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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Flecainide then placebo | Other | 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. |
|
| Placebo then flecainide | Other | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Flecainide Acetate | Drug | oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml |
|
| 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 |
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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:
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| Name | Affiliation | Role |
|---|---|---|
| Prince J Kannankeril, MD, MSCI | Vanderbilt University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California Los Angeles | Los Angeles | California | 90095 | United States | ||
| Children's Hospital of Orange County |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19330009 | Background | 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. | |
| 21616285 | Background | 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, Haissaguerre 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Flecainide Then Placebo | In this crossover study, half of the subjects will be randomized to flecainide plus standard therapy first, then crossover to placebo plus standard therapy. flecainide: oral flecainide will be added to standard therapy with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Placebo | Drug | placebo, similar in appearance to flecainide |
|
| Beta blocker | Drug | Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial. |
|
| Orange |
| California |
| 92868 |
| United States |
| NYU Langone Medical Center | New York | New York | 10010 | United States |
| Duke University | Durham | North Carolina | 27705 | United States |
| East Carolina University | Greenville | North Carolina | 27834 | United States |
| MetroHealth Medical Center | Cleveland | Ohio | 44109 | United States |
| Nationwide Children's Hospital | Columbus | Ohio | 43205 | United States |
| Vanderbilt University | Nashville | Tennessee | 37027 | United States |
| Cook Children's Hospital | Fort Worth | Texas | 76104 | United States |
| University of Utah | Salt Lake City | Utah | 84112 | United States |
| 28492868 | Background | 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. |
| Placebo Then Flecainide |
In this crossover study, half of the subjects will be randomized to placebo plus standard therapy first, then crossover to flecainide plus standard therapy. flecainide: oral flecainide will be added to standard therapy with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Flecainide Then Placebo | In this crossover study, half of the subjects will be randomized to flecainide plus standard therapy first, then crossover to placebo plus standard therapy. flecainide: oral flecainide will be added to standard therapy with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml |
| BG001 | Placebo Then Flecainide | In this crossover study, half of the subjects will be randomized to placebo plus standard therapy first, then crossover to flecainide plus standard therapy. flecainide: oral flecainide will be added to standard therapy with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 1 participant did not complete treadmill test | Posted | Count of Participants | Participants | 3 months |
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Participants were followed for the duration of the study, an average of 26 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Flecainide | All participants when receiving flecainide | 0 | 13 | 2 | 13 | 11 | 13 |
| EG001 | Placebo | All participants when receving placebo | 0 | 13 | 2 | 13 | 6 | 13 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Suicidal Ideation | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Implantable Cardioverter-Defibrillator Infection | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Back pain requiring Surgery | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Allergic Reaction requiring Hospitalization | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Supraventricular Tachycardia | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Vasovagal Syncope | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Headache | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| Musculoskelatal Injury | Injury, poisoning and procedural complications | CTCAE (4.0) | Systematic Assessment |
| |
| lightheadedness | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| palpitations | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| dizziness | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
| |
| phantom shock | Psychiatric disorders | CTCAE (4.0) | Systematic Assessment |
| |
| anorexia | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| fatigue | General disorders | CTCAE (4.0) | Systematic Assessment |
| |
| blurry vision | Eye disorders | CTCAE (4.0) | Systematic Assessment |
| |
| constipation | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
| |
| influenza | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
| |
| insominia | General disorders | CTCAE (4.0) | Systematic Assessment |
| |
| left side pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Hypertension | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| |
| Hypotension | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Prince J. Kannankeril, MD, MSCI | Vanderbilt University Medical Center | 615 322-7447 | prince.kannankeril@vanderbilt.edu |
| ID | Term |
|---|---|
| D000098850 | Polymorphic Catecholaminergic Ventricular Tachycardia |
| ID | Term |
|---|---|
| D017180 | Tachycardia, Ventricular |
| D013610 | Tachycardia |
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D000075224 | Cardiac Conduction System Disease |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D005424 | Flecainide |
| D000319 | Adrenergic beta-Antagonists |
| ID | Term |
|---|---|
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D018674 | Adrenergic Antagonists |
| D018663 | Adrenergic Agents |
| D018377 | Neurotransmitter Agents |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D045505 | Physiological Effects of Drugs |
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| >=65 years |
|
| Male |
|