Pilot Randomized Trial With Flecainide in ARVC Patients

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).

Study Overview

• Status: Completed
• Conditions: Arrhythmogenic Right Ventricular Cardiomyopathy
• Intervention / Treatment: Drug: Flecainide Pill; Drug: Placebo

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. VPBs on ECG monitoring,
   2. nonsustained and sustained VT/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 VPBs 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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins University
  • New York
    • New York, New York, United States, 10016
      • New York University
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pensylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 VPBs 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, mexilitene, 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, CMRI, or cardiac nuclear test on the most recent test.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Flecainide Pill; Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each; Other Names: Tambocor; Drug: Placebo; Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each
Placebo Comparator: 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.	Drug: Flecainide Pill; Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each; Other Names: Tambocor; Drug: Placebo; Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of ventricular premature beats (VPBs)	Number of ventricular premature beats (VPBs) in a 7-day ECG recording	7-day period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proarrhythmic response to Flecainide	VPBs in 7-day ECG recording; nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator during 4-week treatment periods; QRS morphology and duration in ECG.	7-day period
VT burden	Number of VT runs recorded on 7-day ECG recording	7-day period
Number of atrial premature beats (APBs)	Number of atrial premature beats (APBs) in a 7-day ECG recording	7-day period
Ratio of eligible to enrolled participants	Number of eligible subjects to enrolled subjects	18-month period

Collaborators and Investigators

• Sponsor: Wojciech Zareba
• Investigators: Principal Investigator: Wojciech Zareba, MD, PhD, University of Rochester

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2019
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: September 21, 2018
• First Submitted That Met QC Criteria: September 24, 2018
• First Posted (Actual): September 26, 2018

Study Record Updates

• Last Update Posted (Actual): September 9, 2022
• Last Update Submitted That Met QC Criteria: September 8, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: implantable cardioverter-defibrillator; Flecainide; arrhythmogenic right ventricular cardiomyopathy; ARVC; ventricualr arrhythmias
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiomyopathies; Arrhythmogenic Right Ventricular Dysplasia; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Flecainide
• Other Study ID Numbers: HL143372-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: This is a small pilot trial with limited dataset which will be mostly explored by enrolling center investigators.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No