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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01522651
• Collaborator: (none)
• Enrollment: 134
• Locations: 50
• Arms: 5
• Actual Duration (Months): 25.5
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Ranolazine; Drug: Dronedarone; Drug: Ranolazine placebo; Drug: Dronedarone placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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
• Actual Study Start Date: Jan 24, 2012
• Actual Primary Completion Date: Mar 10, 2014
• Actual Study Completion Date: Mar 10, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Ranolazine placebo plus dronedarone placebo for 12 weeks.	Drug: Ranolazine placebo; Tablets administered orally twice daily.; Drug: Dronedarone placebo; Capsules administered orally twice daily
Experimental: Ranolazine 750 mg Ranolazine 750 mg plus dronedarone placebo for 12 weeks.	Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa® ; Drug: Dronedarone placebo; Capsules administered orally twice daily
Experimental: Dronedarone 225 mg Ranolazine placebo plus dronedarone 225 mg for 12 weeks.	Drug: Dronedarone; Capsule administered orally twice daily; Drug: Ranolazine placebo; Tablets administered orally twice daily.
Experimental: Ranolazine 750 mg + Dronedarone 225 mg Ranolazine 750 mg plus dronedarone 225 mg for 12 weeks.	Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa® ; Drug: Dronedarone; Capsule administered orally twice daily
Experimental: Ranolazine 750 mg + Dronedarone 150 mg Ranolazine 750 mg plus dronedarone 150 mg for 12 weeks.	Drug: Ranolazine; Tablets administered orally twice daily.; Other Names: Ranexa® ; Drug: Dronedarone; Capsule administered orally twice daily

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site	Beverly Hills	California	United States	90211
2	Investigational Site	Newport Beach	California	United States	92663
3	Investigational Site	San Francisco	California	United States	94143
4	Investigational Site	Aurora	Colorado	United States	80012
5	Investigational Site	Washington	District of Columbia	United States	20010
6	Investigational Site	Lakeland	Florida	United States	33805
7	Investigational Site	Takoma Park	Maryland	United States	20912
8	Investigational Site	Towson	Maryland	United States	21204
9	Investigational Site	Utica	New York	United States	13501
10	Investigational Site	Cleveland	Ohio	United States	44106
11	Investigational Site	Warwick	Rhode Island	United States	02886
12	Investigational Site	Houston	Texas	United States	77030
13	Investigational Site	Murray	Utah	United States	84107
14	Investigational Site	Seattle	Washington	United States	98122
15	Investigational Site	Wausau	Wisconsin	United States	54401
16	Investigational Site	München	Bayern	Germany	81377
17	Investigational Site	Würzburg	Bayern	Germany	97080
18	Investigational Site	Bonn	Nordrhein-westfalen	Germany	53105
19	Investigational Site	Coburg		Germany	96450
20	Investigational Site	Frankfurt		Germany	60594
21	Investigational Site	Göttingen		Germany	37075
22	Investigational Site	Ingolstadt		Germany	85049
23	Investigational Site	Lubeck		Germany	D23538
24	Investigational Site	Ashkelon	Ashqelon	Israel	78287
25	Investigational Site	Afula	Zefat	Israel	18101
26	Investigational Site	Hadera		Israel	38100
27	Investigational Site	Haifa		Israel	31096
28	Investigational Site	Holon		Israel	58100
29	Investigational Site	Jerusalem		Israel	91031
30	Investigational Site	Nahariya		Israel	22100
31	Investigational Site	Rehovot		Israel	76100
32	Investigational Site	Como		Italy	22020
33	Investigational Site	Firenze		Italy	50134
34	Investigational Site	Maastricht	Limburg	Netherlands	6229 HX
35	Investigational Site	Groningen		Netherlands	9700 RB
36	Investigational Site	Torun	Kujawsko-pomorskie	Poland	87-100
37	Investigational Site	Lodz	Lodzkie	Poland	90-553
38	Investigational Site	Kraków	Malopolskie	Poland	31-501
39	Investigational Site	Warsaw	Mazowieckie	Poland	01-211
40	Investigational Site	Warsaw	Mazowieckie	Poland	04-628
41	Investigational Site	Bialystok	Podlaskie	Poland	15-276
42	Investigational Site	Gdansk	Pomorskie	Poland	80-219
43	Investigational Site	Sopot	Pomorskie	Poland	81-717
44	Investigational Site	Katowice	Slaskie	Poland	40-635
45	Investigational Site	Zabrze	Slaskie	Poland	41-800
46	Investigational Site	Poznań	Wielkopolskie	Poland	61-848
47	Investigational Site	Szczecin	Zachodniop	Poland	70-203
48	Investigational Site	Lodz		Poland	91-425
49	Investigational Site	Warszawa		Poland	02-097
50	Investigational Site	London	England	United Kingdom	SE5 9RS

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01522651
• Other Study ID Numbers: GS-US-291-0102; 2011-001134-42
• First Posted: Jan 31, 2012
• Last Update Posted: Nov 6, 2020
• Last Verified: Sep 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Gilead Sciences: Atrial Fibrillation; Ranolazine; Dronedarone; Dual Chamber Pacemakers
• Additional relevant MeSH terms: Atrial Fibrillation; Dronedarone; Ranolazine

Study Results

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 Detail	327 participants were screened.

Arm/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 milligrams (mg) tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
Period Title: Overall Study
STARTED	26	27	26	28	27
COMPLETED	17	19	22	20	21
NOT COMPLETED	9	8	4	8	6

Baseline Characteristics

Arm/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg	Total
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.	Total of all reporting groups
Overall Participants	26	26	26	27	26	131
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72 (8.4)	70 (10.8)	75 (7.8)	71 (7.1)	73 (9.4)	72 (8.8)
Sex: Female, Male (Count of Participants)
Female	13 50%	16 61.5%	16 61.5%	12 44.4%	11 42.3%	68 51.9%
Male	13 50%	10 38.5%	10 38.5%	15 55.6%	15 57.7%	63 48.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 7.7%	0 0%	0 0%	3 11.1%	1 3.8%	6 4.6%
Not Hispanic or Latino	22 84.6%	25 96.2%	26 100%	24 88.9%	25 96.2%	122 93.1%
Unknown or Not Reported	2 7.7%	1 3.8%	0 0%	0 0%	0 0%	3 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	1 3.8%	1 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	26 100%	26 100%	26 100%	27 100%	25 96.2%	130 99.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Germany	5 19.2%	4 15.4%	8 30.8%	4 14.8%	2 7.7%	23 17.6%
Israel	5 19.2%	6 23.1%	1 3.8%	6 22.2%	6 23.1%	24 18.3%
Italy	0 0%	0 0%	0 0%	1 3.7%	0 0%	1 0.8%
Netherlands	0 0%	0 0%	0 0%	0 0%	1 3.8%	1 0.8%
Poland	10 38.5%	12 46.2%	11 42.3%	11 40.7%	15 57.7%	59 45%
United States	6 23.1%	4 15.4%	6 23.1%	5 18.5%	2 7.7%	23 17.6%

Outcome Measures

1. Primary Outcome

Title	Atrial Fibrillation Burden (AFB) at Baseline
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
Measure Participants	18	18	23	20	22
Geometric Mean (Standard Error) [Percentage of total recording time]	12.7 (2.21)	10.8 (2.70)	11.6 (2.47)	11.7 (2.40)	11.7 (2.04)

2. Primary Outcome

Title	Percent Change From Baseline in Atrial Fibrillation Burden (AFB) by Week 12
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
Measure Participants	18	18	23	20	22
Geometric Mean (Standard Error) [percent change]	-5.9 (18.00)	-23.0 (21.17)	3.5 (15.68)	-59.1 (10.47)	-45.5 (10.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ranolazine 750 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.493
	Comments	An equal-slopes analysis of covariance (ANCOVA) model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-19.8
	Confidence Interval	(2-Sided) 95%; -57.5 to 51.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 25.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dronedarone 225 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.780
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 95%; -40.2 to 98.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 32.9
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ranolazine 750 mg + Dronedarone 225 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.008
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-57.0
	Confidence Interval	(2-Sided) 95%; -76.8 to -20.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 13.4
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ranolazine 750 mg + Dronedarone 150 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.072
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Percentage Difference
	Estimated Value	-42.6
	Confidence Interval	(2-Sided) 95%; -68.7 to 5.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 17.5
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 750 mg, Dronedarone 225 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.315
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 750 mg, Ranolazine 750 mg + Dronedarone 225 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.049
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 750 mg, Ranolazine 750 mg + Dronedarone 150 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.275
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 225 mg, Ranolazine 750 mg + Dronedarone 225 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.002
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Dronedarone 225 mg, Ranolazine 750 mg + Dronedarone 150 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.028
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 750 mg + Dronedarone 225 mg, Ranolazine 750 mg + Dronedarone 150 mg
	Comments
	Type of Statistical Test	Other
	Comments	Pairwise Comparative analysis
Statistical Test of Hypothesis	p-Value	0.334
	Comments	An equal-slopes ANCOVA model was fitted to log-transformed AFB over 12 weeks, with baseline AFB as the covariate. AFB values < 1% (> 99%) were set to 1% (99%) before transformation.
	Method	ANCOVA
	Comments

3. Primary Outcome

Title	Absolute Change From Baseline in AFB by Week 12
Description	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

Outcome Measure Data

Analysis Population Description

Participants in Full Analysis Set with available data were analyzed.

Arm/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
Measure Participants	18	18	23	20	22
Baseline	16.8 (3.66)	17.3 (3.74)	19.1 (4.14)	16.8 (3.11)	16.7 (3.52)
Absolute Change From Baseline in AFB by Week 12	4.6 (3.19)	-3.1 (2.17)	5.6 (2.65)	-4.7 (3.24)	-3.9 (3.11)

4. Secondary Outcome

Title	Percentage of Participants Who Had ≥ 30%, ≥ 50%, or ≥ 70% Reduction From Baseline in AFB
Description	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

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	Placebo	Ranolazine 750 mg	Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 225 mg	Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.	Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.	Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
Measure Participants	18	18	23	20	22
≥ 30% Reduction From Baseline AFB	22.2 85.4%	50.0 192.3%	21.7 83.5%	45.0 166.7%	54.5 209.6%
≥ 50% Reduction From Baseline AFB	16.7 64.2%	22.2 85.4%	13.0 50%	45.0 166.7%	54.5 209.6%
≥ 70% Reduction From Baseline AFB	11.1 42.7%	16.7 64.2%	8.7 33.5%	45.0 166.7%	27.3 105%

Adverse Events

Time Frame	Adverse Events: First dose date up to the last dose date (maximum 102 days) plus 30 days
Adverse Event Reporting Description	The Safety Analysis Set included participants who received ≥1 dose of study drug (ranolazine/placebo tablets or dronedarone/placebo capsules).
Arm/Group Title	Placebo		Ranolazine 750 mg		Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 150 mg
Arm/Group Description	Placebo to match ranolazine tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.		Ranolazine 750 mg tablet orally twice daily + placebo to match dronedarone capsule orally twice daily for 12 weeks.		Placebo to match ranolazine tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.		Ranolazine 750 mg tablet orally twice daily + dronedarone 225 mg capsule orally twice daily for 12 weeks.		Ranolazine 750 mg tablet orally twice daily + dronedarone 150 mg capsule orally twice daily for 12 weeks.
All Cause Mortality
	Placebo		Ranolazine 750 mg		Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Serious Adverse Events
	Placebo		Ranolazine 750 mg		Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		7/26 (26.9%)		2/26 (7.7%)		5/27 (18.5%)		1/26 (3.8%)
Cardiac disorders
Atrial fibrillation	0/26 (0%)		3/26 (11.5%)		1/26 (3.8%)		0/27 (0%)		1/26 (3.8%)
Atrial flutter	1/26 (3.8%)		0/26 (0%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Cardiac failure congestive	0/26 (0%)		0/26 (0%)		1/26 (3.8%)		0/27 (0%)		0/26 (0%)
Tachyarrhythmia	0/26 (0%)		0/26 (0%)		1/26 (3.8%)		0/27 (0%)		0/26 (0%)
Ear and labyrinth disorders
Vertigo	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/26 (0%)		1/26 (3.8%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
General disorders
Chest pain	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Infections and infestations
Clostridium difficile colitis	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Enterococcal bacteraemia	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Investigations
International normalised ratio increased	0/26 (0%)		1/26 (3.8%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Nervous system disorders
Cerebrovascular accident	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Presyncope	0/26 (0%)		1/26 (3.8%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Syncope	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Vascular disorders
Hypertension	0/26 (0%)		1/26 (3.8%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Hypotension	0/26 (0%)		0/26 (0%)		0/26 (0%)		1/27 (3.7%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Ranolazine 750 mg		Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 225 mg		Ranolazine 750 mg + Dronedarone 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		15/26 (57.7%)		14/26 (53.8%)		12/27 (44.4%)		14/26 (53.8%)
Cardiac disorders
Atrial fibrillation	2/26 (7.7%)		0/26 (0%)		4/26 (15.4%)		1/27 (3.7%)		2/26 (7.7%)
Ear and labyrinth disorders
Vertigo	0/26 (0%)		3/26 (11.5%)		0/26 (0%)		0/27 (0%)		1/26 (3.8%)
Gastrointestinal disorders
Abdominal distension	0/26 (0%)		0/26 (0%)		2/26 (7.7%)		0/27 (0%)		0/26 (0%)
Abdominal pain	0/26 (0%)		0/26 (0%)		3/26 (11.5%)		2/27 (7.4%)		0/26 (0%)
Constipation	0/26 (0%)		1/26 (3.8%)		1/26 (3.8%)		1/27 (3.7%)		4/26 (15.4%)
Diarrhoea	0/26 (0%)		2/26 (7.7%)		2/26 (7.7%)		1/27 (3.7%)		1/26 (3.8%)
Gastritis	0/26 (0%)		0/26 (0%)		0/26 (0%)		0/27 (0%)		2/26 (7.7%)
Gastrooesophageal reflux disease	0/26 (0%)		0/26 (0%)		0/26 (0%)		0/27 (0%)		2/26 (7.7%)
Nausea	0/26 (0%)		3/26 (11.5%)		1/26 (3.8%)		2/27 (7.4%)		1/26 (3.8%)
General disorders
Asthenia	2/26 (7.7%)		1/26 (3.8%)		0/26 (0%)		0/27 (0%)		2/26 (7.7%)
Fatigue	0/26 (0%)		3/26 (11.5%)		0/26 (0%)		2/27 (7.4%)		1/26 (3.8%)
Oedema peripheral	0/26 (0%)		0/26 (0%)		3/26 (11.5%)		2/27 (7.4%)		0/26 (0%)
Infections and infestations
Nasopharyngitis	0/26 (0%)		2/26 (7.7%)		1/26 (3.8%)		0/27 (0%)		0/26 (0%)
Urinary tract infection	3/26 (11.5%)		1/26 (3.8%)		2/26 (7.7%)		0/27 (0%)		0/26 (0%)
Injury, poisoning and procedural complications
Overdose	0/26 (0%)		0/26 (0%)		0/26 (0%)		2/27 (7.4%)		0/26 (0%)
Investigations
International normalised ratio increased	0/26 (0%)		1/26 (3.8%)		1/26 (3.8%)		1/27 (3.7%)		2/26 (7.7%)
Prothrombin time prolonged	0/26 (0%)		2/26 (7.7%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/26 (3.8%)		2/26 (7.7%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Nervous system disorders
Dizziness	1/26 (3.8%)		3/26 (11.5%)		2/26 (7.7%)		0/27 (0%)		2/26 (7.7%)
Presyncope	0/26 (0%)		0/26 (0%)		0/26 (0%)		2/27 (7.4%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/26 (0%)		0/26 (0%)		1/26 (3.8%)		1/27 (3.7%)		2/26 (7.7%)
Dyspnoea	1/26 (3.8%)		1/26 (3.8%)		2/26 (7.7%)		1/27 (3.7%)		1/26 (3.8%)
Skin and subcutaneous tissue disorders
Pruritus	0/26 (0%)		0/26 (0%)		2/26 (7.7%)		0/27 (0%)		0/26 (0%)
Vascular disorders
Haematoma	2/26 (7.7%)		1/26 (3.8%)		0/26 (0%)		0/27 (0%)		0/26 (0%)
Hypertension	0/26 (0%)		0/26 (0%)		2/26 (7.7%)		0/27 (0%)		1/26 (3.8%)
Hypotension	0/26 (0%)		0/26 (0%)		0/26 (0%)		3/27 (11.1%)		1/26 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years