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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Dronedarone
* Drug: Placebo (for Dronedarone)


Participation Criteria
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Eligibility Criteria
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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.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 |