Effects of Dronedarone on Cardiac Geometry and Function in Patients With Atrial Fibrillation and Left Atrial Enlargement

Study Overview
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Brief Summary
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Primary Objective: - Evaluate the effect of dronedarone versus placebo (standard therapy) in slowing the progression of adverse left atrial remodeling in patients with atrial fibrillation (AF) following 12 months of treatment. Secondary Objectives: Evaluate the effects of dronedarone versus placebo on left atrial function; Evaluate the effects of dronedarone versus placebo on left atrial dimension; Evaluate the effects of dronedarone versus placebo on left ventricular function (LVEF, E, E', A, E/E') Evaluate the safety and tolerability of dronedarone.

Detailed Description
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The planned total study period per participant was 12 months and 3 weeks broken down as follows: Screening period: up to 1 week; Treatment period: 12 months; Follow-up period: 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 on Cardiac Geometry and Function in Patients With Atrial Fibrillation and Left Atrial Enlargement

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: Signed written informed consent and Health Insurance Portability and Accountability Act (HIPAA) Authorization; Nonpermanent AF or AF/Atrial Flutter (AFL) documented electrocardiographically by both AF (or AF/AFL) and sinus rhythm within the prior 12 months; At screening, sinus rhythm and Left Atrial Volume index (LAVi) ≥32 mL/m2 based on 2D-echocardiography; At least one of the following cardiovascular (CV) risk factors: Age >70 years at start of screening, hypertension, diabetes mellitus, prior CV accident (stroke or transient ischemic attack) or systemic embolism, or left ventricular ejection fraction <0.40. Exclusion criteria: Permanent AF defined as continuous AF for 6 months or longer; Persistent AF defined as sustained AF >7 days duration and/or requiring cardioversion in the 4 weeks before screening; Prior valvular heart surgery or significant valvular heart disease including rheumatic heart disease or acquired valvular heart disease; Aortic or mitral regurgitation greater than mild (>1+) or any degree of mitral stenosis at the screening echocardiogram; Myocardial infarction within the 6 months prior to screening or stroke within 2 months prior to screening; Pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy devices placed within the 6 months prior to screening or at anytime during the study; Ongoing potentially dangerous symptoms when in AF/AFL such as angina pectoris, transient ischemic attacks, stroke, syncope as judged by the Investigator; Cardiac ablative procedure or cardiac surgery within 3 months prior to screening, or percutaneous coronary intervention within 4 weeks prior to screening; Need for concomitant medication that is prohibited in this trial, and would preclude the use of the study drug during the planned study period including the following: Antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol); Drugs or products that are strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, and grapefruit juice); Drugs that are inducers of CYP3A (eg, rifampin, phenobarbital, carbamazepine, phenytoin, and St John's wort); QTc Bazett interval ≥500 msec on the screening ECG; Bradycardia <50 bpm and/or PR interval ≥0.28 sec on the screening ECG unless the patient has a functional pacemaker; 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. 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 | 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 | 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 |
| --- | --- | --- |
| Change From Baseline in Left Atrial Volume Index (LAVi) | Left Atrial Volume index (LAVi) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis. | baseline (before randomization) and post-baseline (after 3-12 months of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes From Baseline in Left Atrial Function | left atrial (LA) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis. | baseline (before randomization) and post-baseline (after 3-12 months of treatment) | 
| Changes From Baseline in Left Atrial Dimension | Maximal left atrial diameter in the anteroposterior dimension was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis. | baseline (before randomization) and post-baseline (after 3-12 months of treatment) | 
| Changes From Baseline in Left Ventricular Ejection Fraction (LVEF) | Left Ventricular Ejection Fraction (LVEF) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis. | baseline (before randomization) and post-baseline (after 3-12 months of treatment) | 
| Changes From Baseline in Left Ventricular Function | left ventricular (LV) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis. | baseline (before randomization) and post-baseline (after 3-12 months of treatment) |