Clinical trial NCT01522651: Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination in Patients With Paroxysmal Atrial Fibrillation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atrial Fibrillation
Keywords: Atrial Fibrillation
Ranolazine
Dronedarone
Dual Chamber Pacemakers
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2012-01-31
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Atrial Fibrillation Burden (AFB) at Baseline
timeFrame: Baseline
measure: Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12
timeFrame: Baseline; Week 12
measure: Absolute Change From Baseline in AFB by Week 12
timeFrame: Baseline; Week 12
Secondary outcomes:
measure: Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB
timeFrame: Week 12
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Investigational Site
state: California
city: Newport Beach
country: United States
facility: Investigational Site
state: California
city: San Francisco
country: United States
facility: Investigational Site
state: California
city: Aurora
country: United States
facility: Investigational Site
state: Colorado
city: Washington
country: United States
facility: Investigational Site
state: District of Columbia
city: Lakeland
country: United States
facility: Investigational Site
state: Florida
city: Takoma Park
country: United States
facility: Investigational Site
state: Maryland
city: Towson
country: United States
facility: Investigational Site
state: Maryland
city: Utica
country: United States
facility: Investigational Site
state: New York
city: Cleveland
country: United States
facility: Investigational Site
state: Ohio
city: Warwick
country: United States
facility: Investigational Site
state: Rhode Island
city: Houston
country: United States
facility: Investigational Site
state: Texas
city: Murray
country: United States
facility: Investigational Site
state: Utah
city: Seattle
country: United States
facility: Investigational Site
state: Washington
city: Wausau
country: United States
facility: Investigational Site
state: Wisconsin
city: München
country: Germany
facility: Investigational Site
state: Bayern
city: Würzburg
country: Germany
facility: Investigational Site
state: Bayern
city: Bonn
country: Germany
facility: Investigational Site
state: Nordrhein-westfalen
city: Coburg
country: Germany
facility: Investigational Site
city: Frankfurt
country: Germany
facility: Investigational Site
city: Göttingen
country: Germany
facility: Investigational Site
city: Ingolstadt
country: Germany
facility: Investigational Site
city: Lubeck
country: Germany
facility: Investigational Site
city: Ashkelon
country: Israel
facility: Investigational Site
state: Ashqelon
city: Afula
country: Israel
facility: Investigational Site
state: Zefat
city: Hadera
country: Israel
facility: Investigational Site
city: Haifa
country: Israel
facility: Investigational Site
city: Holon
country: Israel
facility: Investigational Site
city: Jerusalem
country: Israel
facility: Investigational Site
city: Nahariya
country: Israel
facility: Investigational Site
city: Rehovot
country: Israel
facility: Investigational Site
city: Como
country: Italy
facility: Investigational Site
city: Firenze
country: Italy
facility: Investigational Site
city: Maastricht
country: Netherlands
facility: Investigational Site
state: Limburg
city: Groningen
country: Netherlands
facility: Investigational Site
city: Torun
country: Poland
facility: Investigational Site
state: Kujawsko-pomorskie
city: Lodz
country: Poland
facility: Investigational Site
state: Lodzkie
city: Kraków
country: Poland
facility: Investigational Site
state: Malopolskie
city: Warsaw
country: Poland
facility: Investigational Site
state: Mazowieckie
city: Warsaw
country: Poland
facility: Investigational Site
state: Mazowieckie
city: Bialystok
country: Poland
facility: Investigational Site
state: Podlaskie
city: Gdansk
country: Poland
facility: Investigational Site
state: Pomorskie
city: Sopot
country: Poland
facility: Investigational Site
state: Pomorskie
city: Katowice
country: Poland
facility: Investigational Site
state: Slaskie
city: Zabrze
country: Poland
facility: Investigational Site
state: Slaskie
city: Poznań
country: Poland
facility: Investigational Site
state: Wielkopolskie
city: Szczecin
country: Poland
facility: Investigational Site
state: Zachodniop
city: Lodz
country: Poland
facility: Investigational Site
city: Warszawa
country: Poland
facility: Investigational Site
city: London
country: United Kingdom
facility: Investigational Site
state: England
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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.