Pilot Randomized Trial With Flecainide in ARVC Patients

Study Overview
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Brief Summary
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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
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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: to assess safety of flecainide administration with particular emphasis on proarrhythmic response measured by: VPBs on ECG monitoring, nonsustained and sustained VT/VF episodes documented on ICD interrogation, and effects of Flecainide on QRS morphology and duration. to assess effects of flecainide on burden of VT runs in 7-day ECG recordings. to assess effects of flecainide on burden of atrial premature beats in 7-day recordings. 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.

Official Title
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Pilot Randomized Trial With Flecainide in ARVC Patients

Conditions
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Arrhythmogenic Right Ventricular Cardiomyopathy

Intervention / Treatment
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* Drug: Flecainide Pill
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Flecainide<br>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<br>* Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each<br>* Other names: Tambocor;Drug: Placebo<br>* Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each<br>|
| Placebo Comparator: Placebo<br>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<br>* Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each<br>* Other names: Tambocor;Drug: Placebo<br>* Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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arrhythmogenic right ventricular cardiomyopathy, ARVC, Flecainide, ventricualr arrhythmias, implantable cardioverter-defibrillator