Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination in Patients With Paroxysmal Atrial Fibrillation
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation
Intervention: Ranolazine; Dronedarone; Ranolazine placebo; Dronedarone placebo
Intervention description: Tablets administered orally twice daily.; Capsule administered orally twice daily; Tablets administered orally twice daily.; Capsules administered orally twice daily
Intervention MeSH terms: Dronedarone; Ranolazine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 134.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Atrial Fibrillation; Ranolazine; Dronedarone; Dual Chamber Pacemakers

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.
    

Eligibility criteria:

        Key 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.