Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia

Study Overview
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Brief Summary
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The purpose of this study is to test whether the addition of oral flecainide to standard therapy will reduce ventricular ectopy on exercise test compared to placebo plus standard therapy in patients with Catecholaminergic Polymorphic Ventricular Tachycardia.

Detailed Description
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Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a genetic arrhythmia syndrome characterized by frequent ventricular ectopy and polymorphic, classically bidirectional ventricular tachycardia with physical or emotional stress, which also carries a risk of ventricular fibrillation and sudden death, despite no structural heart abnormality. Treatment consists of beta-blockers and/or calcium channel blockers, but up to 30% of patients require implantable cardioverter-defibrillators (ICDs) due to recurrent symptoms on medical therapy. In an animal model, flecainide was found to directly target the molecular defect in CPVT. In a retrospective clinical study in patients with CPVT we have seen improvement of ventricular ectopy on exercise tests when flecainide is added to standard therapy. We propose a prospective trial of flecainide added to standard therapy in CPVT patients to test the hypothesis that flecainide will reduce ventricular ectopy on exercise testing compared to placebo plus standard therapy. This will be a single-blind (blinded subjects) randomized cross-over study, in which each patient will receive treatment A (flecainide or placebo) for at least 3 months and, after a 1 week wash-out, treatment B (placebo or flecainide) for at least 3 months.

Official Title
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A Prospective Randomized Crossover Trial of Oral Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia

Conditions
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Catecholaminergic Polymorphic Ventricular Tachycardia

Intervention / Treatment
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* Drug: Flecainide Acetate
* Drug: Placebo
* Drug: Beta blocker


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of CPVT, based on: A. reproducible polymorphic or bidirectional ventricular tachycardia with exercise OR B. Ventricular ectopy on exercise test with RYR2 or CASQ2 mutation Functioning ICD in place On stable dose of standard therapy defined as the maximal tolerated dose of beta-blocker and may include a calcium channel blocker Patients on flecainide or mexiletine are also eligible for enrollment after a 1 week washout period during which flecainide or mexiletine is discontinued, and standard therapy alone is used. Exclusion Criteria: Females who are pregnant or plan to be pregnant during the study period Children < 5 years of age Patients unable to perform treadmill exercise Patients with significant structural heart disease Patients with features consistent with Andersen-Tawil syndrome A. Periodic paralysis or unexplained weakness B. Dysmorphic facies C. Known KCNJ2 mutation Patients with known hypersensitivity to flecainide Patients on amiodarone Patients not expected to comply with follow-up

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 99 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Flecainide then placebo<br>In this crossover study, half of the subjects will be randomized to flecainide plus standard therapy with beta-blockers first, then crossover to placebo plus standard therapy with beta-blockers. | Drug: Flecainide Acetate<br>* oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml<br>Drug: Placebo<br>* placebo, similar in appearance to flecainide<br>Drug: Beta blocker<br>* Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial.<br>|
| Other: Placebo then flecainide<br>In this crossover study, half of the subjects will be randomized to placebo plus standard therapy with beta-blockers first, then crossover to flecainide plus standard therapy with beta-blockers. | Drug: Flecainide Acetate<br>* oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml<br>Drug: Placebo<br>* placebo, similar in appearance to flecainide<br>Drug: Beta blocker<br>* Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Ventricular Ectopy or VT During Exercise Treadmill Testing | Hypothesis: the addition of oral flecainide to standard therapy will reduce ventricular ectopy and/or VT on treadmill exercise treadmill testing in patients with CPVT, compared to placebo plus standard therapy. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Catecholaminergic Polymorphic Ventricular Tachycardia, implantable cardioverter-defibrillator, flecainide