Catecholaminergic Polymorphic Ventricular Tachycardia
Conditions
Keywords
Catecholaminergic Polymorphic Ventricular Tachycardia, implantable cardioverter-defibrillator, flecainide
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.
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.
Interventions
oral flecainide with the dose titrated to achieve a serum level between 0.5-0.8 mcg/ml
DRUGPlacebo
placebo, similar in appearance to flecainide
DRUGBeta blocker
Standard therapy with beta-blocker (nadolol, atenolol, metoprolol, or propranolol) continues throughout the trial.
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
5 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Ventricular Ectopy or VT During Exercise Treadmill Testing | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 6 |
| 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 | 8 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pregnancy | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Flecainide Then Placebo | Placebo Then Flecainide |
|---|---|---|---|
| Age, Categorical <=18 years | 10 Participants | 3 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 14 participants | 6 participants | 8 participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 11 / 13 | 6 / 13 |
| serious Total, serious adverse events | 2 / 13 | 2 / 13 |
Outcome results
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.
Time frame: 3 months
Population: 1 participant did not complete treadmill test
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Flecainide | Number of Patients With Ventricular Ectopy or VT During Exercise Treadmill Testing | 2 Participants |
| Placebo | Number of Patients With Ventricular Ectopy or VT During Exercise Treadmill Testing | 9 Participants |
p-value: 0.008Wilcoxon (Mann-Whitney)