serum creatinine >2.0 mg/dL at screening;
• Uncontrolled diabetes mellitus (documented history of HbA1c >10% at the most recent assessment prior to screening);
• Pregnant woman or woman of childbearing potential not on adequate birth control;
• Breastfeeding woman;
• Previous (within 2 months prior to screening) or current participation in another clinical trial with an investigational drug (under development) or investigational device.

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: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dronedarone; Dronedarone 400 mg twice a day for 12 weeks	Drug: Dronedarone; Film-coated tablet Oral administration under fed conditions (during breakfast and dinner); Other Names: Multaq®; SR33589
Placebo Comparator: Placebo; Placebo (for Dronedarone) twice a day for 12 weeks	Drug: Placebo (for Dronedarone); Film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atrial Fibrillation (AF) Burden During the 12-week Treatment Period	AF burden, defined as the percent time a subject is in AF, was evaluated centrally by a Pacemaker Core Lab based on pacemaker interrogation reports including Electrogram (EGM) data provided by the Investigator. AF burden during the 12-week treatment period was defined as the duration-weighted average of AF burden collected at Week 4 and Week 12. It was calculated from the single available measurement when one measurement was missing.	Baseline (before randomization), 4 weeks and 12 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment	AF burden at each pacemaker interrogation as evaluated centrally by the Pacemaker Core Lab	4 weeks and 12 weeks after randomization
Average Ventricular Rate During AF Episodes	Ventricular rates of AF episodes were obtained from pacemaker interrogation and EGM review. The average ventricular rate during AF episodes in the 12-week treatment period was defined as the duration-weighted average of the ventricular rates collected at Week 4 and Week 12. It was calculated from the single available measurement when one measurement was missing.	Baseline (before randomization), 4 weeks and 12 weeks after randomization
Atrial Fibrillation Severity Scale (AFSS) Scores	The University of Toronto Atrial Fibrillation Severity Scale is an instrument to assess the subject-perceived AF burden and AF symptom severity. It consists in a questionnaire plus a scoring algorithm. AF Burden score ranges from 3 to 30 and higher scores indicate greater AF burden. AF symptoms severity score ranges from 0 to 35 and higher scores indicate extremely severe AF symptoms.	Baseline (before randomization) and 12 weeks after randomization
Incidence Rate of Electrical Cardioversion (or Overdrive Pacing)	Electrical cardioversion is a procedure in which an electric shock is used to restore normal heart rhythm. Overdrive pacing is a procedure in which an artificial cardiac pacemaker is used to increase the heart rate in order to suppress certain arrhythmias. Incidence rate of electrical cardioversion (or overdrive pacing) is expressed as the number of participants that was cardioverted or paced during the study.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overview of Adverse Events (AE)	AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.	from first study drug intake up to 10 days after the last study drug intake

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: May 28, 2010
• First Submitted That Met QC Criteria: May 28, 2010
• First Posted (Estimate): June 2, 2010

Study Record Updates

• Last Update Posted (Estimate): April 11, 2013
• Last Update Submitted That Met QC Criteria: April 5, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Anti-Arrhythmia Agents; Dronedarone
• Other Study ID Numbers: DRONE_L_04316; U1111-1117-0024 (Other Identifier: UTN)