Effect of Dronedarone on Atrial Fibrosis Progression and Atrial Fibrillation Recurrence

Atrial Fibrillation Clinical Trial

— EDORA  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04704050
• Other study ID #: 2830294
• Status: Terminated
• Phase: Phase 4
• Start date: May 15, 2021
• Est. completion date: December 20, 2022

Study information

• Verified date: April 2023
• Source: Tulane University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 22
• Est. completion date: December 20, 2022
• Est. primary completion date: December 20, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atrial Fibrillation
• Atrial Fibrillation Recurrent
• Disease Progression
• Fibrosis
• Recurrence

Intervention

Drug:
• dronedarone 400 mg Oral Tablet
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.
• Placebo
Participants will receive a placebo tablet matching the physical appearance of dronedarone, to be taken orally and twice daily for 52 weeks.

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	University of Colorado Health Memorial	Colorado Springs	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	Tulane University School of Medicine	New Orleans	Louisiana

Sponsors (6)

Lead Sponsor	Collaborator
Tulane University School of Medicine	Marrek, INC, Mckesson, Preventice, Sanofi, University of Washington

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View 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. — View 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. — View 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. Erratum In: N Engl J Med. 2009 Jun 4;360(23):2487. N Engl J Med. 2011 Apr 14;364(15):1481. — View 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. — View 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. — View 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. Erratum In: JAMA. 2014 Nov 5;312(17):1805. — View Citation

Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019 Apr 2;321(13):1261-1274. doi: 10.1001/jama.2019.0693. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hospitalization	Records of any cardiac events requiring hospitalization.	1 year
Other	Mortality	Records of mortality associated with cardiovascular events.	1 year
Other	Stroke/ Transient Ischemic Attacks (TIA)	Records of stroke or TIA based on cardiac emboli.	1 year
Primary	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.
Primary	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.
Primary	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	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.
Secondary	Atrial Fibrillation Episodes	Incidences or symptoms of atrial fibrillation (e.g. palpitations, chest pain, dyspnea, dizziness, syncope, unusual fatigue and weakness).	1 year
Secondary	Repeat Cardiac Ablation	Whether patients in either treatment arm require a repeat cardiac ablation.	1 year
Secondary	Cardioversion	Whether patients in either treatment arm require cardioversion.	1 year
Secondary	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
Secondary	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
Secondary	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.
Secondary	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