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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT01522651
First received: January 18, 2012
Last updated: August 8, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation
Drug: Ranolazine
Drug: Dronedarone low dose 1
Drug: Dronedarone low dose 2
Drug: Ranolazine placebo
Drug: Dronedarone placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • 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 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Atrial Fibrillation Burden (AFB) is defined as the total time a subject is in atrial tachycardia/atrial fibrillation (AT/AF) expressed as a percentage of total recording time.


Secondary Outcome Measures:
  • 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 ]

Enrollment: 134
Study Start Date: January 2012
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Ranolazine placebo plus dronedarone placebo for 12 weeks
Drug: Ranolazine placebo
Placebo to match ranolazine administered orally twice daily
Drug: Dronedarone placebo
Placebo to match dronedarone administered orally twice daily
Experimental: Ranolazine
Ranolazine plus dronedarone placebo for 12 weeks
Drug: Ranolazine
Ranolazine 750 mg tablet administered orally twice daily
Other Name: Ranexa®
Drug: Dronedarone placebo
Placebo to match dronedarone administered orally twice daily
Experimental: Dronedarone low dose 1
Ranolazine placebo plus dronedarone low dose 1 for 12 weeks
Drug: Dronedarone low dose 1
Dronedarone 225 mg capsule administered orally twice daily
Drug: Ranolazine placebo
Placebo to match ranolazine administered orally twice daily
Experimental: Ranolazine + dronedarone low dose 1
Ranolazine plus dronedarone low dose 1 for 12 weeks
Drug: Ranolazine
Ranolazine 750 mg tablet administered orally twice daily
Other Name: Ranexa®
Drug: Dronedarone low dose 1
Dronedarone 225 mg capsule administered orally twice daily
Experimental: Ranolazine + dronedarone low dose 2
Ranolazine plus dronedarone low dose 2 for 12 weeks
Drug: Ranolazine
Ranolazine 750 mg tablet administered orally twice daily
Other Name: Ranexa®
Drug: Dronedarone low dose 2
Dronedarone 150 mg capsule administered orally twice daily

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01522651

  Hide Study Locations
Locations
United States, California
Investigational Site
Beverly Hills, California, United States, 90211
Investigational Site
Newport Beach, California, United States, 92663
Investigational Site
San Francisco, California, United States, 94143
United States, Colorado
Investigational Site
Aurora, Colorado, United States, 80012
United States, District of Columbia
Investigational Site
Washington DC, District of Columbia, United States, 20010
United States, Florida
Investigational Site
Lakeland, Florida, United States, 33805
United States, Maryland
Investigational Site
Takoma Park, Maryland, United States, 20912
Investigational Site
Towson, Maryland, United States, 21204
United States, New York
Investigational Site
Utica, New York, United States, 13501
United States, Ohio
Investigational Site
Cleveland, Ohio, United States, 44106
United States, Rhode Island
Investigational Site
Warwick, Rhode Island, United States, 02886
United States, Texas
Investigational Site
Houston, Texas, United States, 77030
United States, Utah
Investigational Site
Murray, Utah, United States, 84107
United States, Washington
Investigational Site
Seattle, Washington, United States, 98122
United States, Wisconsin
Investigational Site
Wausau, Wisconsin, United States, 54401
Germany
Investigational Site
München, Bayern, Germany, 81377
Investigational Site
Würzburg, Bayern, Germany, 97080
Investigational Site
Bonn, Germany, 53105
Investigational Site
Coburg, Germany, 96450
Investigational Site
Frankfurt, Germany, 60594
Investigational Site
Goettingen, Germany, 37075
Investigational Site
Ingolstadt, Germany, 85049
Investigational Site
Lubeck, Germany, D23538
Israel
Investigational Site
Ashkelon, Ashqelon, Israel, 78287
Investigational Site
Afula, Zefat, Israel, 18101
Investigational Site
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
Italy
Investigational Site
Como, Italy, 22020
Investigational Site
Firenze, Italy, 50134
Netherlands
Investigational Site
Maastricht, Limburg, Netherlands, 6229 HX
Investigational Site
Groningen, Netherlands, 9700 RB
Poland
Investigational Site
Torun, Kujawsko-pomorskie, Poland, 87-100
Investigational Site
Lodz, Lodzkie, Poland, 90-553
Investigational Site
Lódz, Lodzkie, Poland, 90-553
Investigational Site
Kraków, Malopolskie, Poland, 31-501
Investigational Site
Warsaw, Mazowieckie, Poland, 04-628
Investigational Site
Warsaw, Mazowieckie, Poland, 01-211
Investigational Site
Bialystok, Podlaskie, Poland, 15-276
Investigational Site
Gdansk, Pomorskie, Poland, 80-219
Investigational Site
Sopot, Pomorskie, Poland, 81-717
Investigational Site
Katowice, Slaskie, Poland, 40-635
Investigational Site
Zabrze, Slaskie, Poland, 41-800
Investigational Site
Posnan, Wielkopolskie, Poland, 61-848
Investigational Site
Szczecin, Zachodniop, Poland, 70-203
Investigational Site
Lodz, Poland, 91-425
Investigational Site
Warszawa, Poland, 02-097
United Kingdom
Investigational Site
London, England, United Kingdom, SE5 9RS
Investigational Site
Cardiff, United Kingdom, CF14 4XW
Investigational Site
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Cardiovascular Clinical Research, Gilead Sciences Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01522651     History of Changes
Other Study ID Numbers: GS-US-291-0102, 2011-001134-42
Study First Received: January 18, 2012
Last Updated: August 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: National Health Service
United Kingdom: Research Ethics Committee
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Italy: Ethics Committee
Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
Italy: The Italian Medicines Agency
Israel: Ethics Commission
Israel: Ministry of Health
Poland: Ethics Committee
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products

Keywords provided by Gilead Sciences:
Atrial Fibrillation
Ranolazine
Dronedarone
Dual Chamber Pacemakers

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Cardiovascular Diseases
Heart Diseases
Pathologic Processes
Amiodarone
Ranolazine
Anti-Arrhythmia Agents
Cardiovascular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 29, 2014