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

Atrial Fibrillation Clinical Trial

— HARMONY  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01522651
• Other study ID #: GS-US-291-0102
• Secondary ID: 2011-001134-42
• Status: Completed
• Phase: Phase 2
• Start date: January 24, 2012
• Est. completion date: March 10, 2014

Study information

• Verified date: September 2020
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: March 10, 2014
• Est. primary completion date: March 10, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Ranolazine
Tablets administered orally twice daily.
• Dronedarone
Capsule administered orally twice daily
• Ranolazine placebo
Tablets administered orally twice daily.
• Dronedarone placebo
Capsules administered orally twice daily

Locations

Country	Name	City	State
Germany	Investigational Site	Bonn	Nordrhein-westfalen
Germany	Investigational Site	Coburg
Germany	Investigational Site	Frankfurt
Germany	Investigational Site	Göttingen
Germany	Investigational Site	Ingolstadt
Germany	Investigational Site	Lubeck
Germany	Investigational Site	München	Bayern
Germany	Investigational Site	Würzburg	Bayern
Israel	Investigational Site	Afula	Zefat
Israel	Investigational Site	Ashkelon	Ashqelon
Israel	Investigational Site	Hadera
Israel	Investigational Site	Haifa
Israel	Investigational Site	Holon
Israel	Investigational Site	Jerusalem
Israel	Investigational Site	Nahariya
Israel	Investigational Site	Rehovot
Italy	Investigational Site	Como
Italy	Investigational Site	Firenze
Netherlands	Investigational Site	Groningen
Netherlands	Investigational Site	Maastricht	Limburg
Poland	Investigational Site	Bialystok	Podlaskie
Poland	Investigational Site	Gdansk	Pomorskie
Poland	Investigational Site	Katowice	Slaskie
Poland	Investigational Site	Kraków	Malopolskie
Poland	Investigational Site	Lodz
Poland	Investigational Site	Lodz	Lodzkie
Poland	Investigational Site	Poznan	Wielkopolskie
Poland	Investigational Site	Sopot	Pomorskie
Poland	Investigational Site	Szczecin	Zachodniop
Poland	Investigational Site	Torun	Kujawsko-pomorskie
Poland	Investigational Site	Warsaw	Mazowieckie
Poland	Investigational Site	Warsaw	Mazowieckie
Poland	Investigational Site	Warszawa
Poland	Investigational Site	Zabrze	Slaskie
United Kingdom	Investigational Site	London	England
United States	Investigational Site	Aurora	Colorado
United States	Investigational Site	Beverly Hills	California
United States	Investigational Site	Cleveland	Ohio
United States	Investigational Site	Houston	Texas
United States	Investigational Site	Lakeland	Florida
United States	Investigational Site	Murray	Utah
United States	Investigational Site	Newport Beach	California
United States	Investigational Site	San Francisco	California
United States	Investigational Site	Seattle	Washington
United States	Investigational Site	Takoma Park	Maryland
United States	Investigational Site	Towson	Maryland
United States	Investigational Site	Utica	New York
United States	Investigational Site	Warwick	Rhode Island
United States	Investigational Site	Washington	District of Columbia
United States	Investigational Site	Wausau	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Germany,  Israel,  Italy,  Netherlands,  Poland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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