Pharmacokinetics and Optimal Timing of Dronedarone Initiation Following Long-term Amiodarone in Patients With Paroxysmal or Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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Primary Objective: - Explore Dronedarone and active metabolite pharmacokinetic (PK) profiles according to different timings of Dronedarone initiation. Secondary Objective: Explore potential PK interaction between Dronedarone and Amiodarone Evaluate the rate of Atrial Fibrillation (AF) recurrence during the study period (from randomization up to 60 days after) To assess the safety of the change from Amiodarone to Dronedarone and Dronedarone safety

Detailed Description
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The maximum study duration per patient is 10 weeks

Official Title
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A Randomized, International, Multi-center, Open-label Study to Document Pharmacokinetics and Optimal Timing of Initiation of Dronedarone Treatment Following Long-term Amiodarone in Patients With Paroxysmal or Persistent Atrial Fibrillation Whatever the Reason for the Change of Treatment.

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: Paroxysmal or persistent AF having received at least 6 months of amiodarone before screening with at least the last 2 months at a regimen of 200 mg/day (during at least 5 days per week) prior to screening Requiring a change from amiodarone treatment whatever the reason, but without liver, lung or thyroid toxicity related to previous use of amiodarone At least one cardiovascular risk factor (i.e. age > 70, hypertension, diabetes, prior cerebrovascular disease or left atrial diameter >= 50 mm Effective anticoagulation treatments verified by International Normalized Ratio (INR) (target INR > 2) QTc Bazett < 500 ms on 12-lead ECG Randomization: Outpatients and Inpatients (except patients hospitalized during screening period for SAE) Sinus rhythm Effective oral anticoagulation treatment verified by INR (target INR > 2). INR should be closely monitored after initiating dronedarone in patients taking vitamin K antagonist as per their label QTc Bazett < 500 ms and PR < 280 ms on 12-lead ECG Exclusion criteria: Screening: Contraindication to oral anticoagulation Acute condition known to cause AF Permanent AF Bradycardia < 50 bpm at rest on the 12-lead ECG History of, or current heart failure or left ventricular systolic dysfunction Unstable hemodynamic conditions Severe hepatic impairment Wolff-Parkinson-White Syndrome Previous catheter ablation for atrial fibrillation or catheter ablation scheduled in the next 10 weeks Previous history of Amiodarone intolerance or toxicity History of thyroid dysfunction Mandatory contraindicated concomitant treatment: potent cytochrome P450 (CYP3A4) inhibitors drugs or herbal products that prolong the QT interval and known to increase the risk of Torsade de Pointes Previous treatment with class I or class III anti-arrhythmic drugs (including sotalol) other than amiodarone if the anti-arrhythmic drug was taken less than one week before the day of screening (if taken more than one week before screening, the patient can be included) Randomization Bradycardia < 50 bpm on the 12-lead ECG History of, or current heart failure or left ventricular systolic dysfunction Unstable hemodynamic conditions Severe hepatic impairment Mandatory contraindicated concomitant treatment: potent cytochrome P450 (CYP3A4) inhibitors drugs or herbal products that prolong the QT interval and known to increase the risk of Torsade de Pointes 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>Dronedarone 400 mg twice daily for 8 weeks starting from randomization. The last 2 months regimen of Amiodarone 200 mg/day is continued until randomization. | Drug: Dronedarone<br>* Pharmaceutical form: tablet Route of administration: oral (together with meal) Dose regimen: 400 mg twice daily<br>* Other names: SR33589;|
| Experimental: Group B<br>Dronedarone 400 mg twice daily for 6 weeks starting 2 weeks after randomization. The last 2 months regimen of Amiodarone 200 mg/day is continued until randomization. | Drug: Dronedarone<br>* Pharmaceutical form: tablet Route of administration: oral (together with meal) Dose regimen: 400 mg twice daily<br>* Other names: SR33589;|
| Experimental: Group C<br>Dronedarone 400 mg twice daily for 4 weeks starting 4 weeks after randomization. The last 2 months regimen of Amiodarone 200 mg/day is continued until randomization. | Drug: Dronedarone<br>* Pharmaceutical form: tablet Route of administration: oral (together with meal) Dose regimen: 400 mg twice daily<br>* Other names: SR33589;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma levels of dronedarone and its metabolite |  | At randomization (baseline), 3 hours after the first dose of dronedarone, after 1, 2 and 4 weeks of treatment with dronedarone (before dronedarone dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma levels of amiodarone and its metabolite |  | At randomization (baseline), 3 hours after the first dose of dronedarone, after 1, 2 and 4 weeks of treatment with dronedarone (before dronedarone dose) | 
| Number of patients with AF recurrence |  | From randomization up to 60 days after | 
| Number of patients with Adverse Events of Special Interest (AESIs) | Specific AESIs are: congestive Heart Failure (CHF), Interstitial lung disease , severe skin disorders, peripheral neuropathy including optic neuropathy and increase in alanine aminotransferase (ALT) | Up to 8 weeks after randomization | 
| Number of patients with symptomatic bradycardia (Heart Rate (HR) < 50 beats per minute at rest) |  | Up to 8 weeks after randomization | 
| Number of patients with symptomatic tachycardia (HR > 120 beats per minute at rest) |  | Up to 8 weeks after randomization |