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

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

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01198873

Acronym

ODYSSEUS

Enrollment

Registered

2010-09-10

Start date

2010-09-30

Completion date

2012-01-31

Last updated

2013-02-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Atrial Fibrillation

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.

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.

Interventions

DRUGDronedarone

Film-coated tablet Oral administration under fed conditions (during breakfast and dinner)

DRUGPlacebo (for Dronedarone)

film-coated tablet strictly identical in appearance Oral administration under fed conditions (during breakfast and dinner)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

21 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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.
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.
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.
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.

Countries

Canada, United States

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 details

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.

Participants by arm

Arm	Count
Placebo Placebo (for Dronedarone) twice a day (average treatment duration of approximatively 6 months)	41
Dronedarone Dronedarone 400 mg twice a day (average treatment duration of approximatively 6 months)	35
Total	76

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	7
Overall Study	Other than above	4	2
Overall Study	Study closure	29	23

Baseline characteristics

Characteristic	Placebo	Dronedarone	Total
Age Continuous	70.3 years STANDARD_DEVIATION 8.2	74.1 years STANDARD_DEVIATION 9.7	72.0 years STANDARD_DEVIATION 9.1
Sex: Female, Male Female	15 Participants	13 Participants	28 Participants
Sex: Female, Male Male	26 Participants	22 Participants	48 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	5 / 41	14 / 35
serious Total, serious adverse events	1 / 41	5 / 35

Outcome results

Primary

Change From Baseline in Left Atrial Volume Index (LAVi)

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.