Arrhythmogenic Right Ventricular Cardiomyopathy
Conditions
Keywords
arrhythmogenic right ventricular cardiomyopathy, ARVC, Flecainide, ventricular arrhythmias, implantable cardioverter-defibrillator
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.
Interventions
DRUGFlecainide Pill
Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each
DRUGPlacebo
Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is double-blinded trial with all participants, investigators, and outcome assessors being blinded with except for the Data and Safety Monitoring Board (DSMB) members.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ventricular Ectopic Beats (VEBs) Per Day | 7-day period | Number of ventricular ectopic beats (VEBs) per day in a 7-day ECG recording |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Proarrhythmic Response to Flecainide | 4 weeks | Nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator (ICD) during 4-week treatment periods. |
| Ventricular Tachycardia (VT) Burden | 7-day period | Number of VT runs/episodes recorded per day on a 7-day ECG recording |
| Number of Atrial Premature Beats (APBs) Per Day | 7-day period | Number of atrial premature beats (APBs) per day in a 7-day ECG recording |
Countries
United States
Participant flow
Recruitment details
There were 7 enrolling sites in the study. Recruitment took place at 6 enrolling sites between July 23, 2019 and May 2, 2022.
Participants by arm
| Arm | Count |
|---|---|
| Placebo, Then Flecainide Participants first received Placebo pill (matching Flecainide 100 mg) twice a day for 4 weeks. After a washout period of 1 week, they then received Flecainide pill (100 mg) twice a day for 4 weeks with subsequent 1 week of washout. | 11 |
| Flecainide, Then Placebo Participants first received Flecainide pill (100 mg) twice a day for 4 weeks. After a washout period of 1 week, they then received Placebo pill (matching Flecainide 100 mg) twice a day for 4 weeks, with subsequent 1 week of washout. | 11 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (4 Weeks) | Adverse Event | 0 | 2 |
| First Intervention (4 Weeks) | Withdrawal by Subject | 1 | 0 |
| Second Intervention (4 Weeks) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo, Then Flecainide | Flecainide, Then Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 47 years STANDARD_DEVIATION 13 | 43 years STANDARD_DEVIATION 14 | 45 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 11 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 11 Participants | 22 Participants |
| Region of Enrollment United States | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 22 |
| other Total, other adverse events | 7 / 22 | 2 / 22 |
| serious Total, serious adverse events | 1 / 22 | 1 / 22 |
Outcome results
Primary
Number of Ventricular Ectopic Beats (VEBs) Per Day
Number of ventricular ectopic beats (VEBs) per day in a 7-day ECG recording
Time frame: 7-day period
Population: 18 subjects had ECG recordings on placebo and 18 had on flecainide, with 2 recordings missing, 17 subjects had both recordings
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Number of Ventricular Ectopic Beats (VEBs) Per Day | 2685 number of VEBs per day |
| Flecainide | Number of Ventricular Ectopic Beats (VEBs) Per Day | 677 number of VEBs per day |
p-value: <0.000195% CI: [56, 82]Mixed Models Analysis
Secondary
Number of Atrial Premature Beats (APBs) Per Day
Number of atrial premature beats (APBs) per day in a 7-day ECG recording
Time frame: 7-day period
Population: 18 subjects had ECG recordings on placebo and 18 had on flecainide, with 2 recordings missing, 17 subjects had both recordings
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Number of Atrial Premature Beats (APBs) Per Day | 32 number of APBs per day |
| Flecainide | Number of Atrial Premature Beats (APBs) Per Day | 8 number of APBs per day |
p-value: 0.207Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With Proarrhythmic Response to Flecainide
Nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator (ICD) during 4-week treatment periods.
Time frame: 4 weeks
Population: 19 subjects had data regarding ICD-documented arrhythmias
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Proarrhythmic Response to Flecainide | 3 Participants |
| Flecainide | Number of Participants With Proarrhythmic Response to Flecainide | 3 Participants |
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Ventricular Tachycardia (VT) Burden
Number of VT runs/episodes recorded per day on a 7-day ECG recording
Time frame: 7-day period
Population: 18 subjects had ECG recordings on placebo and 18 had on flecainide, with 2 recordings missing, 17 subjects had both recordings
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ventricular Tachycardia (VT) Burden | 0.4 number of VTs per day | Standard Deviation 0.5 |
| Flecainide | Ventricular Tachycardia (VT) Burden | 0 number of VTs per day | Standard Deviation 0.1 |
p-value: 0.009Wilcoxon (Mann-Whitney)