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

NCT ID: NCT01522651

Last Updated: 2020-11-06

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

134 participants

Study Classification

INTERVENTIONAL

Study Start Date

2012-01-24

Study Completion Date

2014-03-10

Brief Summary

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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.

Detailed Description

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Conditions

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Atrial Fibrillation

Keywords

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Atrial Fibrillation Ranolazine Dronedarone Dual Chamber Pacemakers

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Placebo

Ranolazine placebo plus dronedarone placebo for 12 weeks.

Group Type PLACEBO_COMPARATOR

Ranolazine placebo

Intervention Type DRUG

Tablets administered orally twice daily.

Dronedarone placebo

Intervention Type DRUG

Capsules administered orally twice daily

Ranolazine 750 mg

Ranolazine 750 mg plus dronedarone placebo for 12 weeks.

Group Type EXPERIMENTAL

Ranolazine

Intervention Type DRUG

Tablets administered orally twice daily.

Dronedarone placebo

Intervention Type DRUG

Capsules administered orally twice daily

Dronedarone 225 mg

Ranolazine placebo plus dronedarone 225 mg for 12 weeks.

Group Type EXPERIMENTAL

Dronedarone

Intervention Type DRUG

Capsule administered orally twice daily

Ranolazine placebo

Intervention Type DRUG

Tablets administered orally twice daily.

Ranolazine 750 mg + Dronedarone 225 mg

Ranolazine 750 mg plus dronedarone 225 mg for 12 weeks.

Group Type EXPERIMENTAL

Ranolazine

Intervention Type DRUG

Tablets administered orally twice daily.

Dronedarone

Intervention Type DRUG

Capsule administered orally twice daily

Ranolazine 750 mg + Dronedarone 150 mg

Ranolazine 750 mg plus dronedarone 150 mg for 12 weeks.

Group Type EXPERIMENTAL

Ranolazine

Intervention Type DRUG

Tablets administered orally twice daily.

Dronedarone

Intervention Type DRUG

Capsule administered orally twice daily

Interventions

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Ranolazine

Tablets administered orally twice daily.

Intervention Type DRUG

Dronedarone

Capsule administered orally twice daily

Intervention Type DRUG

Ranolazine placebo

Tablets administered orally twice daily.

Intervention Type DRUG

Dronedarone placebo

Capsules administered orally twice daily

Intervention Type DRUG

Other Intervention Names

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Ranexa®

Eligibility Criteria

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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
* 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)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Gilead Sciences

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Gilead Study Director

Role: STUDY_DIRECTOR

Gilead Sciences

Locations

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Investigational Site

Beverly Hills, California, United States

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Newport Beach, California, United States

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San Francisco, California, United States

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Aurora, Colorado, United States

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Washington D.C., District of Columbia, United States

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Lakeland, Florida, United States

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Takoma Park, Maryland, United States

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Towson, Maryland, United States

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Utica, New York, United States

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Cleveland, Ohio, United States

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Warwick, Rhode Island, United States

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Houston, Texas, United States

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Murray, Utah, United States

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Seattle, Washington, United States

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Wausau, Wisconsin, United States

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München, Bavaria, Germany

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Würzburg, Bavaria, Germany

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Bonn, North Rhine-Westphalia, Germany

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Coburg, , Germany

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Frankfurt, , Germany

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Göttingen, , Germany

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Ingolstadt, , Germany

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Lübeck, , Germany

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Ashkelon, Ashqelon, Israel

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Afula, Zefat, Israel

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Hadera, , Israel

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Haifa, , Israel

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Holon, , Israel

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Jerusalem, , Israel

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Nahariya, , Israel

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Rehovot, , Israel

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Como, , Italy

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Florence, , Italy

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Maastricht, Limburg, Netherlands

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Groningen, , Netherlands

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Poznan, Greater Poland Voivodeship, Poland

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Torun, Kuyavian-Pomeranian Voivodeship, Poland

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Krakow, Lesser Poland Voivodeship, Poland

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Warsaw, Masovian Voivodeship, Poland

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Warsaw, Masovian Voivodeship, Poland

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Bialystok, Podlaskie Voivodeship, Poland

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Gdansk, Pomeranian Voivodeship, Poland

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Sopot, Pomeranian Voivodeship, Poland

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Katowice, Silesian Voivodeship, Poland

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Zabrze, Silesian Voivodeship, Poland

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Szczecin, Zachodniop, Poland

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Lodz, , Poland

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Warsaw, , Poland

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Lodz, Łódź Voivodeship, Poland

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London, England, United Kingdom

Site Status

Countries

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United States Germany Israel Italy Netherlands Poland United Kingdom

References

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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.

Reference Type DERIVED
PMID: 26226999 (View on PubMed)

Other Identifiers

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2011-001134-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GS-US-291-0102

Identifier Type: -

Identifier Source: org_study_id