Optimal Timing of Dronedarone Initiation After Conversion in Patients With Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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Primary Objective: - Evaluate the rate of Atrial Fibrillation (AF) recurrences one month after randomization according to different timings of initiation of dronedarone. Secondary Objective: Evaluate the rate of AF recurrences two months after randomization. Assess the safety of the change from amiodarone to dronedarone Assess dronedarone safety Explore dronedarone and its active metabolite plasma level (in a subset of countries) Explore potential Pharmacokinetic (PK) interaction between dronedarone and amiodarone (in a subset of countries)

Official Title
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A Randomized, International, Multi-center, Open-label Study to Document Optimal Timing of Initiation of Dronedarone Treatment After Conversion With Loading Dose of Amiodarone in Patients With Persistent Atrial Fibrillation Requiring Conversion of AF.

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: DRONEDARONE


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Screening: Persistent AF for more than 72 hours (documented by an ECG taken within the last 72 hours) for whom cardioversion, anti-arrhythmic treatment and anticoagulation treatment are indicated in the opinion of the Investigator Naive of amiodarone treatment in the last three months QTc Bazett < 500 ms on 12-lead ECG, At least one cardiovascular risk factor (i.e. age > 70, hypertension, diabetes, prior cerebrovascular disease or left atrial diameter >= 50 mm Randomization: Outpatient and Inpatients (except patients hospitalized during screening period for SAE) Sinus rhythm Effective oral anticoagulation verified by International Normalized Ratio/INR (target > 2) QTc Bazett < 500 ms and PR < 280 ms on 12-lead ECG Completed treatment period with amiodarone (28 days ± 2 days) Exclusion criteria: Screening: Contraindication to oral anticoagulation Acute condition known to cause AF Permanent AF Paroxysmal AF Bradycardia < 50 bpm on the 12-lead ECG Clinically overt congestive heart failure: with New York Heart Association (NYHA) classes III and IV heart failure with LVEF < 35% or NYHA class II with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic or unstable hemodynamic conditions Severe hepatic impairment Previous treatment with class I or class III anti-arrhythmic drugs (including sotalol) if taken less than one week Previous history of amiodarone intolerance or toxicity Any contraindication as per dronedarone and amiodarone labelling Wolff-Parkinson-White Syndrome Previous ablation for atrial fibrillation or any planned ablation in the next 2 months Contraindicated concomitant treatment: Potent cytochrome P450 (CYP3A4) inhibitors Use of drugs or herbal products that prolong the QT interval and known to increase the risk of Torsades de Pointes Class I or III anti-arrhythmic drugs (including sotalol) Randomization: Bradycardia < 50 bpm on the 12-lead ECG Clinically overt congestive heart failure: with New York Heart Association (NYHA) classes III and IV heart failure with LVEF < 35% or NYHA class II with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic or unstable hemodynamic conditions Severe hepatic impairment Previous treatment with class I or class III anti-arrhythmic drugs (including sotalol) if taken less than one week Patient in whom the following contraindicated concomitant treatment is mandatory: Potent cytochrome P450 (CYP3A4) inhibitors Use of drugs or herbal products that prolong the QT interval and known to increase the risk of Torsades de Pointes Class I or III anti-arrhythmic drugs (including sotalol) 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: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Amiodarone 600 mg daily for 1 week then 400 mg daily for 1 week then 200 mg daily for 2 weeks followed by dronedarone 400 mg twice daily for 8 weeks | Drug: DRONEDARONE<br>* Pharmaceutical form: tablet Route of administration: oral Dose regimen: 400 mg<br>|
| Experimental: Group B<br>Amiodarone 600 mg daily for 1 week then 400 mg daily for 1 week then 200 mg daily for 2 weeks. Two weeks wash-out followed by dronedarone 400 mg twice daily for 6 weeks | Drug: DRONEDARONE<br>* Pharmaceutical form: tablet Route of administration: oral Dose regimen: 400 mg<br>|
| Experimental: Group C<br>Amiodarone 600 mg daily for 1 week then 400 mg daily for 1 week then 200 mg daily for 2 weeks. Four weeks wash-out followed by dronedarone 400 mg twice daily for 4 weeks | Drug: DRONEDARONE<br>* Pharmaceutical form: tablet Route of administration: oral Dose regimen: 400 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AF recurrences | two consecutives 12-lead ECG or Trans-Telephonic ECG monitoring (TTEM) approximatively 10 minutes apart and both showing AF | one month after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AF recurrences |  | two months after randomization | 
| Symptomatic bradycardia | Heart rate at rest < 50 beats per minute | two months after randomization | 
| Tachycardia | Heart rate at rest > 120 beats per minute | two months after randomization | 
| Dronedarone and amiodarone concentrations in plasma | Limited to a subset of countries | 3 hours, 1 week, 2 weeks and 4 weeks after 1st Dronedarone intake |