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

• Plasma levels of amiodarone and its metabolite [ Time Frame: First 4 weeks of treatment with Dronedarone ] [ Designated as safety issue: No ]
• AF recurrence [ Time Frame: Up to 60 days after randomization ] [ Designated as safety issue: No ]
  AF recurrence is documented by at least two consecutive scheduled or unscheduled 12-lead ECGs approximately 10 minutes apart and both showing AF
• Number of patients with Adverse Events of Special Interest (AESIs) [ Time Frame: Up to 8 weeks after randomization ] [ Designated as safety issue: Yes ]
  Specific AESIs are: congestive Heart Failure (CHF), Interstitial lung disease , severe skin disorders, peripheral neuropathy including optic neuropathy and increase in ALT
• Symptomatic bradycardia (Heart Rate (HR) < 50 beats per minute at rest) and tachycardia (HR > 120 beats per minute at rest) [ Time Frame: Up to 8 weeks after randomization ] [ Designated as safety issue: Yes ]

• Plasma levels of amiodarone and its metabolite (AUC0-12hours and Cmax) [ Time Frame: First 4 weeks of treatment with Dronedarone ] [ Designated as safety issue: No ]
• AF recurrence [ Time Frame: Up to 60 days after randomization ] [ Designated as safety issue: No ]
  AF recurrence is documented by at least two consecutive scheduled or unscheduled 12-lead ECGs approximately 10 minutes apart and both showing AF
• Adverse Events of Special Interest (AESIs); Congestive Heart Failure (CHF), Interstitial lung disease , severe skin disorders, peripheral neuropathy including optic neuropathy and increase in ALT [ Time Frame: Up to 8 weeks after randomization ] [ Designated as safety issue: Yes ]
• Symptomatic bradycardia (Heart Rate (HR) < 50 beats per minute at rest) and tachycardia (HR > 120 beats per minute at rest) [ Time Frame: Up to 8 weeks after randomization ] [ Designated as safety issue: Yes ]

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 one month and two months after randomization
• To assess the safety of the change from Amiodarone to Dronedarone and Dronedarone safety

The maximum study duration per patient is 10 weeks

• Experimental: Group A
  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.
  Intervention: Drug: DRONEDARONE
• Experimental: Group B

  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.

  Intervention: Drug: DRONEDARONE
• Experimental: Group C

  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.

  Intervention: Drug: DRONEDARONE

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 major amiodarone-related toxicity (interstitial lung disease, thyroid or hepatotoxicity)
• 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

• Clinically overt congestive heart failure:

  • with New York Heart Association (NYHA) class III or 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
• 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

• Clinically overt congestive heart failure:

  • with New York Heart Association (NYHA) class III or 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

• 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.