Atrial Fibrillation
Conditions
Keywords
Atrial Fibrillation, Ranolazine, Dronedarone, Dual Chamber Pacemakers
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.
Interventions
DRUGRanolazine
Tablets administered orally twice daily.
DRUGDronedarone
Capsule administered orally twice daily
Tablets administered orally twice daily.
DRUGDronedarone placebo
Capsules administered orally twice daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Atrial Fibrillation Burden (AFB) at Baseline | 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. |
| Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | Baseline; 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. |
| Absolute Change From Baseline in AFB by Week 12 | Baseline; 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | Week 12 | AFB was defined as the total time a participant was in AT/AF expressed as a percentage of total recording time. |
Countries
Germany, Israel, Italy, Netherlands, Poland, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Germany, Israel, Italy, Netherlands, Poland, and the United States. The first participant was screened on 24 January 2012. The last study visit occurred on 10 March 2014.
Pre-assignment details
327 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks. | 26 |
| Ranolazine 750 mg Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks. | 26 |
| Dronedarone 225 mg Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks. | 26 |
| Ranolazine 750 mg + Dronedarone 225 mg Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks. | 27 |
| Ranolazine 750 mg + Dronedarone 150 mg Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks. | 26 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 4 | 5 | 4 |
| Overall Study | Cardioversion | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Device Malfunction | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Investigator's Discretion | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Participant Non-Compliance | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 3 | 0 | 0 | 0 | 0 |
| Overall Study | Randomized but Never Treated | 0 | 1 | 0 | 1 | 1 |
| Overall Study | Reason Not Specified | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrew Consent | 1 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Ranolazine 750 mg | Dronedarone 225 mg | Ranolazine 750 mg + Dronedarone 225 mg | Ranolazine 750 mg + Dronedarone 150 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 8.4 | 70 years STANDARD_DEVIATION 10.8 | 75 years STANDARD_DEVIATION 7.8 | 71 years STANDARD_DEVIATION 7.1 | 73 years STANDARD_DEVIATION 9.4 | 72 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 25 Participants | 26 Participants | 24 Participants | 25 Participants | 122 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 26 Participants | 26 Participants | 27 Participants | 25 Participants | 130 Participants |
| Region of Enrollment Germany | 5 participants | 4 participants | 8 participants | 4 participants | 2 participants | 23 participants |
| Region of Enrollment Israel | 5 participants | 6 participants | 1 participants | 6 participants | 6 participants | 24 participants |
| Region of Enrollment Italy | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Netherlands | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Poland | 10 participants | 12 participants | 11 participants | 11 participants | 15 participants | 59 participants |
| Region of Enrollment United States | 6 participants | 4 participants | 6 participants | 5 participants | 2 participants | 23 participants |
| Sex: Female, Male Female | 13 Participants | 16 Participants | 16 Participants | 12 Participants | 11 Participants | 68 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 10 Participants | 15 Participants | 15 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 | 0 / 26 | 0 / 27 | 0 / 26 |
| other Total, other adverse events | 9 / 26 | 15 / 26 | 14 / 26 | 12 / 27 | 14 / 26 |
| serious Total, serious adverse events | 1 / 26 | 7 / 26 | 2 / 26 | 5 / 27 | 1 / 26 |
Outcome results
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.
Time frame: Baseline; Week 12
Population: Participants in Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Absolute Change From Baseline in AFB by Week 12 | Baseline | 16.8 percentage of total recording time | Standard Error 3.66 |
| Placebo | Absolute Change From Baseline in AFB by Week 12 | Absolute Change From Baseline in AFB by Week 12 | 4.6 percentage of total recording time | Standard Error 3.19 |
| Ranolazine 750 mg | Absolute Change From Baseline in AFB by Week 12 | Baseline | 17.3 percentage of total recording time | Standard Error 3.74 |
| Ranolazine 750 mg | Absolute Change From Baseline in AFB by Week 12 | Absolute Change From Baseline in AFB by Week 12 | -3.1 percentage of total recording time | Standard Error 2.17 |
| Dronedarone 225 mg | Absolute Change From Baseline in AFB by Week 12 | Baseline | 19.1 percentage of total recording time | Standard Error 4.14 |
| Dronedarone 225 mg | Absolute Change From Baseline in AFB by Week 12 | Absolute Change From Baseline in AFB by Week 12 | 5.6 percentage of total recording time | Standard Error 2.65 |
| Ranolazine 750 mg + Dronedarone 225 mg | Absolute Change From Baseline in AFB by Week 12 | Absolute Change From Baseline in AFB by Week 12 | -4.7 percentage of total recording time | Standard Error 3.24 |
| Ranolazine 750 mg + Dronedarone 225 mg | Absolute Change From Baseline in AFB by Week 12 | Baseline | 16.8 percentage of total recording time | Standard Error 3.11 |
| Ranolazine 750 mg + Dronedarone 150 mg | Absolute Change From Baseline in AFB by Week 12 | Baseline | 16.7 percentage of total recording time | Standard Error 3.52 |
| Ranolazine 750 mg + Dronedarone 150 mg | Absolute Change From Baseline in AFB by Week 12 | Absolute Change From Baseline in AFB by Week 12 | -3.9 percentage of total recording time | Standard Error 3.11 |
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.
Time frame: Baseline
Population: The Full Analysis Set included randomized participants who received ≥ 1 dose of study drug (ranolazine, dronedarone, or placebo) and had ≥ 2 weeks (14 days) of AFB data for both the period from screening to Day 1 and following the start of treatment. Participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Atrial Fibrillation Burden (AFB) at Baseline | 12.7 Percentage of total recording time | Standard Error 2.21 |
| Ranolazine 750 mg | Atrial Fibrillation Burden (AFB) at Baseline | 10.8 Percentage of total recording time | Standard Error 2.7 |
| Dronedarone 225 mg | Atrial Fibrillation Burden (AFB) at Baseline | 11.6 Percentage of total recording time | Standard Error 2.47 |
| Ranolazine 750 mg + Dronedarone 225 mg | Atrial Fibrillation Burden (AFB) at Baseline | 11.7 Percentage of total recording time | Standard Error 2.4 |
| Ranolazine 750 mg + Dronedarone 150 mg | Atrial Fibrillation Burden (AFB) at Baseline | 11.7 Percentage of total recording time | Standard Error 2.04 |
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.
Time frame: Baseline; Week 12
Population: The Full Analysis Set included randomized participants who received ≥ 1 dose of study drug (ranolazine, dronedarone, or placebo) and had ≥ 2 weeks (14 days) of AFB data for both the period from screening to Day 1 and following the start of treatment. Participants with available data were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | -5.9 percent change | Standard Error 18 |
| Ranolazine 750 mg | Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | -23.0 percent change | Standard Error 21.17 |
| Dronedarone 225 mg | Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | 3.5 percent change | Standard Error 15.68 |
| Ranolazine 750 mg + Dronedarone 225 mg | Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | -59.1 percent change | Standard Error 10.47 |
| Ranolazine 750 mg + Dronedarone 150 mg | Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12 | -45.5 percent change | Standard Error 10.73 |
p-value: 0.49395% CI: [-57.5, 51.5]ANCOVA
p-value: 0.7895% CI: [-40.2, 98.2]ANCOVA
p-value: 0.00895% CI: [-76.8, -20.1]ANCOVA
p-value: 0.07295% CI: [-68.7, 5.2]ANCOVA
p-value: 0.315ANCOVA
p-value: 0.049ANCOVA
p-value: 0.275ANCOVA
p-value: 0.002ANCOVA
p-value: 0.028ANCOVA
p-value: 0.334ANCOVA
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.
Time frame: Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 30% Reduction From Baseline AFB | 22.2 percentage of participants |
| Placebo | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 70% Reduction From Baseline AFB | 11.1 percentage of participants |
| Placebo | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 50% Reduction From Baseline AFB | 16.7 percentage of participants |
| Ranolazine 750 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 50% Reduction From Baseline AFB | 22.2 percentage of participants |
| Ranolazine 750 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 30% Reduction From Baseline AFB | 50.0 percentage of participants |
| Ranolazine 750 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 70% Reduction From Baseline AFB | 16.7 percentage of participants |
| Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 50% Reduction From Baseline AFB | 13.0 percentage of participants |
| Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 30% Reduction From Baseline AFB | 21.7 percentage of participants |
| Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 70% Reduction From Baseline AFB | 8.7 percentage of participants |
| Ranolazine 750 mg + Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 30% Reduction From Baseline AFB | 45.0 percentage of participants |
| Ranolazine 750 mg + Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 70% Reduction From Baseline AFB | 45.0 percentage of participants |
| Ranolazine 750 mg + Dronedarone 225 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 50% Reduction From Baseline AFB | 45.0 percentage of participants |
| Ranolazine 750 mg + Dronedarone 150 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 50% Reduction From Baseline AFB | 54.5 percentage of participants |
| Ranolazine 750 mg + Dronedarone 150 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 30% Reduction From Baseline AFB | 54.5 percentage of participants |
| Ranolazine 750 mg + Dronedarone 150 mg | Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB | ≥ 70% Reduction From Baseline AFB | 27.3 percentage of participants |