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

Phase 2

Completed

Interventions: Drug: Ranolazine placebo
Drug: Ranolazine
Drug: Dronedarone placebo
Drug: Dronedarone

Brief Summary: The primary objective of this study is to evaluate the effect of ranolazine and of low-dose dronedarone when given alone and in combination at different dose levels on atrial fibrillation burden (AFB) over 12 weeks of treatment. AFB is defined as the total time a participant is in atrial tachycardia/atrial fibrillation (AT/AF) expressed as a percentage of total recording time.

Recruitment & Eligibility

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

Key

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
Corrected QT interval (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 cytochrome P450 3A (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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin > 2 x upper limit of normal (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 individual'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)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Arm && Interventions

Group	Intervention	Description
Placebo	Ranolazine placebo	Ranolazine placebo plus dronedarone placebo for 12 weeks.
Placebo	Dronedarone placebo	Ranolazine placebo plus dronedarone placebo for 12 weeks.
Ranolazine 750 mg + Dronedarone 150 mg	Dronedarone	Ranolazine 750 mg plus dronedarone 150 mg for 12 weeks.
Dronedarone 225 mg	Ranolazine placebo	Ranolazine placebo plus dronedarone 225 mg for 12 weeks.
Ranolazine 750 mg	Dronedarone placebo	Ranolazine 750 mg plus dronedarone placebo for 12 weeks.
Ranolazine 750 mg	Ranolazine	Ranolazine 750 mg plus dronedarone placebo for 12 weeks.
Dronedarone 225 mg	Dronedarone	Ranolazine placebo plus dronedarone 225 mg for 12 weeks.
Ranolazine 750 mg + Dronedarone 225 mg	Dronedarone	Ranolazine 750 mg plus dronedarone 225 mg for 12 weeks.
Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine	Ranolazine 750 mg plus dronedarone 225 mg for 12 weeks.
Ranolazine 750 mg + Dronedarone 150 mg	Ranolazine	Ranolazine 750 mg plus dronedarone 150 mg for 12 weeks.

Primary Outcome Measures

Name	Time	Method
Absolute Change From Baseline in AFB by Week 12	Baseline; Week 12	AFB is defined as the total time a participant is in AT/AF expressed as a percentage of total recording time. Data are presented for baseline-adjusted AFB over 12 weeks of treatment.
Atrial Fibrillation Burden (AFB) at Baseline	Baseline	AFB was defined as the total time a participant was in atrial tachycardia (AT)/atrial fibrillation (AF) expressed as a percentage of total recording time. Geometric mean is the mean of log-transformed AFB exponentiated.
Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12	Baseline; Week 12	AFB was defined as the total time a participant was in atrial tachycardia (AT)/atrial fibrillation (AF) expressed as a percentage of total recording time. Data are presented for baseline-adjusted AFB over 12 weeks of treatment. Geometric mean is the mean of log-transformed AFB exponentiated.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB	Week 12	AFB was defined as the total time a participant was in AT/AF expressed as a percentage of total recording time.