Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia

• ClinicalTrials.gov Identifier: NCT01117454
• Recruitment Status: Completed
• First Posted: May 5, 2010
• Results First Posted: May 17, 2017
• Last Update Posted: June 14, 2017
• Sponsor: Vanderbilt University Medical Center
• Information provided by (Responsible Party): Prince Joseph Kannankeril, Vanderbilt University Medical Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Catecholaminergic Polymorphic Ventricular Tachycardia	Drug: Flecainide Acetate; Drug: Placebo; Drug: Beta blocker	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: A Prospective Randomized Crossover Trial of Oral Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
• Study Start Date: December 2011
• Actual Primary Completion Date: December 2015
• Actual Study Completion Date: December 2015

Arms and Interventions

Arm	Intervention/treatment
Flecainide then placebo; 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; oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml; Drug: Placebo; placebo, similar in appearance to flecainide; Drug: Beta blocker; Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial.
Placebo then flecainide; 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; oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml; Drug: Placebo; placebo, similar in appearance to flecainide; Drug: Beta blocker; Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial.

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Ventricular Ectopy or VT During Exercise Treadmill Testing [ Time Frame: 3 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 5 Years to 99 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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

2. Functioning ICD in place
3. 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:

1. Females who are pregnant or plan to be pregnant during the study period
2. Children < 5 years of age
3. Patients unable to perform treadmill exercise
4. Patients with significant structural heart disease
5. Patients with features consistent with Andersen-Tawil syndrome A. Periodic paralysis or unexplained weakness B. Dysmorphic facies C. Known KCNJ2 mutation
6. Patients with known hypersensitivity to flecainide
7. Patients on amiodarone
8. Patients not expected to comply with follow-up

Contacts and Locations

Locations

United States, California

University of California Los Angeles

Los Angeles, California, United States, 90095

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, New York

NYU Langone Medical Center

New York, New York, United States, 10010

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27705

East Carolina University

Greenville, North Carolina, United States, 27834

United States, Ohio

MetroHealth Medical Center

Cleveland, Ohio, United States, 44109

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37027

United States, Texas

Cook Children's Hospital

Fort Worth, Texas, United States, 76104

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

• Principal Investigator: Prince J Kannankeril, MD, MSCI; Vanderbilt University

More Information

Additional Information:

Full text of publication in JAMA Cardiology 

Publications:

Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009 Apr;15(4):380-3. doi: 10.1038/nm.1942. Epub 2009 Mar 29.

van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, Shimizu W, Sumitomo N, Fish FA, Bhuiyan ZA, Willems AR, van der Veen MJ, Watanabe H, Laborderie J, Haïssaguerre M, Knollmann BC, Wilde AA. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011 May 31;57(22):2244-54. doi: 10.1016/j.jacc.2011.01.026.

Kannankeril PJ, Moore JP, Cerrone M, Priori SG, Kertesz NJ, Ro PS, Batra AS, Kaufman ES, Fairbrother DL, Saarel EV, Etheridge SP, Kanter RJ, Carboni MP, Dzurik MV, Fountain D, Chen H, Ely EW, Roden DM, Knollmann BC. Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial. JAMA Cardiol. 2017 Jul 1;2(7):759-766. doi: 10.1001/jamacardio.2017.1320.

• Responsible Party: Prince Joseph Kannankeril, Principal Investigator, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT01117454
• Other Study ID Numbers: 100472
• First Posted: May 5, 2010
• Results First Posted: May 17, 2017
• Last Update Posted: June 14, 2017
• Last Verified: May 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Prince Joseph Kannankeril, Vanderbilt University Medical Center:

Catecholaminergic Polymorphic Ventricular Tachycardia; implantable cardioverter-defibrillator; flecainide

Additional relevant MeSH terms:

Tachycardia; Tachycardia, Ventricular; Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Pathologic Processes; Flecainide; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators