A Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination in Patients With Paroxysmal Atrial Fibrillation (HARMONY)

• AFB for each visit period (Weeks 4, 8 and 12) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Number of atrial fibrillation (AF) episodes, duration of AF episodes, and ventricular rate during AF episodes [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Ventricular rate over 12 weeks of treatment and for each visit period (Weeks 4, 8, and 12) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Percentage of ventricular pacing [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Percentage of atrial pacing [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Incidence of persistent AF [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Incidence of electrical cardioversion [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Incidence of symptomatic episodes [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• The percentage of subjects who have ≥ 30% (≥ 50%) reduction from baseline in AFB [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• The percentage of subjects who have total duration of AF episodes ≥ 5.5 hours per day at any point during the Treatment period [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate whether treatment with ranolazine or low dose dronedarone reduces atrial fibrillation burden (AFB) in subjects with paroxysmal atrial fibrillation (PAF), and whether combination therapy (ranolazine and low dose dronedarone) is superior to individual drug therapy in reducing AFB.

This phase 2 clinical trial will be conducted over 16 weeks and involves a Screening period (4 weeks) and a Treatment period (12 weeks). The final follow up visit will occur 2 weeks after the end of the Treatment period. Primary and Secondary endpoints will be evaluated according to treatment group, clinic visit period, and the overall Treatment period. Safety analyses will be conducted at each clinic visit, and include: cardiac rhythm monitoring, ECG testing, laboratory evaluation, and symptom and adverse event assessment.

• Drug: Placebo
  Placebo, 1 tablet and 1 capsule, oral, administered BID
• Drug: Ranolazine
  Ranolazine, 1 tablet, oral, BID
  Other Name: Ranexa
• Drug: Dronedarone
  Dronedarone, low dose 1, 1 capsule, oral, BID
• Drug: Ranolazine and Dronedarone low dose 1
  Ranolazine, 1 tablet, oral, BID Dronedarone low dose 1, 1 capsule, oral, BID
  Other Name: Ranexa
• Drug: Ranolazine and Dronedarone low dose 2
  Ranolazine, 1 tablet, oral, BID Dronedarone low dose 2, 1 capsule, oral, BID
  Other Name: Ranexa

• Placebo Comparator: Placebo
  Placebo for Ranolazine + placebo for Dronedarone
  Intervention: Drug: Placebo
• Experimental: Ranolazine
  Ranolazine + placebo for Dronedarone
  Intervention: Drug: Ranolazine
• Experimental: Dronedarone low dose 1
  Dronedarone low dose 1 + placebo for Ranolazine
  Intervention: Drug: Dronedarone
• Experimental: Ranolazine and Dronedarone low dose 1
  Ranolazine + Dronedarone low dose 1
  Intervention: Drug: Ranolazine and Dronedarone low dose 1
• Experimental: Ranolazine and Dronedarone low dose 2
  Ranolazine + Dronedarone low dose 2
  Intervention: Drug: Ranolazine and Dronedarone low dose 2

Inclusion Criteria:

• Males and females aged 18 years and older
• Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures

• History of PAF documented within the prior 12 months

  — Patients with PAF undergoing cardioversion greater than 4 weeks prior to Screening are eligible

• Implanted (at least 3 months prior to Screening) dual chamber programmable pacemakers with AF detection capabilities
• AFB ≥ 1% and ≤ 70% between the last clinic evaluation and Screening (minimum of 1 month observation period) and AFB ≥ 2% and ≤ 70% during the Run in period
• Sexually active females of childbearing potential must agree to utilize effective methods of contraception during heterosexual intercourse throughout the treatment period and for 14 days following discontinuation of the study medication

Exclusion Criteria:

Disease - specific:

• Persistent AF or Permanent AF
• History of atrial flutter or atrial tachycardia without successful ablation
• Other acutely reversible causes of AF, including but not limited to: hyperthyroidism, pericarditis, myocarditis, or pulmonary embolism
• New York Heart Association (NYHA) Class III and IV heart failure or NYHA Class II heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic within 4 weeks prior to Screening.
• Recent history of left ventricular ejection fraction (LVEF) < 40%
• Myocardial infarction, unstable angina, or coronary artery bypass graft (CABG) surgery within three months prior to Screening or percutaneous coronary intervention (PCI) within 4 weeks prior to Screening
• Clinically significant valvular disease in the opinion of the Investigator
• Stroke within 3 months prior to Screening
• History of serious ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation) within 4 weeks prior to Screening
• Family history of long QT syndrome
• QTc ≥ 500 msec (Bazett) at Screening ECG if in sinus rhythm (SR). If in AF, evidence of QTc ≥ 500 msec (Bazett) within 4 weeks prior to Screening
• Prior heart transplant
• Cardiac ablation within 4 months prior to Screening, or planned ablation during the course of the study

Concomitant medications/food

• Need for concomitant treatment during the trial, with drugs or products that are strong inhibitors of CYP3A, or inducers of CYP3A

  — Such medications should be discontinued 5-half lives prior to the Run-in period

• Use of grapefruit juice or Seville orange juice during the study
• Use of Class I and Class III antiarrhythmic drugs other than amiodarone within 5-half lives prior to the Run-in period
• Use of amiodarone within 3 months prior to Screening
• Use of drugs that prolong the QT interval
• Previous use of ranolazine or dronedarone within 2 months prior to screening
• Prior use of ranolazine or dronedarone which was discontinued for safety or tolerability
• Use of dabigatran during the study
• Use of digitalis preparations (eg, digoxin) during the study
• Use of a greater than 1000 mg total daily dose of metformin during the study

Laboratory tests:

• Hypokalemia (serum potassium < 3.5 mEq/L) at Screening that cannot be corrected to a level of potassium ≥ 3.5 mEq/L prior to randomization
• Moderate and severe hepatic impairment (ie, Child-Pugh Class B and C), abnormal liver function test defined as ALT, AST, or bilirubin > 2 x ULN at Screening
• Severe renal impairment defined as creatinine clearance ≤ 30 mL/min at Screening

Others:

• Females who are pregnant or are breastfeeding
• In the judgment of the Investigator, any clinically-significant ongoing medical condition that might jeopardize the subject's safety or interfere with the study, including participation in another clinical trial within the previous 30 days using a therapeutic modality which could have potential residual effects that might confound the results of this study
• Any device-related technical issue which in the judgment of the investigator would disrupt adequate data collection or interpretation (eg, anticipated pulse generator change or lead revision)