Atrial Fibrillation
Conditions
Brief summary
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
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.
Interventions
DRUGDronedarone
Film-coated tablet Oral administration under fed conditions (during breakfast and dinner)
Film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Atrial Fibrillation (AF) Burden During the 12-week Treatment Period | Baseline (before randomization), 4 weeks and 12 weeks after randomization | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment | 4 weeks and 12 weeks after randomization | AF burden at each pacemaker interrogation as evaluated centrally by the Pacemaker Core Lab |
| Average Ventricular Rate During AF Episodes | Baseline (before randomization), 4 weeks and 12 weeks after randomization | 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. |
| Atrial Fibrillation Severity Scale (AFSS) Scores | Baseline (before randomization) and 12 weeks after randomization | 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. |
| Incidence Rate of Electrical Cardioversion (or Overdrive Pacing) | 12 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overview of Adverse Events (AE) | from first study drug intake up to 10 days after the last study drug intake | AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. |
Countries
United States
Participant flow
Recruitment details
Recruitment initiated in July 2010 was discontinued in December, 2011 due to significantly lower than planned enrollment with no feasibility to complete the trial within reasonable, meaningful timelines and despite a protocol amendment that extended the recruitment period and reduced the sample size from 424 to 286 participants.
Pre-assignment details
After signature of the informed consent and after eligibility was confirmed, group assignment was made at site in a 1:1 ratio using a treatment code list generated centrally by Sanofi. Participants were considered as randomized as soon as the assignment was made. Only 112 patients were randomized at 62 sites.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for Dronedarone) twice a day for 12 weeks | 55 |
| Dronedarone Dronedarone 400 mg twice a day for 12 weeks | 57 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 8 |
| Overall Study | Other than above | 3 | 4 |
Baseline characteristics
| Characteristic | Dronedarone | Total | Placebo |
|---|---|---|---|
| Age Continuous | 77.3 years STANDARD_DEVIATION 8.6 | 75.9 years STANDARD_DEVIATION 9.1 | 74.5 years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 28 Participants | 45 Participants | 17 Participants |
| Sex: Female, Male Male | 29 Participants | 67 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 55 | 16 / 57 |
| serious Total, serious adverse events | 7 / 55 | 7 / 57 |
Outcome results
Primary
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.
Time frame: Baseline (before randomization), 4 weeks and 12 weeks after randomization
Population: The analysis included all randomized and treated participants with post-baseline AF burden assessment. Participants were included in the treatment group to which they were randomized (Modified Intent-to-treat analysis).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo | Atrial Fibrillation (AF) Burden During the 12-week Treatment Period | Baseline | 8.77 percent time in AF |
| Placebo | Atrial Fibrillation (AF) Burden During the 12-week Treatment Period | 12-week treatment period | 9.90 percent time in AF |
| Dronedarone | Atrial Fibrillation (AF) Burden During the 12-week Treatment Period | Baseline | 10.14 percent time in AF |
| Dronedarone | Atrial Fibrillation (AF) Burden During the 12-week Treatment Period | 12-week treatment period | 4.63 percent time in AF |
Comparison: The planned sample size of 286 participants was estimated to have 70% power to detect a reduction in mean AF burden of 30% relative to the placebo group.~Due to the smaller-than-planned sample size, the power to detect this difference was estimated to be only 44%, based on the original assumption. However, the power to detect larger treatment effects (\>40% reduction) remained high and the posthoc power to detect a 60% reduction in AF burden was 99%.p-value: 0.001595% CI: [-76.322, -29.457]ANCOVA
Secondary
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
Time frame: 4 weeks and 12 weeks after randomization
Population: Modified intent-to-treat population as previously defined
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo | AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment | Week 1 - 4 (n =54, 49) | 8.99 percent time in AF |
| Placebo | AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment | Week 5 - 12 (n =54, 54) | 9.37 percent time in AF |
| Dronedarone | AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment | Week 1 - 4 (n =54, 49) | 3.62 percent time in AF |
| Dronedarone | AF Burden During the First 4 Weeks of Treatment and After 4-week Treatment | Week 5 - 12 (n =54, 54) | 4.28 percent time in AF |
Secondary
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.
Time frame: Baseline (before randomization) and 12 weeks after randomization
Population: Modified intent-to-treat population as previously defined
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Atrial Fibrillation Severity Scale (AFSS) Scores | AF burden at baseline (n =45, 34) | 13.72 units on a scale | Standard Deviation 4.59 |
| Placebo | Atrial Fibrillation Severity Scale (AFSS) Scores | AF burden after 12-week treatment (n =38, 31) | 13.30 units on a scale | Standard Deviation 5.4 |
| Placebo | Atrial Fibrillation Severity Scale (AFSS) Scores | AF symptoms at baseline (n =55, 55) | 8.47 units on a scale | Standard Deviation 6.97 |
| Placebo | Atrial Fibrillation Severity Scale (AFSS) Scores | AF symptoms after 12-week treatment (n =54, 53) | 8.06 units on a scale | Standard Deviation 7.11 |
| Dronedarone | Atrial Fibrillation Severity Scale (AFSS) Scores | AF symptoms after 12-week treatment (n =54, 53) | 7.42 units on a scale | Standard Deviation 7.48 |
| Dronedarone | Atrial Fibrillation Severity Scale (AFSS) Scores | AF burden at baseline (n =45, 34) | 12.76 units on a scale | Standard Deviation 4.62 |
| Dronedarone | Atrial Fibrillation Severity Scale (AFSS) Scores | AF symptoms at baseline (n =55, 55) | 8.36 units on a scale | Standard Deviation 6.83 |
| Dronedarone | Atrial Fibrillation Severity Scale (AFSS) Scores | AF burden after 12-week treatment (n =38, 31) | 12.48 units on a scale | Standard Deviation 5.45 |
Secondary
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.
Time frame: Baseline (before randomization), 4 weeks and 12 weeks after randomization
Population: Modified intent-to-treat population as previously defined
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Average Ventricular Rate During AF Episodes | Baseline (n =49, 47) | 93.02 beats/min | Standard Deviation 16.74 |
| Placebo | Average Ventricular Rate During AF Episodes | Week 1-12 (n =49, 48) | 95.67 beats/min | Standard Deviation 17.43 |
| Placebo | Average Ventricular Rate During AF Episodes | --- Week 1-4 (n =44, 41) | 96.80 beats/min | Standard Deviation 20.09 |
| Placebo | Average Ventricular Rate During AF Episodes | --- Week 5-12 (n =47, 42) | 95.58 beats/min | Standard Deviation 18.72 |
| Dronedarone | Average Ventricular Rate During AF Episodes | --- Week 5-12 (n =47, 42) | 88.56 beats/min | Standard Deviation 20.69 |
| Dronedarone | Average Ventricular Rate During AF Episodes | Baseline (n =49, 47) | 90.68 beats/min | Standard Deviation 19.8 |
| Dronedarone | Average Ventricular Rate During AF Episodes | --- Week 1-4 (n =44, 41) | 91.93 beats/min | Standard Deviation 21.89 |
| Dronedarone | Average Ventricular Rate During AF Episodes | Week 1-12 (n =49, 48) | 91.28 beats/min | Standard Deviation 20.3 |
Secondary
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.
Time frame: 12 weeks
Population: Modified intent-to-treat population as previously defined
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Incidence Rate of Electrical Cardioversion (or Overdrive Pacing) | 1 participants |
| Dronedarone | Incidence Rate of Electrical Cardioversion (or Overdrive Pacing) | 0 participants |
Other Pre-specified
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.
Time frame: from first study drug intake up to 10 days after the last study drug intake
Population: All randomized and treated participants. Participants were considered according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Overview of Adverse Events (AE) | Any AE | 31 participants |
| Placebo | Overview of Adverse Events (AE) | - Any serious AE | 7 participants |
| Placebo | Overview of Adverse Events (AE) | - Any AE leading to death | 0 participants |
| Placebo | Overview of Adverse Events (AE) | - Any AE leading to treatment discontinuation | 3 participants |
| Dronedarone | Overview of Adverse Events (AE) | - Any AE leading to treatment discontinuation | 8 participants |
| Dronedarone | Overview of Adverse Events (AE) | Any AE | 37 participants |
| Dronedarone | Overview of Adverse Events (AE) | - Any AE leading to death | 0 participants |
| Dronedarone | Overview of Adverse Events (AE) | - Any serious AE | 7 participants |