ODYSSEUS: Effects of Dronedarone on Cardiac Geometry and Function in Patients With Atrial Fibrillation and Left Atrial Enlargement

• Sponsor: Sanofi (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01198873
• Collaborator: (none)
• Enrollment: 76
• Locations: 57
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary Objective:

• Evaluate the effect of dronedarone versus placebo (standard therapy) in slowing the progression of adverse left atrial remodeling in patients with atrial fibrillation (AF) following 12 months of treatment.

Secondary Objectives:

• Evaluate the effects of dronedarone versus placebo on left atrial function;

• Evaluate the effects of dronedarone versus placebo on left atrial dimension;

• Evaluate the effects of dronedarone versus placebo on left ventricular function (LVEF, E, E', A, E/E')

• Evaluate the safety and tolerability of dronedarone.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Dronedarone; Drug: Placebo (for Dronedarone)	Phase 4

Detailed Description

The planned total study period per participant was 12 months and 3 weeks broken down as follows:

• Screening period: up to 1 week;

• Treatment period: 12 months;

• Follow-up period: 2 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled, Double-Blind, Randomized, Multi-center Study to Assess the Effects of Dronedarone 400 mg BID on Cardiac Geometry and Function in Patients With Atrial Fibrillation and Left Atrial Enlargement
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dronedarone Dronedarone 400 mg twice a day	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	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. Change From Baseline in Left Atrial Volume Index (LAVi) [baseline (before randomization) and post-baseline (after 3-12 months of treatment)]

   Left Atrial Volume index (LAVi) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.

Secondary Outcome Measures

1. Changes From Baseline in Left Atrial Function [baseline (before randomization) and post-baseline (after 3-12 months of treatment)]

   left atrial (LA) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.

2. Changes From Baseline in Left Atrial Dimension [baseline (before randomization) and post-baseline (after 3-12 months of treatment)]

   Maximal left atrial diameter in the anteroposterior dimension was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis.

3. Changes From Baseline in Left Ventricular Ejection Fraction (LVEF) [baseline (before randomization) and post-baseline (after 3-12 months of treatment)]

   Left Ventricular Ejection Fraction (LVEF) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis.

4. Changes From Baseline in Left Ventricular Function [baseline (before randomization) and post-baseline (after 3-12 months of treatment)]

   left ventricular (LV) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Signed written informed consent and Health Insurance Portability and Accountability Act (HIPAA) Authorization;

• Nonpermanent AF or AF/Atrial Flutter (AFL) documented electrocardiographically by both AF (or AF/AFL) and sinus rhythm within the prior 12 months;

• At screening, sinus rhythm and Left Atrial Volume index (LAVi) ≥32 mL/m2 based on 2D-echocardiography;

• At least one of the following cardiovascular (CV) risk factors: Age >70 years at start of screening, hypertension, diabetes mellitus, prior CV accident (stroke or transient ischemic attack) or systemic embolism, or left ventricular ejection fraction <0.40.

Exclusion criteria:

• Permanent AF defined as continuous AF for 6 months or longer;

• Persistent AF defined as sustained AF >7 days duration and/or requiring cardioversion in the 4 weeks before screening;

• Prior valvular heart surgery or significant valvular heart disease including rheumatic heart disease or acquired valvular heart disease;

• Aortic or mitral regurgitation greater than mild (>1+) or any degree of mitral stenosis at the screening echocardiogram;

• Myocardial infarction within the 6 months prior to screening or stroke within 2 months prior to screening;

• Pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy devices placed within the 6 months prior to screening or at anytime during the study;

• Ongoing potentially dangerous symptoms when in AF/AFL such as angina pectoris, transient ischemic attacks, stroke, syncope as judged by the Investigator;

• Cardiac ablative procedure or cardiac surgery within 3 months prior to screening, or percutaneous coronary intervention within 4 weeks prior to screening;

• Need for concomitant medication that is prohibited in this trial, and would preclude the use of the study drug during the planned study period including the following:

• Antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol);

• Drugs or products that are strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, and grapefruit juice);

• Drugs that are inducers of CYP3A (eg, rifampin, phenobarbital, carbamazepine, phenytoin, and St John's wort);

• QTc Bazett interval ≥500 msec on the screening ECG;

• Bradycardia <50 bpm and/or PR interval ≥0.28 sec on the screening ECG unless the patient has a functional pacemaker;

• New York Heart Association (NYHA) Class IV heart failure or NYHA Class II or III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic within 4 weeks prior to screening.

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	Investigational Site Number 840072	Phoenix	Arizona	United States	85006
2	Investigational Site Number 840015	Little Rock	Arkansas	United States	72204
3	Investigational Site Number 840086	Beverly Hills	California	United States	90211
4	Investigational Site Number 840018	Loma Linda	California	United States	92354
5	Investigational Site Number 840029	Merced	California	United States	95348
6	Investigational Site Number 840044	Redwood City	California	United States	94062
7	Investigational Site Number 840042	Santa Ana	California	United States	92704
8	Investigational Site Number 840060	Vista	California	United States	92083
9	Investigational Site Number 840057	Stamford	Connecticut	United States	06905
10	Investigational Site Number 840002	Newark	Delaware	United States	19713
11	Investigational Site Number 840063	Wilmington	Delaware	United States	19808
12	Investigational Site Number 840070	Bradenton	Florida	United States	34205
13	Investigational Site Number 840010	Jacksonville	Florida	United States	32216
14	Investigational Site Number 840071	Jupiter	Florida	United States	33458
15	Investigational Site Number 840061	Lakeland	Florida	United States	33805
16	Investigational Site Number 840096	Lauderdale Lakes	Florida	United States	33313
17	Investigational Site Number 840031	Ocala	Florida	United States	34471
18	Investigational Site Number 840074	Orlando	Florida	United States	32803
19	Investigational Site Number 840016	Ormond Beach	Florida	United States	32174
20	Investigational Site Number 840051	St Petersburg	Florida	United States	33709
21	Investigational Site Number 840081	Roswell	Georgia	United States	30076
22	Investigational Site Number 840103	Jerseyville	Illinois	United States	62052
23	Investigational Site Number 840106	Peoria	Illinois	United States	61606
24	Investigational Site Number 840066	Elkhart	Indiana	United States	46514
25	Investigational Site Number 840099	Lexington	Kentucky	United States	40504
26	Investigational Site Number 840039	Owensboro	Kentucky	United States	42303
27	Investigational Site Number 840092	Baton Rouge	Louisiana	United States	70808
28	Investigational Site Number 840040	Auburn	Maine	United States	04210
29	Investigational Site Number 840077	Ayer	Massachusetts	United States	01432
30	Investigational Site Number 840050	Alpena	Michigan	United States	49707
31	Investigational Site Number 840041	Saginaw	Michigan	United States	48670
32	Investigational Site Number 840058	Minneapolis	Minnesota	United States	55422
33	Investigational Site Number 840101	Picayune	Mississippi	United States	39466
34	Investigational Site Number 840078	St Louis	Missouri	United States	63122
35	Investigational Site Number 840038	St Louis	Missouri	United States	63128
36	Investigational Site Number 840102	St. Louis	Missouri	United States	63128
37	Investigational Site Number 840012	Kalispell	Montana	United States	59901
38	Investigational Site Number 840090	Lincoln	Nebraska	United States	68506
39	Investigational Site Number 840003	Bronx	New York	United States	10468
40	Investigational Site Number 840045	Buffalo	New York	United States	14215
41	Investigational Site Number 840055	Manhasset	New York	United States	11030
42	Investigational Site Number 840004	Troy	New York	United States	12180
43	Investigational Site Number 840009	Maumee	Ohio	United States	43537
44	Investigational Site Number 840028	Camp Hill	Pennsylvania	United States	17011
45	Investigational Site Number 840067	Wyomissing	Pennsylvania	United States	19610
46	Investigational Site Number 840027	Wakefield	Rhode Island	United States	02879
47	Investigational Site Number 840046	Knoxville	Tennessee	United States	37917
48	Investigational Site Number 840014	Longview	Texas	United States	75605
49	Investigational Site Number 840068	Danville	Virginia	United States	24541
50	Investigational Site Number 840069	Manassas	Virginia	United States	20109
51	Investigational Site Number 840087	Richmond	Virginia	United States	23249
52	Investigational Site Number 840085	Winchester	Virginia	United States	22601
53	Investigational Site Number 840013	Burien	Washington	United States	98166
54	Investigational Site Number 840091	Spokane	Washington	United States	99204
55	Investigational Site Number 840080	Madison	Wisconsin	United States	53713
56	Investigational Site Number 840023	Milwaukee	Wisconsin	United States	53215
57	Investigational Site Number 124003	Cambridge	Ontario	Canada

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: NCT01198873
• Other Study ID Numbers: DRONE_L_04315
• First Posted: Sep 10, 2010
• Last Update Posted: Feb 12, 2013
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Atrial Fibrillation; Dronedarone

Study Results

Participant Flow

Recruitment Details	Recruitment initiated in September 2010 was discontinued in September, 2011 due to significantly lower than planned enrollment with no feasibility to complete the trial within reasonable, meaningful timelines. At that time 57 sites in US and Canada had screened at least one patient.
Pre-assignment Detail	After signature of the informed consent and after eligibility was confirmed, group assignment was made at site in a 1:1 ratio using a treatment code list generated centrally by Sanofi. Participants were considered as randomized as soon as the assignment was made. A total of 76 participants were randomized at 39 sites.

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Period Title: Overall Study
STARTED	41	35
Treated	41	35
Evaluable for Efficacy	33	26
COMPLETED	4	3
NOT COMPLETED	37	32

Baseline Characteristics

Arm/Group Title	Placebo	Dronedarone	Total
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)	Total of all reporting groups
Overall Participants	41	35	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.3 (8.2)	74.1 (9.7)	72.0 (9.1)
Sex: Female, Male (Count of Participants)
Female	15 36.6%	13 37.1%	28 36.8%
Male	26 63.4%	22 62.9%	48 63.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Left Atrial Volume Index (LAVi)
Description	Left Atrial Volume index (LAVi) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.
Time Frame	baseline (before randomization) and post-baseline (after 3-12 months of treatment)

Outcome Measure Data

Analysis Population Description

The analysis included all randomized and treated participants with at least one post-baseline echocardiographic assessment. Participants were included in the treatment group to which they were randomized (Modified Intent-to-treat analysis). The quality of the post-baseline echocardiography was inadequate for determining LAVi in one participant.

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Measure Participants	33	26
Baseline (n =33, 26)	37.555 (5.899)	37.715 (6.597)
Post-baseline (n =32, 26)	29.191 (5.994)	30.823 (5.364)
Change from baseline (n =32, 26)	-8.438 (4.743)	-6.892 (5.759)

2. Secondary Outcome

Title	Changes From Baseline in Left Atrial Function
Description	left atrial (LA) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.
Time Frame	baseline (before randomization) and post-baseline (after 3-12 months of treatment)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Measure Participants	33	26
LA passive emptying volume (n = 19, 19)	-10.783 (7.798)	-4.566 (9.094)
LA conduit volume (n =29, 25)	-1.366 (5.652)	-0.764 (5.759)
LA active emptying volume (n = 19, 19)	-0.052 (4.707)	1.198 (5.695)
LA passive emptying fraction (n = 19, 19)	-0.074 (0.074)	-0.019 (0.117)
LA active emptying fraction (n = 19, 19)	0.057 (0.104)	0.067 (0.105)

3. Secondary Outcome

Title	Changes From Baseline in Left Atrial Dimension
Description	Maximal left atrial diameter in the anteroposterior dimension was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis.
Time Frame	baseline (before randomization) and post-baseline (after 3-12 months of treatment)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Measure Participants	33	26
Mean (Standard Deviation) [centimeters]	-0.124 (0.188)	-0.166 (0.161)

4. Secondary Outcome

Title	Changes From Baseline in Left Ventricular Ejection Fraction (LVEF)
Description	Left Ventricular Ejection Fraction (LVEF) was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last drug intake and data were included in the analysis.
Time Frame	baseline (before randomization) and post-baseline (after 3-12 months of treatment)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population as previously defined

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Measure Participants	33	26
Mean (Standard Deviation) [percentage of blood pumped out]	0.948 (3.333)	1.147 (3.997)

5. Secondary Outcome

Title	Changes From Baseline in Left Ventricular Function
Description	left ventricular (LV) function was assessed at baseline and after 12 months treatment using 2-D echocardiography and interpreted blindly via a central Echocardiography Core Lab. Participants who discontinued after completing at least 3 months of treatment were assessed after last study drug intake and data were included in the analysis.
Time Frame	baseline (before randomization) and post-baseline (after 3-12 months of treatment)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Dronedarone
Arm/Group Description	Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
Measure Participants	33	26
Peak early diastolic transmitral flow velocity (E)	5.165 (15.440)	-10.497 (27.890)
Mitral annular velocity (E')	0.847 (2.002)	-0.119 (1.845)
Peak late diastolic transmitral flow velocity (A)	0.076 (11.674)	4.319 (14.275)
E/E' ratio	-0.787 (3.346)	-1.443 (4.288)

Adverse Events

Time Frame	All Adverse Events (AE) were collected regardless of seriousness or relationship to the drug in the period 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 (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)		Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)
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	1/41 (2.4%)		5/35 (14.3%)
Cardiac disorders
Cardiac failure congestive	0/41 (0%)		1/35 (2.9%)
Angina pectoris	1/41 (2.4%)		0/35 (0%)
Atrial fibrillation	1/41 (2.4%)		0/35 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/41 (0%)		1/35 (2.9%)
Pancreatic cyst	0/41 (0%)		1/35 (2.9%)
General disorders
Asthenia	0/41 (0%)		1/35 (2.9%)
Injury, poisoning and procedural complications
Femoral neck fracture	0/41 (0%)		1/35 (2.9%)
Musculoskeletal and connective tissue disorders
Gouty arthritis	0/41 (0%)		1/35 (2.9%)
Renal and urinary disorders
Renal failure acute	0/41 (0%)		1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/41 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Placebo		Dronedarone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/41 (12.2%)		14/35 (40%)
Gastrointestinal disorders
Diarrhoea	1/41 (2.4%)		4/35 (11.4%)
Nausea	0/41 (0%)		3/35 (8.6%)
Constipation	0/41 (0%)		2/35 (5.7%)
Flatulence	0/41 (0%)		2/35 (5.7%)
General disorders
Fatigue	1/41 (2.4%)		4/35 (11.4%)
Oedema peripheral	2/41 (4.9%)		2/35 (5.7%)
Infections and infestations
Pneumonia	0/41 (0%)		2/35 (5.7%)
Sinusitis	0/41 (0%)		2/35 (5.7%)
Nervous system disorders
Dizziness	0/41 (0%)		3/35 (8.6%)
Psychiatric disorders
Insomnia	0/41 (0%)		3/35 (8.6%)
Depression	0/41 (0%)		2/35 (5.7%)
Vascular disorders
Hypertension	3/41 (7.3%)		0/35 (0%)

Limitations/Caveats

Due to the early termination of the study, results should be cautiously interpreted. Indeed the number of participants was lower than planned (76 instead of 334) and the treatment period was shorter than planned (6 months instead of 12 months).

More Information

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.