Pilot Randomized Trial With Flecainide in ARVC Patients

NCT ID: NCT03685149

Last Updated: 2024-08-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-23
• Study Completion Date: 2022-07-31

Brief Summary

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with high risk of ventricular tachycardia or fibrillation, and implantable cardioverter defibrillator remains as therapy of choice. Antiarrhythmic therapy with different agents including beta-blockers, sotalol and amiodarone are usually not effective in reducing risk of arrhythmic events. Recent data indicated that flecainide effectively prevented the arrhythmias observed in the experimental ARVC animals and in small series of ARVC patients. These observations provide a strong rationale for conducting a pilot randomized clinical trial to determine whether flecainide will reduce ventricular arrhythmias in high-risk ARVC patients. This pilot study is designed as randomized double-blinded placebo-controlled crossover trial with administration of 100 mg of Flecainide or matching placebo twice a day for 4 weeks each with a washout period.

Primary specific aim of this pilot trial is to determine whether Flecainide administration is associated with a significant reduction of number of ventricular ectopic beats (VEBs) in ARVC patients with implantable cardioverter-defibrillator (ICD).

Detailed Description

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited arrhythmia disorder with high risk of ventricular tachycardia or fibrillation, and implantable cardioverter defibrillator remains as therapy of choice. Antiarrhythmic therapy with different agents including beta-blockers, sotalol and amiodarone are usually not effective in reducing risk of arrhythmic events. Recent data indicated that flecainide effectively prevented the arrhythmias observed in the experimental ARVC animals and in small series of ARVC patients. These observations provide a strong rationale for conducting a pilot randomized clinical trial to determine whether flecainide will reduce ventricular arrhythmias in high-risk ARVC patients. This pilot study is designed as randomized double-blinded placebo-controlled crossover trial with administration of 100 mg of Flecainide or matching placebo twice a day for 4 weeks each with a washout period.

Primary specific aim of this pilot trial is to determine whether Flecainide administration is associated with a significant reduction of number of ventricular ectopic beats (VEBs) in ARVC patients with implantable cardioverter-defibrillator (ICD).

Secondary specific aims are:

1. to assess safety of flecainide administration with particular emphasis on proarrhythmic response measured by:

1. VEBs on ECG monitoring,

2. nonsustained and sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) episodes documented on ICD interrogation, and

3. effects of Flecainide on QRS morphology and duration.

2. to assess effects of flecainide on burden of VT runs in 7-day ECG recordings.

3. to assess effects of flecainide on burden of atrial premature beats in 7-day recordings.

4. to demonstrate feasibility of enrollment of rare inherited arrhythmia ARVC patients in a randomized study in the light of planned future large clinical trial with VT/VF/death as endpoint.

Study population will include 38 ARVC patients diagnosed with the 2010 ARVC Task Force Criteria who are at least 18 years old, have implanted ICD, and show at least 500 VEBs in a 24-hour Holter recording. Patients on other pharmacological antiarrhythmic treatment other than beta-blockers and patients with prior catheter VT ablation will be excluded.

Conditions

Arrhythmogenic Right Ventricular Cardiomyopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Flecainide

The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.

Group Type: ACTIVE_COMPARATOR

Flecainide Pill

Intervention Type: DRUG

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Placebo

Intervention Type: DRUG

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Placebo

The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.

Group Type: PLACEBO_COMPARATOR

Flecainide Pill

Intervention Type: DRUG

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Placebo

Intervention Type: DRUG

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Interventions

Flecainide Pill

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Intervention Type: DRUG

Placebo

Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Intervention Type: DRUG

Other Intervention Names

Tambocor

Eligibility Criteria

Inclusion Criteria

• Age > 18 years.
• Subjects who have been diagnosed with ARVC and meet 2010 Modified Task Force Criteria for ARVC as affected.
• At minimum 500 VEBs on the most recent 24-hour Holter monitor recording prior to consent or after consent if a subsequent recording is required after 5 day washout following discontinuation of anti-arrhythmic medication.
• Functioning implanted cardioverter defibrillator with remote interrogation capability.
• Subjects should be on a beta-blocker including metoprolol, propranolol, atenolol, nadolol, carvedilol or bisoprolol unless contraindication to beta-blockers exists.
• Persons prescribed quinidine, procainamide, propafenone, disopyramide, dronedarone phenytoin, mexiletene, flecainide, may be included after 5 day washout period with subsequent 24 Hour Holter obtained after washout period.
• Persons prescribed sotalol must be included after 5 day washout period during which another beta-blocker may be administered with subsequent 24 Hour Holter obtained.
• Subject and personal physician and or cardiologist must agree not to use any antiarrhythmic medications during the 10 weeks of participation, unless needed for management of life-threatening arrhythmias.
• All subjects must agree to use medically acceptable contraceptive measures during participation unless documented as surgically sterile or post-menopausal (no menstrual periods for more than one year).

Exclusion Criteria

• Prescribed amiodarone or dofetilide at the time of consent.
• Left ventricular ejection fraction ≤40% by any imaging modality: echocardiography, angiography, cardiac magnetic resonance imaging (CMRI), or cardiac nuclear test on the most recent test.
• New York Heart Association (NYHA) heart failure class III or IV at time of consent.
• Prior myocardial infarction at any time in the past.
• Pacemaker dependent rhythm at the time of consent.
• Renal impairment (GFR <30 mL/min/m2).
• Prior diagnosis of severe hepatic impairment.
• Pregnant or plan to become pregnant during the course of the trial (Flecainide has not been adequately studied in pregnant women). Pregnancy test is required for women of child-bearing potential prior to randomization.
• Participating in any other interventional clinical trial.
• Unwilling or unable to cooperate with the protocol.
• Lives at such a distance from the clinic that travel for the consent visit would be unusually difficult.
• Decisionally impaired adults, those of questionable capacity, those who cannot manage taking the study drug per the prescribed regimen, and those who cannot consent for themselves will not be recruited for this study.
• Unwilling to sign the consent for participation.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: lead

Responsible Party

Wojciech Zareba

Professor of Medicine/Cardiology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wojciech Zareba, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Locations

University of Colorado

Denver, Colorado, United States

John Hopkins University

Baltimore, Maryland, United States

New York University

New York, New York, United States

University of Rochester Medical Center

Rochester, New York, United States

Duke University

Durham, North Carolina, United States

University of Pensylvania

Philadelphia, Pennsylvania, United States

Countries

United States

References

Marcus FI, Zareba W, Calkins H, Towbin JA, Basso C, Bluemke DA, Estes NA 3rd, Picard MH, Sanborn D, Thiene G, Wichter T, Cannom D, Wilber DJ, Scheinman M, Duff H, Daubert J, Talajic M, Krahn A, Sweeney M, Garan H, Sakaguchi S, Lerman BB, Kerr C, Kron J, Steinberg JS, Sherrill D, Gear K, Brown M, Severski P, Polonsky S, McNitt S. Arrhythmogenic right ventricular cardiomyopathy/dysplasia clinical presentation and diagnostic evaluation: results from the North American Multidisciplinary Study. Heart Rhythm. 2009 Jul;6(7):984-92. doi: 10.1016/j.hrthm.2009.03.013. Epub 2009 Mar 11.

Reference Type: BACKGROUND

PMID: 19560088 (View on PubMed)

Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010 Apr 6;121(13):1533-41. doi: 10.1161/CIRCULATIONAHA.108.840827. Epub 2010 Feb 19.

Reference Type: BACKGROUND

PMID: 20172911 (View on PubMed)

Corrado D, Link MS, Calkins H. Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med. 2017 Jan 5;376(1):61-72. doi: 10.1056/NEJMra1509267. No abstract available.

Reference Type: BACKGROUND

PMID: 28052233 (View on PubMed)

Cerrone M, Montnach J, Lin X, Zhao YT, Zhang M, Agullo-Pascual E, Leo-Macias A, Alvarado FJ, Dolgalev I, Karathanos TV, Malkani K, Van Opbergen CJM, van Bavel JJA, Yang HQ, Vasquez C, Tester D, Fowler S, Liang F, Rothenberg E, Heguy A, Morley GE, Coetzee WA, Trayanova NA, Ackerman MJ, van Veen TAB, Valdivia HH, Delmar M. Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun. 2017 Jul 24;8(1):106. doi: 10.1038/s41467-017-00127-0.

Reference Type: BACKGROUND

PMID: 28740174 (View on PubMed)

Ermakov S, Gerstenfeld EP, Svetlichnaya Y, Scheinman MM. Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2017 Apr;14(4):564-569. doi: 10.1016/j.hrthm.2016.12.010. Epub 2016 Dec 9.

Reference Type: BACKGROUND

PMID: 27939893 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

R34HL143372

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00001910

Identifier Type: -

Identifier Source: org_study_id