PALLAS: Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01151137
• Collaborator: (none)
• Enrollment: 3,236
• Locations: 37
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 87.5
• Patients Per Site Per Month: 6.2

Study Details

Study Description

Brief Summary

Primary Objective:

• Demonstrate the efficacy of Dronedarone in preventing major cardiovascular events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death) or unplanned cardiovascular hospitalization or death from any cause in patients with permanent Atrial Fibrillation [AF] and additional risk factors

Secondary Objective:

• Demonstrate the efficacy of Dronedarone in preventing cardiovascular death

This was an event-driven study where a common study end date [CSED] was to be determined by Steering Committee based on the number of events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death).

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Dronedarone; Drug: Placebo (for Dronedarone)	Phase 3

Detailed Description

The study period per participant was variable depending on the enrollment in the study.

A final follow-up visit had to occur within 1 month after the CSED.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3236 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Placebo Controlled, Parallel Group Trial for Assessing the Clinical Benefit of Dronedarone 400mg BID on Top of Standard Therapy in Patients With Permanent Atrial Fibrillation and Additional Risk Factors
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dronedarone Dronedarone 400 mg twice a day until the CSED	Drug: Dronedarone; Film-coated tablet Oral administration under fed conditions (during breakfast and dinner); Other Names: MULTAQ SR33589
Placebo Comparator: placebo Placebo (for Dronedarone) twice a day until the CSED	Drug: Placebo (for Dronedarone); film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)

Outcome Measures

Primary Outcome Measures

1. Overview of the Two Co-primary Outcomes [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

   First co-primary outcome was defined as the first event among stroke, systemic arterial embolism, Myocardial Infarctions [MI], or cardiovascular death. Second co-primary outcome was defined as the first event among unscheduled cardiovascular hospitalization or death from any cause. Both co-primary outcomes were determined based on the central review and adjudication by a blinded Adjudication Committee of all reported deaths (from any cause), MI, systemic arterial embolisms, strokes, Transient Ischemic Attacks [TIA], Heart Failure hospitalization and unplanned hospitalisations for cardiovascular cause.

2. Time to First Co-primary Outcome (Cumulative Incidence Function) [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

   Time to first co-primary outcome was defined as the time from randomization to the first event among stroke, systemic arterial embolism, MI or cardiovascular death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.

3. Time to Second Co-primary Outcome (Cumulative Incidence Function) [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

   Time to second co-primary outcome was defined as the time from randomization to the first event among unscheduled cardiovascular hospitalization or death from any cause. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.

Secondary Outcome Measures

1. Deaths [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

   Deaths were classified according to the primary cause of death.

2. Time to Cardiovascular Death (Cumulative Incidence Function) [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

   Time to cardiovascular death was defined as the time from randomization to the death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.

Other Outcome Measures

1. Overview of Cardiovascular Events [From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)]

2. Overview of Adverse Events [AE] [from first study drug intake up to 10 days after the last study drug intake]

   AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Permanent AF defined by the presence of all of the following criteria:

• Availability of one 12-lead ECG not more than 14 days prior to randomization showing that the patient is in AF or atrial flutter;

• Availability of documentation (including either rhythm strips or medical report of the rhythm) showing that the patient was in AF or atrial flutter at least 6 months prior to randomization;

• No evidence of sinus rhythm in the period between these two documentations of AF;

• Decision of the patient and physician to allow AF to continue without further efforts to restore sinus rhythm.

• At least one of the following risk criteria:

• Coronary artery disease;

• Prior stroke or Transient Ischemic Attack [TIA];

• Symptomatic heart failure;

• Left ventricular ejection fraction [LVEF] less or equal to 0.40;

• Peripheral arterial occlusive disease;

• Aged 75 years or older with both hypertension and diabetes mellitus.

Exclusion criteria:

• Paroxysmal AF;

• Persistent AF without a decision to allow AF to continue without further efforts to restore sinus rhythm;

• Heart failure of New-York Heart Association [NYHA] class IV or recent unstable NYHA class III.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey	United States	08807
2	Sanofi-Aventis Administrative Office	Buenos Aires		Argentina
3	Sanofi-Aventis Administrative Office	Macquarie Park		Australia
4	Sanofi-Aventis Administrative Office	Vienna		Austria
5	Sanofi-Aventis Administrative Office	Diegem		Belgium
6	Sanofi-Aventis Administrative Office	Sao Paulo		Brazil
7	Sanofi-Aventis Administrative Office	Sofia		Bulgaria
8	Sanofi-Aventis Administrative Office	Laval		Canada
9	Sanofi-Aventis Administrative Office	Providencia Santiago		Chile
10	Sanofi-Aventis Administrative Office	Praha		Czech Republic
11	Sanofi-Aventis Administrative Office	Horsholm		Denmark
12	Sanofi-Aventis Administrative Office	Helsinki		Finland
13	Sanofi-Aventis Administrative Office	Paris		France
14	Sanofi-Aventis Administrative Office	Frankfurt		Germany
15	Sanofi-Aventis Administrative Office	Kallithea		Greece
16	Sanofi-Aventis Administrative Office	Hong Kong		Hong Kong
17	Sanofi-Aventis Administrative Office	Budapest		Hungary
18	Sanofi-Aventis Administrative Office	Natanya		Israel
19	Sanofi-Aventis Administrative Office	Milan		Italy
20	Sanofi-Aventis Administrative Office	Seoul		Korea, Republic of
21	Sanofi-Aventis Administrative Office	Kuala Lumpur		Malaysia
22	Sanofi-Aventis Administrative Office	Col. Coyoacan		Mexico
23	Sanofi-Aventis Administrative Office	Gouda		Netherlands
24	Sanofi-Aventis Administrative Office	Auckland		New Zealand
25	Sanofi-Aventis Administrative Office	Lysaker		Norway
26	Sanofi-Aventis Administrative Office	Warsaw		Poland
27	Sanofi-Aventis Administrative Office	Bucuresti		Romania
28	Sanofi-Aventis Administrative Office	Moscow		Russian Federation
29	Sanofi-Aventis Administrative Office	Singapore		Singapore
30	Sanofi-Aventis Administrative Office	Bratislava		Slovakia
31	Sanofi-Aventis Administrative Office	Gauteng		South Africa
32	Sanofi-Aventis Administrative Office	Barcelona		Spain
33	Sanofi-Aventis Administrative Office	Bromma		Sweden
34	Sanofi-Aventis Administrative Office	Geneva		Switzerland
35	Sanofi-Aventis Administrative Office	Taipei		Taiwan
36	Sanofi-Aventis Administrative Office	Kiev		Ukraine
37	Sanofi-Aventis Administrative Office	Guildford Surrey		United Kingdom

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01151137
• Other Study ID Numbers: EFC11405; 2010-019791-73; U1111-1116-5566
• First Posted: Jun 25, 2010
• Last Update Posted: Oct 26, 2012
• Last Verified: Oct 1, 2012

• Additional relevant MeSH terms: Atrial Fibrillation; Dronedarone

Study Results

Participant Flow

Recruitment Details	Recruitment initiated in July 2010 was discontinued on July 6, 2011 upon recommendations of the Data Monitoring Committee due to an increased number of observed cardiovascular events in the Dronedarone group. The common study end date [CSED] was defined as July 15, 2011. At that time 494 sites in 37 countries had enrolled at least one patient.
Pre-assignment Detail	Assignment to groups was done centrally using an Interactive Voice Response System [IVRS] or an Interactive Web Response System [IWRS] in a 1:1 ratio. A total of 3236 participants were randomized at 489 sites (instead of 10800 as initially planned). The median duration of their participation in the study was 3.5 months.

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Period Title: Overall Study
STARTED	1617	1619
Treated	1610	1613
Discontinued Treatment	171	342
COMPLETED	1601	1591
NOT COMPLETED	16	28

Baseline Characteristics

Arm/Group Title	Placebo	Dronedarone	Total
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)	Total of all reporting groups
Overall Participants	1617	1619	3236
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75.0 (5.9)	75.0 (5.9)	75.0 (5.9)
Sex: Female, Male (Count of Participants)
Female	577 35.7%	568 35.1%	1145 35.4%
Male	1040 64.3%	1051 64.9%	2091 64.6%
Region of Enrollment (participants) [Number]
North America	281 17.4%	266 16.4%	547 16.9%
South America	227 14%	236 14.6%	463 14.3%
Western Europe	459 28.4%	475 29.3%	934 28.9%
Eastern Europe	495 30.6%	488 30.1%	983 30.4%
Asia	53 3.3%	47 2.9%	100 3.1%
Rest of the word	102 6.3%	107 6.6%	209 6.5%
Permanent atrial fibrillation [AF] history (participants) [Number]
6 months to 2 years	490 30.3%	498 30.8%	988 30.5%
> 2 years	1124 69.5%	1119 69.1%	2243 69.3%
Unknown	3 0.2%	2 0.1%	5 0.2%
CHADS2 Score (participants) [Number]
< 2	172 10.6%	191 11.8%	363 11.2%
≥ 2	1444 89.3%	1427 88.1%	2871 88.7%
Unavailable	1 0.1%	1 0.1%	2 0.1%
New York Heart Association [NYHA] class (participants) [Number]
No congestive heart failure [CHF]	535 33.1%	512 31.6%	1047 32.4%
NYHA Class I	209 12.9%	234 14.5%	443 13.7%
NYHA Class II	749 46.3%	732 45.2%	1481 45.8%
NYHA Class III	124 7.7%	141 8.7%	265 8.2%

Outcome Measures

1. Primary Outcome

Title	Overview of the Two Co-primary Outcomes
Description	First co-primary outcome was defined as the first event among stroke, systemic arterial embolism, Myocardial Infarctions [MI], or cardiovascular death. Second co-primary outcome was defined as the first event among unscheduled cardiovascular hospitalization or death from any cause. Both co-primary outcomes were determined based on the central review and adjudication by a blinded Adjudication Committee of all reported deaths (from any cause), MI, systemic arterial embolisms, strokes, Transient Ischemic Attacks [TIA], Heart Failure hospitalization and unplanned hospitalisations for cardiovascular cause.
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants considered in the treatment group to which they were randomized regardless of the treatment they actually received

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
First co-primary endpoint	19 1.2%	43 2.7%
Second co-primary endpoint	67 4.1%	127 7.8%

2. Primary Outcome

Title	Time to First Co-primary Outcome (Cumulative Incidence Function)
Description	Time to first co-primary outcome was defined as the time from randomization to the first event among stroke, systemic arterial embolism, MI or cardiovascular death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
Cumulative incidence at 14 days	0.002 0%	0.009 0%
Cumulative incidence at 30 days	0.003 0%	0.013 0%
Cumulative incidence at 90 days	0.007 0%	0.021 0%
Cumulative incidence at 180 days	0.013 0%	0.042 0%
Cumulative incidence at 270 days	0.038 0%	0.045 0%
Cumulative incidence at 360 days	0.038 0%	0.045 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dronedarone
	Comments	As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments	A priori threshold for statistical significance: 0.05
	Method	Log Rank
	Comments	2-sided Log-rank's asymptotic test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.294
	Confidence Interval	(2-Sided) 95%; 1.337 to 3.936
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (HR) of Dronedarone versus placebo for stroke, systemic arterial embolism, myocardial infarction or cardiovascular death HR and confidence interval were estimated using Cox regression model with treatment group as the only factor.

3. Primary Outcome

Title	Time to Second Co-primary Outcome (Cumulative Incidence Function)
Description	Time to second co-primary outcome was defined as the time from randomization to the first event among unscheduled cardiovascular hospitalization or death from any cause. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
Cumulative incidence at 14 days	0.005 0%	0.020 0%
Cumulative incidence at 30 days	0.014 0%	0.034 0%
Cumulative incidence at 90 days	0.033 0%	0.069 0%
Cumulative incidence at 180 days	0.059 0%	0.110 0%
Cumulative incidence at 270 days	0.099 0%	0.137 0%
Cumulative incidence at 360 days	0.099 0%	0.137 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dronedarone
	Comments	As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A priori threshold for statistical significance: 0.05
	Method	Log Rank
	Comments	2-sided Log-rank's asymptotic test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.947
	Confidence Interval	(2-Sided) 95%; 1.448 to 2.617
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (HR) of Dronedarone versus placebo for unscheduled cardiovascular hospitalization or death from any cause HR and confidence interval were estimated using Cox regression model with treatment group as the only factor.

4. Secondary Outcome

Title	Deaths
Description	Deaths were classified according to the primary cause of death.
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
Any death	13 0.8%	25 1.5%
- Cardiovascular death	10 0.6%	21 1.3%
--- Cardiac arrhythmic death	4 0.2%	13 0.8%

5. Secondary Outcome

Title	Time to Cardiovascular Death (Cumulative Incidence Function)
Description	Time to cardiovascular death was defined as the time from randomization to the death. Cumulative incidence function in each treatment group was calculated using non-parametric Kaplan-Meier estimate. 95% confidence interval was computed at each time-point using Greenwood's variance estimation.
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
Cumulative incidence at 14 days	0.001 0%	0.003 0%
Cumulative incidence at 30 days	0.003 0%	0.005 0%
Cumulative incidence at 90 days	0.004 0%	0.008 0%
Cumulative incidence at 180 days	0.004 0%	0.022 0%
Cumulative incidence at 270 days	0.027 0%	0.026 0%
Cumulative incidence at 360 days	0.027 0%	0.026 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dronedarone
	Comments	As a consequence of the early termination of the study, the analysis was performed for information only without any adjustment.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0460
	Comments	A priori threshold for statistical significance: 0.05
	Method	Log Rank
	Comments	2-sided Log-rank's asymptotic test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.115
	Confidence Interval	(2-Sided) 95%; 0.996 to 4.490
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (HR) of Dronedarone versus placebo for cardiovascular death HR and confidence interval were estimated using Cox regression model with treatment group as the only factor.

6. Other Pre-specified Outcome

Title	Overview of Cardiovascular Events
Time Frame	From randomization up to the CSED which occurred at study termination (maximum follow-up of 1 year)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1617	1619
MI or unstable angina pectoris	8 0.5%	15 0.9%
- MI	2 0.1%	3 0.2%
Stroke	10 0.6%	23 1.4%
- Ischemic stroke	9 0.6%	18 1.1%
Systemic arterial embolism	0 0%	1 0.1%
Episode of heart failure	55 3.4%	115 7.1%
- Hospitalization due to heart failure	24 1.5%	43 2.7%
Unplanned hospitalization for cardiovascular cause	59 3.6%	113 7%

7. Other Pre-specified Outcome

Title	Overview of Adverse Events [AE]
Description	AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Time Frame	from first study drug intake up to 10 days after the last study drug intake

Outcome Measure Data

Analysis Population Description

Safety population: all randomized and treated participants. Participants were considered according to the treatment actually received. Consequently the participant randomized to the placebo group who received Dronedarone was included in the Dronedarone group.

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)	Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
Measure Participants	1609	1614
Any AE	600 37.1%	797 49.2%
- Any serious AE	77 4.8%	113 7%
- Any AE leading to death	0 0%	4 0.2%
- Any AE leading to treatment discontinuation	80 4.9%	212 13.1%
- Any AE leading to hospitalization	71 4.4%	95 5.9%

Adverse Events

Time Frame	All Adverse Events (AE) were collected regardless of seriousness or relationship to the drug, spanning from signature of the Informed Consent Form up to the last visit.
Adverse Event Reporting Description	The analysis included all randomized participants who received at least one dose of study drug and all AE that developed or worsened from randomization up to 10 days after last study drug intake. Participants were considered according to the treatment actually received regardless the amount of treatment administered.
Arm/Group Title	Placebo		Dronedarone
Arm/Group Description	Placebo twice daily until the CSED (median treatment duration of 87.5 days)		Dronedarone 400 mg twice daily until the CSED (median treatment duration of 74 days)
All Cause Mortality
	Placebo		Dronedarone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Dronedarone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	77/1609 (4.8%)		113/1614 (7%)
Blood and lymphatic system disorders
Anaemia	1/1609 (0.1%)		2/1614 (0.1%)
Iron deficiency anaemia	1/1609 (0.1%)		2/1614 (0.1%)
Coagulopathy	1/1609 (0.1%)		0/1614 (0%)
Cardiac disorders
Bradycardia	1/1609 (0.1%)		1/1614 (0.1%)
Tachycardia	0/1609 (0%)		1/1614 (0.1%)
Ear and labyrinth disorders
Vertigo	0/1609 (0%)		1/1614 (0.1%)
Eye disorders
Cataract	0/1609 (0%)		1/1614 (0.1%)
Optic ischaemic neuropathy	0/1609 (0%)		1/1614 (0.1%)
Gastrointestinal disorders
Diarrhoea	0/1609 (0%)		1/1614 (0.1%)
Nausea	0/1609 (0%)		1/1614 (0.1%)
Abdominal pain	1/1609 (0.1%)		0/1614 (0%)
Dyspepsia	0/1609 (0%)		1/1614 (0.1%)
Vomiting	0/1609 (0%)		1/1614 (0.1%)
Constipation	1/1609 (0.1%)		0/1614 (0%)
Gastrointestinal haemorrhage	0/1609 (0%)		3/1614 (0.2%)
Colitis	0/1609 (0%)		1/1614 (0.1%)
Enteritis	1/1609 (0.1%)		0/1614 (0%)
Subileus	0/1609 (0%)		1/1614 (0.1%)
Gastrointestinal ulcer haemorrhage	0/1609 (0%)		2/1614 (0.1%)
Gastric haemorrhage	0/1609 (0%)		1/1614 (0.1%)
Gastric perforation	0/1609 (0%)		1/1614 (0.1%)
Gastric ulcer haemorrhage	1/1609 (0.1%)		1/1614 (0.1%)
Gastrointestinal necrosis	0/1609 (0%)		1/1614 (0.1%)
Ileitis	0/1609 (0%)		1/1614 (0.1%)
Inguinal hernia	0/1609 (0%)		1/1614 (0.1%)
Large intestine perforation	0/1609 (0%)		1/1614 (0.1%)
Pancreatitis	0/1609 (0%)		1/1614 (0.1%)
Rectal haemorrhage	0/1609 (0%)		1/1614 (0.1%)
Abdominal wall haematoma	1/1609 (0.1%)		0/1614 (0%)
General disorders
Oedema peripheral	1/1609 (0.1%)		0/1614 (0%)
Chest pain	0/1609 (0%)		2/1614 (0.1%)
Non-cardiac chest pain	1/1609 (0.1%)		1/1614 (0.1%)
Generalised oedema	1/1609 (0.1%)		0/1614 (0%)
Hepatobiliary disorders
Cholecystitis	0/1609 (0%)		2/1614 (0.1%)
Cholelithiasis	2/1609 (0.1%)		2/1614 (0.1%)
Acute hepatic failure	0/1609 (0%)		1/1614 (0.1%)
Cholangitis	0/1609 (0%)		1/1614 (0.1%)
Cholecystitis acute	1/1609 (0.1%)		1/1614 (0.1%)
Hepatic congestion	0/1609 (0%)		1/1614 (0.1%)
Hepatitis	0/1609 (0%)		1/1614 (0.1%)
Bile duct obstruction	0/1609 (0%)		1/1614 (0.1%)
Bile duct stone	1/1609 (0.1%)		0/1614 (0%)
Infections and infestations
Bronchitis	1/1609 (0.1%)		2/1614 (0.1%)
Urinary tract infection	2/1609 (0.1%)		2/1614 (0.1%)
Pneumonia	9/1609 (0.6%)		10/1614 (0.6%)
Gastroenteritis	0/1609 (0%)		3/1614 (0.2%)
Cellulitis	1/1609 (0.1%)		0/1614 (0%)
Respiratory tract infection	0/1609 (0%)		1/1614 (0.1%)
Cystitis	1/1609 (0.1%)		0/1614 (0%)
Erysipelas	2/1609 (0.1%)		0/1614 (0%)
Pneumonia bacterial	0/1609 (0%)		2/1614 (0.1%)
Appendicitis	0/1609 (0%)		1/1614 (0.1%)
Bronchopneumonia	0/1609 (0%)		1/1614 (0.1%)
Escherichia sepsis	0/1609 (0%)		1/1614 (0.1%)
Lobar pneumonia	1/1609 (0.1%)		1/1614 (0.1%)
Otitis media chronic	0/1609 (0%)		1/1614 (0.1%)
Postoperative wound infection	0/1609 (0%)		1/1614 (0.1%)
Sepsis	0/1609 (0%)		1/1614 (0.1%)
Urosepsis	1/1609 (0.1%)		1/1614 (0.1%)
Arthritis bacterial	0/1609 (0%)		1/1614 (0.1%)
Intervertebral discitis	0/1609 (0%)		1/1614 (0.1%)
Clostridial infection	0/1609 (0%)		1/1614 (0.1%)
Fungal peritonitis	0/1609 (0%)		1/1614 (0.1%)
Clostridium difficile colitis	1/1609 (0.1%)		0/1614 (0%)
Diverticulitis	2/1609 (0.1%)		0/1614 (0%)
Gangrene	1/1609 (0.1%)		0/1614 (0%)
Pyelonephritis	1/1609 (0.1%)		0/1614 (0%)
Injury, poisoning and procedural complications
Fall	1/1609 (0.1%)		0/1614 (0%)
Contusion	0/1609 (0%)		1/1614 (0.1%)
Rib fracture	0/1609 (0%)		1/1614 (0.1%)
Toxicity to various agents	0/1609 (0%)		1/1614 (0.1%)
Head injury	0/1609 (0%)		1/1614 (0.1%)
Hip fracture	1/1609 (0.1%)		1/1614 (0.1%)
Multiple fractures	0/1609 (0%)		1/1614 (0.1%)
Cervical vertebral fracture	1/1609 (0.1%)		1/1614 (0.1%)
Post procedural complication	0/1609 (0%)		1/1614 (0.1%)
Upper limb fracture	0/1609 (0%)		1/1614 (0.1%)
Fractured sacrum	1/1609 (0.1%)		0/1614 (0%)
Hand fracture	1/1609 (0.1%)		0/1614 (0%)
Joint dislocation	1/1609 (0.1%)		0/1614 (0%)
Road traffic accident	1/1609 (0.1%)		0/1614 (0%)
Lumbar vertebral fracture	1/1609 (0.1%)		0/1614 (0%)
Investigations
Blood creatinine increased	0/1609 (0%)		2/1614 (0.1%)
Alanine aminotransferase increased	0/1609 (0%)		1/1614 (0.1%)
International normalised ratio increased	1/1609 (0.1%)		0/1614 (0%)
Hepatic enzyme increased	1/1609 (0.1%)		5/1614 (0.3%)
Metabolism and nutrition disorders
Gout	2/1609 (0.1%)		1/1614 (0.1%)
Dehydration	2/1609 (0.1%)		2/1614 (0.1%)
Hypoglycaemia	1/1609 (0.1%)		2/1614 (0.1%)
Hyponatraemia	3/1609 (0.2%)		0/1614 (0%)
Electrolyte depletion	0/1609 (0%)		1/1614 (0.1%)
Electrolyte imbalance	0/1609 (0%)		1/1614 (0.1%)
Metabolic acidosis	0/1609 (0%)		1/1614 (0.1%)
Hyperglycaemia	1/1609 (0.1%)		0/1614 (0%)
Diabetic foot	1/1609 (0.1%)		0/1614 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/1609 (0.1%)		0/1614 (0%)
Osteoarthritis	2/1609 (0.1%)		3/1614 (0.2%)
Musculoskeletal chest pain	0/1609 (0%)		1/1614 (0.1%)
Rhabdomyolysis	0/1609 (0%)		1/1614 (0.1%)
Spinal column stenosis	0/1609 (0%)		1/1614 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer recurrent	0/1609 (0%)		1/1614 (0.1%)
Renal cancer	0/1609 (0%)		1/1614 (0.1%)
Uterine leiomyoma	0/1609 (0%)		1/1614 (0.1%)
Prostate cancer	0/1609 (0%)		1/1614 (0.1%)
B-cell lymphoma	1/1609 (0.1%)		0/1614 (0%)
Bladder cancer	1/1609 (0.1%)		0/1614 (0%)
Hepatic neoplasm malignant	1/1609 (0.1%)		0/1614 (0%)
Myeloproliferative disorder	1/1609 (0.1%)		0/1614 (0%)
Skin cancer	1/1609 (0.1%)		0/1614 (0%)
Squamous cell carcinoma	1/1609 (0.1%)		0/1614 (0%)
Nervous system disorders
Dizziness	1/1609 (0.1%)		0/1614 (0%)
Syncope	2/1609 (0.1%)		1/1614 (0.1%)
Presyncope	0/1609 (0%)		2/1614 (0.1%)
Diabetic neuropathy	0/1609 (0%)		1/1614 (0.1%)
Encephalitis	0/1609 (0%)		1/1614 (0.1%)
Epilepsy	0/1609 (0%)		1/1614 (0.1%)
Peripheral sensory neuropathy	0/1609 (0%)		1/1614 (0.1%)
Cognitive disorder	1/1609 (0.1%)		0/1614 (0%)
Dementia	1/1609 (0.1%)		0/1614 (0%)
Psychiatric disorders
Mental status changes	0/1609 (0%)		1/1614 (0.1%)
Delirium	1/1609 (0.1%)		0/1614 (0%)
Renal and urinary disorders
Renal failure	2/1609 (0.1%)		3/1614 (0.2%)
Renal failure acute	1/1609 (0.1%)		8/1614 (0.5%)
Haematuria	1/1609 (0.1%)		2/1614 (0.1%)
Renal failure chronic	0/1609 (0%)		1/1614 (0.1%)
Nephrolithiasis	1/1609 (0.1%)		0/1614 (0%)
Proteinuria	0/1609 (0%)		1/1614 (0.1%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/1609 (0.1%)		1/1614 (0.1%)
Acquired hydrocele	0/1609 (0%)		1/1614 (0.1%)
Balanoposthitis	1/1609 (0.1%)		0/1614 (0%)
Acquired phimosis	1/1609 (0.1%)		0/1614 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/1609 (0%)		2/1614 (0.1%)
Chronic obstructive pulmonary disease	5/1609 (0.3%)		6/1614 (0.4%)
Epistaxis	1/1609 (0.1%)		0/1614 (0%)
Atelectasis	0/1609 (0%)		1/1614 (0.1%)
Pleural effusion	0/1609 (0%)		1/1614 (0.1%)
Pneumonia aspiration	0/1609 (0%)		1/1614 (0.1%)
Respiratory failure	0/1609 (0%)		2/1614 (0.1%)
Acute respiratory failure	0/1609 (0%)		1/1614 (0.1%)
Idiopathic pulmonary fibrosis	0/1609 (0%)		1/1614 (0.1%)
Pleurisy	0/1609 (0%)		1/1614 (0.1%)
Pulmonary hypertension	0/1609 (0%)		1/1614 (0.1%)
Acute pulmonary oedema	1/1609 (0.1%)		0/1614 (0%)
Lung infiltration	1/1609 (0.1%)		0/1614 (0%)
Organising pneumonia	1/1609 (0.1%)		0/1614 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	0/1609 (0%)		2/1614 (0.1%)
Eczema	1/1609 (0.1%)		0/1614 (0%)
Toxic skin eruption	0/1609 (0%)		1/1614 (0.1%)
Skin ulcer haemorrhage	1/1609 (0.1%)		0/1614 (0%)
Surgical and medical procedures
Eventration procedure	1/1609 (0.1%)		0/1614 (0%)
Vascular disorders
Hypovolaemic shock	0/1609 (0%)		1/1614 (0.1%)
Orthostatic hypotension	1/1609 (0.1%)		0/1614 (0%)
Haemorrhage	1/1609 (0.1%)		0/1614 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Dronedarone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/1609 (2.4%)		100/1614 (6.2%)
Gastrointestinal disorders
Diarrhoea	38/1609 (2.4%)		100/1614 (6.2%)

Limitations/Caveats

Given that the study was prematurely discontinued after 3236 patients were randomized (30% of the initial planned number), p-values were provided for information without any adjustment for multiplicity.

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Certain Agreements

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

If no publication has occurred within 12 months after trial completion, the investigator can present or publish trial results. A copy is submitted to the sponsor for review and comment at least 30 days in advance of any presentation or submission for publication. The sponsor can require to delay the communication for a period not exceeding 90 days to allow for filing a patent application or such other measures as sponsor deems appropriate to establish and preserve its proprietary rights.