Pilot Randomized Trial With Flecainide in ARVC Patients

Phase 2

Completed

Conditions: Arrhythmogenic Right Ventricular Cardiomyopathy

Interventions: Drug: Flecainide Pill
Drug: Placebo

Registration Number: NCT03685149

Lead Sponsor: University of Rochester

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Flecainide Pill	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.
Flecainide	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.
Placebo	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.
Flecainide	Flecainide Pill	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.

Primary Outcome Measures

Name	Time	Method
Number of Ventricular Ectopic Beats (VEBs) Per Day	7-day period	Number of ventricular ectopic beats (VEBs) per day in a 7-day ECG recording

Secondary Outcome Measures

Name	Time	Method
Number of Atrial Premature Beats (APBs) Per Day	7-day period	Number of atrial premature beats (APBs) per day in a 7-day ECG recording
Number of Participants With Proarrhythmic Response to Flecainide	4 weeks	Nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator (ICD) during 4-week treatment periods.
Ventricular Tachycardia (VT) Burden	7-day period	Number of VT runs/episodes recorded per day on a 7-day ECG recording

Trial Locations

Locations (6): John Hopkins University
🇺🇸
Baltimore, Maryland, United States
University of Pensylvania
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Philadelphia, Pennsylvania, United States
University of Colorado
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Denver, Colorado, United States
University of Rochester Medical Center
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Rochester, New York, United States
Duke University
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Durham, North Carolina, United States
New York University
🇺🇸
New York, New York, United States