Pilot Randomized Trial With Flecainide in ARVC Patients

NCT03685149 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: STUDY00001910R34HL143372
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 6

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).

Conditions

Arrhythmogenic Right Ventricular Cardiomyopathy

Keywords

arrhythmogenic right ventricular cardiomyopathy; ARVC; Flecainide; ventricular arrhythmias; implantable cardioverter-defibrillator

Outcome Measures

Primary Outcomes (1)

• Number of Ventricular Ectopic Beats (VEBs) Per Day

  Number of ventricular ectopic beats (VEBs) per day in a 7-day ECG recording

  7-day period

Secondary Outcomes (3)

• Number of Participants With Proarrhythmic Response to Flecainide

  4 weeks

• Ventricular Tachycardia (VT) Burden

  7-day period

• Number of Atrial Premature Beats (APBs) Per Day

  7-day period

Study Arms (2)

Flecainide

ACTIVE COMPARATOR

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.

Drug: Flecainide Pill; Drug: Placebo

Placebo

PLACEBO COMPARATOR

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.

Drug: Flecainide Pill; Drug: Placebo

Interventions

Flecainide Pill DRUG

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

Also known as: Tambocor

Flecainide; Placebo

Placebo DRUG

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

Flecainide; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Rochester: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (6)

University of Colorado

Denver, Colorado, 80045, United States

Location

John Hopkins University

Baltimore, Maryland, 21287, United States

Location

New York University

New York, New York, 10016, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

University of Pensylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (5)

• 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.

  PMID: 19560088 BACKGROUND

• 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.

  PMID: 20172911 BACKGROUND

• 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.

  PMID: 28052233 BACKGROUND

• 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.

  PMID: 28740174 BACKGROUND

• 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.

  PMID: 27939893 BACKGROUND

MeSH Terms

Conditions

Arrhythmogenic Right Ventricular Dysplasia

Interventions

Flecainide

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiomyopathies; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Wojciech Zareba
• Organization: University of Rochester

wojciech_zareba@urmc.rochester.edu

585-275-5391

Study Officials

• Wojciech Zareba, MD, PhD

  University of Rochester

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is double-blinded trial with all participants, investigators, and outcome assessors being blinded with except for the Data and Safety Monitoring Board (DSMB) members.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine/Cardiology

Model Details: This is a randomized double-blinded placebo-controlled crossover trial on the effect of flecainide on the frequency of ventricular arrhythmias of 38 ARVC patients. The crossover design requires a 10-week treatment with each patient receiving flecainide 100 mg bid and placebo for 4 weeks in a blinded randomized order.

Study Record Dates

• First Submitted: September 21, 2018
• First Posted: September 26, 2018
• Study Start: July 23, 2019
• Primary Completion: July 31, 2022
• Study Completion: July 31, 2022
• Last Updated: August 20, 2024
• Results First Posted: August 20, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)