Effect of Dronedarone on Atrial Fibrosis Progression and Atrial Fibrillation Recurrence

Study Overview
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Brief Summary
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Patients who have undergone cardiac ablation will be randomized and blinded to one of two groups; one group will receive dronedarone while the other group will receive a placebo. The incidence of atrial fibrillation recurrence, as well as atrial fibrosis progression, will be analyzed between the two trial groups.

Detailed Description
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The purpose of this trial is to determine whether dronedarone is effective in slowing the progression of fibrosis and decreasing atrial fibrillation recurrence in patients who have undergone ablation therapy. Patients with atrial fibrillation (AF) undergoing ablation will be stratified by age and gender (>65 years and <65 years, male and female) as well as by type of atrial fibrillation (paroxysmal, persistent, etc.) and then randomized to one of two trial groups. They will either receive dronedarone 400 mg BID (twice daily) (treatment group) or placebo (control group). The control group will be started on placebo, and treating physicians will be advised to limit the initiation of anti-arrhythmic drugs (standard of care, SOC) to necessary cases only, avoiding amiodarone and dronedarone. Each patient will receive a pre-ablation Cardiac Magnetic Resonance imaging (CMR) (SOC) scan, followed by scans at 3 and 12-month post-ablation. Quality of Life (QoL) changes will be evaluated from baseline and at 3 months and 12-months via the Atrial Fibrillation Effect on Quality-Of-Life (AFEQT) online questionnaire form. AF burden (frequency, duration and severity of an AF episode) if present, will be evaluated from baseline and at 3 months and 12-months via the Atrial Fibrillation Severity Scale (AFSS) online questionnaire form. Patients will be followed post-ablation for AF recurrence and burden assessment with a continuous 30-day ECG wearable patch starting at discharge (SOC), then at 3,6,9 and 12 months post-ablation Phone call visits will occur at 6 and 9 months to monitor for medication compliance as well as to assess that devices are working accordingly. Evaluation of adverse events (AE's) as well as whether a patient has reached any trial endpoints will be analyzed at this time. Physicians will be advised to avoid adjustments in drug therapy unless necessary (severely symptomatic patients, patients with heart failure). Severely symptomatic patients will be defined as, patients with non-tolerated palpitations or chest pain, dizziness, syncope, dyspnea, or suddenly reduced ability to exercise. Any initiation or change of an anti-arrhythmic treatment in the treatment or control group will be considered as a secondary endpoint. Patients will continue to be monitored for fibrosis progression and AF burden via CMR scans and ECG wearable devices until the end of the follow-up period. In the case of AF recurrence after ablation, anti-arrhythmic drugs (AAD) initiation or change will be left to the discretion of the treating physician.

Official Title
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Effect of Dronedarone on Atrial Fibrosis Progression and Atrial Fibrillation Recurrence Post Ablation: The EDORA Trial

Conditions
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Atrial Fibrillation, Atrial Fibrillation Recurrent

Intervention / Treatment
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* Drug: dronedarone 400 mg Oral Tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet the following criteria to be enrolled in the trial. Male or female patients aged over 18 years of age. Patients with paroxysmal or persistent atrial fibrillation who are undergoing ablation of atrial fibrillation, regardless of whether they were receiving an anti-arrhythmic drug (AADs) before enrollment or not. Exclusion Criteria: Patients will be excluded from enrollment if any of the following criteria are present. Any health-related gadolinium/MRI contraindications (e.g. allergy to gadolinium, pacemakers, Implantable Cardioverter Defibrillators [ICD's], other devices/implants contraindicated for use of MRI, etc.). Patients weighing >300 Ibs. (MRI quality decreases as BMI increases). Patients with contraindications to dronedarone. (Including patients with decompensated heart failure or class NYHA IV (New York Heart Association Class IV), second or third-degree atrioventricular (AV) block or sick-sinus syndrome [except when used in conjunction with a functioning pacemaker]), concomitant use of strong cytochrome P450, family 3, subfamily A (CYP-3A) inhibitors or other Class I or III AADs, drug or herbal products that prolongs the QT interval and may induce Torsades de Pointes. Liver or lung toxicity related to the previous use of amiodarone, severe hepatic impairment including any stage of cirrhosis and acute liver failure, bradycardia <50bpm, QTc Bazett interval >500ms or PR interval >280ms, or hypersensitivity to the active substance or to any of its excipients. Acute or chronic severe renal disease with a low glomerular filtration rate (GFR), <30 mL per minute per 1.73m2 will be excluded from the trial. Patients with a history of prior left atrial ablation or valvular cardiac surgery (myocardial scarring/fibrosis from prior surgeries may confound data). Pre-menopausal (last menstruation <1 year prior to screening) who: are pregnant or breast-feeding or plan to become pregnant during the study period or, are not surgically sterile or, are of childbearing potential and not practising two acceptable methods of birth control or, do not plan to continue practising two acceptable methods of birth control throughout the trial (highly effective methods of birth control are defined as those, used alone, or in combination, that result in a low failure rate i.e. less than 1% per year when used consistently and correctly). Patients who do not have access to the Internet/e-mail. Patients without daily access to a smart phone-compatible with ECG Check device application and ability to upload ECG tracings for the entire follow-up period. Patients unable or unwilling to return to the clinic for follow up CMR scans. Patients with cognitive impairments who are unable to give informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Group<br>Dronedarone 400 mg orally, twice per day (BID) | Drug: dronedarone 400 mg Oral Tablet<br>* Dronedarone is an anti-arrhythmic drug with properties belonging to Vaughan-Williams class I-IV. Participants will receive dronedarone 400 mg tablet, to be taken orally and twice daily for 52 weeks.<br>* Other names: Multaq®;|
| Placebo Comparator: Control Group<br>Placebo tablet orally, twice per day (BID) | Drug: Placebo<br>* Participants will receive a placebo tablet matching the physical appearance of dronedarone, to be taken orally and twice daily for 52 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-ablation Atrial Fibrillation Recurrence | Time to first atrial fibrillation recurrence after ablation in both treatment groups. | Up to 56 weeks. From date of ablation until the date of first documented Atrial Fibrillation recurrence, whichever came first, assessed up to 56 weeks. | 
| Post-ablation Atrial Fibrillation Recurrence | New anti-arrythmic drug (AAD) initiation for atrial fibrillation recurrence after ablation in both treatment groups. | Through trial completion, an average of 1 year. | 
| Progression of Atrial Fibrosis | To see whether patients in the treatment group have change in atrial fibrosis, visualized on their CMR scans compared to those who were in the placebo group. | Comparing baseline CMR scan to 12 month CMR scan. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antiarrhythmic Initiation or change | Any initiation or change to anti-arrhythmic therapy after ablation to either the treatment or control group. | Up to 56 weeks. From the date of ablation until the date of first documented Antiarrhythmic drug initiation/change, whichever came first, assessed up to 56 weeks. | 
| Atrial Fibrillation Episodes | Incidences or symptoms of atrial fibrillation (e.g. palpitations, chest pain, dyspnea, dizziness, syncope, unusual fatigue and weakness). | 1 year | 
| Repeat Cardiac Ablation | Whether patients in either treatment arm require a repeat cardiac ablation. | 1 year | 
| Cardioversion | Whether patients in either treatment arm require cardioversion. | 1 year | 
| Atrial Fibrillation Burden | The percentage of time a patient is in atrial fibrillation during the monitoring period, 24-48 hours and, at 3 months and 12 months post-ablation. Burden will be recorded as a time-weighted average (%) based on data from wearable devices. | 1 year | 
| Quality of Life (Online questionnaire form) | This will be assessed through the Atrial Fibrillation Effect on Quality-Of-Life (AFEQT) online questionnaire form at baseline, 3 and 12 month follow up visits. | 1 year | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Assessment of adverse events related to dronedarone. Evaluated at 3, 12 months visits and during 6 & 9 month phone call visits. | Through trial completion, up to 56 weeks. | 
| AF Burden (Online questionnaire form) | This will be assessed through the Atrial Fibrillation Severity Scale (AFSS) online questionnaire form at baseline, 3 and 12 month follow up visits. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular Events, Atrial Fibrillation, Atrial Fibrillation Recurrent, Heart Murmur, Dronedarone, Atrial Fibrosis, Atrial Fibrosis Progression, Atrial Fibrosis Regression, Atrial Arrhythmia, Cardiac Arrhythmia, Multaq