Clinical trial NCT03685149: Pilot Randomized Trial With Flecainide in ARVC Patients
Official title: Pilot Randomized Trial With Flecainide in ARVC Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Arrhythmogenic Right Ventricular Cardiomyopathy
Keywords: arrhythmogenic right ventricular cardiomyopathy
ARVC
Flecainide
ventricular arrhythmias
implantable cardioverter-defibrillator
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2018-09-26
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Ventricular Ectopic Beats (VEBs) Per Day
timeFrame: 7-day period
Secondary outcomes:
measure: Number of Participants With Proarrhythmic Response to Flecainide
timeFrame: 4 weeks
measure: Ventricular Tachycardia (VT) Burden
timeFrame: 7-day period
measure: Number of Atrial Premature Beats (APBs) Per Day
timeFrame: 7-day period
Other outcomes:
Locations:
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: New York
country: United States
facility: New York University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pensylvania
state: Pennsylvania
Study officials:
affiliation: University of Rochester
name: Wojciech Zareba, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.