Clinical trial NCT04704050: Effect of Dronedarone on Atrial Fibrosis Progression and Atrial Fibrillation Recurrence
Official title: Effect of Dronedarone on Atrial Fibrosis Progression and Atrial Fibrillation Recurrence Post Ablation: The EDORA Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Atrial Fibrillation
Atrial Fibrillation Recurrent
Keywords: Atrial Fibrillation
Atrial Fibrillation Recurrent
Heart Murmur
Dronedarone
Atrial Fibrosis
Atrial Fibrosis Progression
Atrial Fibrosis Regression
Atrial Arrhythmia
Cardiac Arrhythmia
Cardiovascular Events
Multaq
Lead sponsor: Tulane University
Sponsor class: OTHER
Collaborators: name: University of Washington
name: Marrek, INC
name: Sanofi
name: Preventice
name: Mckesson
First posted: 2021-01-11
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. are pregnant or breast-feeding or plan to become pregnant during the study period or,
  2. are not surgically sterile or,
  3. are of childbearing potential and not practising two acceptable methods of birth control or,
  4. 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.

Primary outcomes:
measure: Post-ablation Atrial Fibrillation Recurrence
timeFrame: 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.
measure: Post-ablation Atrial Fibrillation Recurrence
timeFrame: Through trial completion, an average of 1 year.
measure: Progression of Atrial Fibrosis
timeFrame: Comparing baseline CMR scan to 12 month CMR scan.
Secondary outcomes:
measure: Antiarrhythmic Initiation or change
timeFrame: 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.
measure: Atrial Fibrillation Episodes
timeFrame: 1 year
measure: Repeat Cardiac Ablation
timeFrame: 1 year
measure: Cardioversion
timeFrame: 1 year
measure: Atrial Fibrillation Burden
timeFrame: 1 year
measure: Quality of Life (Online questionnaire form)
timeFrame: 1 year
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: Through trial completion, up to 56 weeks.
measure: AF Burden (Online questionnaire form)
timeFrame: 1 year
Other outcomes:
measure: Hospitalization
timeFrame: 1 year
measure: Mortality
timeFrame: 1 year
measure: Stroke/ Transient Ischemic Attacks (TIA)
timeFrame: 1 year
Locations:
city: Colorado Springs
country: United States
facility: University of Colorado Health Memorial
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: New Orleans
country: United States
facility: Tulane University School of Medicine
state: Louisiana
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Tulane University School of Medicine
name: Nassir F Marrouche, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JG, Kingma JH, Crijns HJ, Van Gelder IC; RACE Study Group. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol. 2004 Jan 21;43(2):241-7. doi: 10.1016/j.jacc.2003.08.037.
citation: Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, Jensen SM, Bergfeldt L, Kenneback G, Rubulis A, Malmborg H, Raatikainen P, Lonnerholm S, Hoglund N, Mortsell D. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA. 2019 Mar 19;321(11):1059-1068. doi: 10.1001/jama.2019.0335.
citation: Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, Merkely B, Pokushalov E, Sanders P, Proff J, Schunkert H, Christ H, Vogt J, Bansch D; CASTLE-AF Investigators. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018 Feb 1;378(5):417-427. doi: 10.1056/NEJMoa1707855.
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citation: Marrouche NF, Wilber D, Hindricks G, Jais P, Akoum N, Marchlinski F, Kholmovski E, Burgon N, Hu N, Mont L, Deneke T, Duytschaever M, Neumann T, Mansour M, Mahnkopf C, Herweg B, Daoud E, Wissner E, Bansmann P, Brachmann J. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study. JAMA. 2014 Feb 5;311(5):498-506. doi: 10.1001/jama.2014.3.
citation: Kheirkhahan M, Baher A, Goldooz M, Kholmovski EG, Morris AK, Csecs I, Chelu MG, Wilson BD, Marrouche NF. Left atrial fibrosis progression detected by LGE-MRI after ablation of atrial fibrillation. Pacing Clin Electrophysiol. 2020 Apr;43(4):402-411. doi: 10.1111/pace.13866.
citation: Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009 Feb 12;360(7):668-78. doi: 10.1056/NEJMoa0803778.
citation: Akoum N, Fernandez G, Wilson B, Mcgann C, Kholmovski E, Marrouche N. Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2013 Oct;24(10):1104-9. doi: 10.1111/jce.12199. Epub 2013 Jul 11.
citation: Marrouche NF, Dagher L, Wazni O, Akoum N, Mansour M, El Hajjar AH, Bhatnagar A, Hua H; EDORA Investigators. Effect of DrOnedarone on atrial fibrosis progression and atrial fibrillation recurrence postablation: Design of the EDORA randomized clinical trial. J Cardiovasc Electrophysiol. 2021 Dec;32(12):3203-3210. doi: 10.1111/jce.15274. Epub 2021 Nov 2.