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

A Phase 2, Proof of Concept, Randomized, Placebo-Controlled, Parallel Group Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination on Atrial Fibrillation Burden in Subjects With Paroxysmal Atrial Fibrillation

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.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Ranolazine placebo; Drug: Dronedarone placebo; Drug: Ranolazine; Drug: Dronedarone

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Coburg, Germany, 96450
    • Investigational Site
  • Frankfurt, Germany, 60594
    • Investigational Site
  • Göttingen, Germany, 37075
    • Investigational Site
  • Ingolstadt, Germany, 85049
    • Investigational Site
  • Lubeck, Germany, D23538
    • Investigational Site
  • Bayern
    • München, Bayern, Germany, 81377
      • Investigational Site
    • Würzburg, Bayern, Germany, 97080
      • Investigational Site
  • Nordrhein-westfalen
    • Bonn, Nordrhein-westfalen, Germany, 53105
      • Investigational Site
• Israel
  • Hadera, Israel, 38100
    • Investigational Site
  • Haifa, Israel, 31096
    • Investigational Site
  • Holon, Israel, 58100
    • Investigational Site
  • Jerusalem, Israel, 91031
    • Investigational Site
  • Nahariya, Israel, 22100
    • Investigational Site
  • Rehovot, Israel, 76100
    • Investigational Site
  • Ashqelon
    • Ashkelon, Ashqelon, Israel, 78287
      • Investigational Site
  • Zefat
    • Afula, Zefat, Israel, 18101
      • Investigational Site
• Italy
  • Como, Italy, 22020
    • Investigational Site
  • Firenze, Italy, 50134
    • Investigational Site
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Investigational Site
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Investigational Site
• Poland
  • Lodz, Poland, 91-425
    • Investigational Site
  • Warszawa, Poland, 02-097
    • Investigational Site
  • Kujawsko-pomorskie
    • Torun, Kujawsko-pomorskie, Poland, 87-100
      • Investigational Site
  • Lodzkie
    • Lodz, Lodzkie, Poland, 90-553
      • Investigational Site
  • Malopolskie
    • Kraków, Malopolskie, Poland, 31-501
      • Investigational Site
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 01-211
      • Investigational Site
    • Warsaw, Mazowieckie, Poland, 04-628
      • Investigational Site
  • Podlaskie
    • Bialystok, Podlaskie, Poland, 15-276
      • Investigational Site
  • Pomorskie
    • Gdansk, Pomorskie, Poland, 80-219
      • Investigational Site
    • Sopot, Pomorskie, Poland, 81-717
      • Investigational Site
  • Slaskie
    • Katowice, Slaskie, Poland, 40-635
      • Investigational Site
    • Zabrze, Slaskie, Poland, 41-800
      • Investigational Site
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 61-848
      • Investigational Site
  • Zachodniop
    • Szczecin, Zachodniop, Poland, 70-203
      • Investigational Site
• United Kingdom
  • England
    • London, England, United Kingdom, SE5 9RS
      • Investigational Site
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Investigational Site
    • Newport Beach, California, United States, 92663
      • Investigational Site
    • San Francisco, California, United States, 94143
      • Investigational Site
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Investigational Site
  • Florida
    • Lakeland, Florida, United States, 33805
      • Investigational Site
  • Maryland
    • Takoma Park, Maryland, United States, 20912
      • Investigational Site
    • Towson, Maryland, United States, 21204
      • Investigational Site
  • New York
    • Utica, New York, United States, 13501
      • Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Investigational Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • Investigational Site
  • Utah
    • Murray, Utah, United States, 84107
      • Investigational Site
  • Washington
    • Seattle, Washington, United States, 98122
      • Investigational Site
  • Wisconsin
    • Wausau, Wisconsin, United States, 54401
      • Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Ranolazine placebo plus dronedarone placebo for 12 weeks.	Drug: Ranolazine placebo; Tablets administered orally twice daily.; Drug: Dronedarone placebo; Capsules administered orally twice daily
Experimental: Ranolazine 750 mg; Ranolazine 750 mg plus dronedarone placebo for 12 weeks.	Drug: Dronedarone placebo; Capsules administered orally twice daily; Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa®
Experimental: Dronedarone 225 mg; Ranolazine placebo plus dronedarone 225 mg for 12 weeks.	Drug: Ranolazine placebo; Tablets administered orally twice daily.; Drug: Dronedarone; Capsule administered orally twice daily
Experimental: Ranolazine 750 mg + Dronedarone 225 mg; Ranolazine 750 mg plus dronedarone 225 mg for 12 weeks.	Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa®; Drug: Dronedarone; Capsule administered orally twice daily
Experimental: Ranolazine 750 mg + Dronedarone 150 mg; Ranolazine 750 mg plus dronedarone 150 mg for 12 weeks.	Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa®; Drug: Dronedarone; Capsule administered orally twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Atrial Fibrillation Burden (AFB) at 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.	Baseline
Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by 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.	Baseline; Week 12
Absolute Change From Baseline in AFB by 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.	Baseline; Week 12

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Reiffel JA, Camm AJ, Belardinelli L, Zeng D, Karwatowska-Prokopczuk E, Olmsted A, Zareba W, Rosero S, Kowey P; HARMONY Investigators. The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1048-56. doi: 10.1161/CIRCEP.115.002856. Epub 2015 Jul 30.

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2012
• Primary Completion (Actual): March 10, 2014
• Study Completion (Actual): March 10, 2014

Study Registration Dates

• First Submitted: January 18, 2012
• First Submitted That Met QC Criteria: January 27, 2012
• First Posted (Estimate): January 31, 2012

Study Record Updates

• Last Update Posted (Actual): November 6, 2020
• Last Update Submitted That Met QC Criteria: November 4, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Ranolazine; Dronedarone; Dual Chamber Pacemakers
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Sodium Channel Blockers; Dronedarone; Ranolazine
• Other Study ID Numbers: GS-US-291-0102; 2011-001134-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No