Back to resultsPilot Randomized Trial With Flecainide in ARVC Patients
Primary Purpose
Arrhythmogenic Right Ventricular Cardiomyopathy
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Flecainide Pill
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Arrhythmogenic Right Ventricular Cardiomyopathy focused on measuring arrhythmogenic right ventricular cardiomyopathy, ARVC, Flecainide, ventricualr arrhythmias, implantable cardioverter-defibrillator
Eligibility Criteria
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 VPBs 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, mexilitene, 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, CMRI, or cardiac nuclear test on the most recent test.
- 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.
Sites / Locations
- University of Colorado
- John Hopkins University
- New York University
- University of Rochester Medical Center
- Duke University
- University of Pensylvania
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Flecainide
Placebo
Arm Description
The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.
The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.
Outcomes
Primary Outcome Measures
Number of ventricular premature beats (VPBs)
Number of ventricular premature beats (VPBs) in a 7-day ECG recording
Secondary Outcome Measures
Proarrhythmic response to Flecainide
VPBs in 7-day ECG recording; nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator during 4-week treatment periods; QRS morphology and duration in ECG.
VT burden
Number of VT runs recorded on 7-day ECG recording
Number of atrial premature beats (APBs)
Number of atrial premature beats (APBs) in a 7-day ECG recording
Ratio of eligible to enrolled participants
Number of eligible subjects to enrolled subjects
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03685149
Brief Title
Pilot Randomized Trial With Flecainide in ARVC Patients
Official Title
Pilot Randomized Trial With Flecainide in ARVC Patients
Study Type
Interventional
2. Study Status
Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
July 31, 2019 (Actual)
Primary Completion Date
July 31, 2022 (Actual)
Study Completion Date
July 31, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Wojciech Zareba
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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:
to assess safety of flecainide administration with particular emphasis on proarrhythmic response measured by:
VPBs on ECG monitoring,
nonsustained and sustained VT/VF episodes documented on ICD interrogation, and
effects of Flecainide on QRS morphology and duration.
to assess effects of flecainide on burden of VT runs in 7-day ECG recordings.
to assess effects of flecainide on burden of atrial premature beats in 7-day recordings.
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 VPBs 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arrhythmogenic Right Ventricular Cardiomyopathy
Keywords
arrhythmogenic right ventricular cardiomyopathy, ARVC, Flecainide, ventricualr arrhythmias, implantable cardioverter-defibrillator
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
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.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
This is double-blinded trial with all participants, investigators, and outcome assessors being blinded with except for DSMB members.
Allocation
Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Flecainide
Arm Type
Active Comparator
Arm Description
The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
The same subjects will be treated in a random order with flecainide or placebo for 4 weeks each with 1 week washout between crossover periods.
Intervention Type
Drug
Intervention Name(s)
Flecainide Pill
Other Intervention Name(s)
Tambocor
Intervention Description
Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each
Primary Outcome Measure Information:
Title
Number of ventricular premature beats (VPBs)
Description
Number of ventricular premature beats (VPBs) in a 7-day ECG recording
Time Frame
7-day period
Secondary Outcome Measure Information:
Title
Proarrhythmic response to Flecainide
Description
VPBs in 7-day ECG recording; nonsustained and sustained ventricular tachycardia and ventricular fibrillation recorded by implantable cardioverter-defibrillator during 4-week treatment periods; QRS morphology and duration in ECG.
Time Frame
7-day period
Title
VT burden
Description
Number of VT runs recorded on 7-day ECG recording
Time Frame
7-day period
Title
Number of atrial premature beats (APBs)
Description
Number of atrial premature beats (APBs) in a 7-day ECG recording
Time Frame
7-day period
Title
Ratio of eligible to enrolled participants
Description
Number of eligible subjects to enrolled subjects
Time Frame
18-month period
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 VPBs 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, mexilitene, 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, CMRI, or cardiac nuclear test on the most recent test.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wojciech Zareba, MD, PhD
Organizational Affiliation
University of Rochester
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
John Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
New York University
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
University of Pensylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
This is a small pilot trial with limited dataset which will be mostly explored by enrolling center investigators.
Citations:
PubMed Identifier
19560088
Citation
Marcus FI, Zareba W, Calkins H, Towbin JA, Basso C, Bluemke DA, Estes NA 3rd, Picard MH, Sanborn D, Thiene G, Wichter T, Cannom D, Wilber DJ, Scheinman M, Duff H, Daubert J, Talajic M, Krahn A, Sweeney M, Garan H, Sakaguchi S, Lerman BB, Kerr C, Kron J, Steinberg JS, Sherrill D, Gear K, Brown M, Severski P, Polonsky S, McNitt S. Arrhythmogenic right ventricular cardiomyopathy/dysplasia clinical presentation and diagnostic evaluation: results from the North American Multidisciplinary Study. Heart Rhythm. 2009 Jul;6(7):984-92. doi: 10.1016/j.hrthm.2009.03.013. Epub 2009 Mar 11.
Results Reference
background
PubMed Identifier
20172911
Citation
Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010 Apr 6;121(13):1533-41. doi: 10.1161/CIRCULATIONAHA.108.840827. Epub 2010 Feb 19.
Results Reference
background
PubMed Identifier
28052233
Citation
Corrado D, Link MS, Calkins H. Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med. 2017 Jan 5;376(1):61-72. doi: 10.1056/NEJMra1509267. No abstract available.
Results Reference
background
PubMed Identifier
28740174
Citation
Cerrone M, Montnach J, Lin X, Zhao YT, Zhang M, Agullo-Pascual E, Leo-Macias A, Alvarado FJ, Dolgalev I, Karathanos TV, Malkani K, Van Opbergen CJM, van Bavel JJA, Yang HQ, Vasquez C, Tester D, Fowler S, Liang F, Rothenberg E, Heguy A, Morley GE, Coetzee WA, Trayanova NA, Ackerman MJ, van Veen TAB, Valdivia HH, Delmar M. Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun. 2017 Jul 24;8(1):106. doi: 10.1038/s41467-017-00127-0.
Results Reference
background
PubMed Identifier
27939893
Citation
Ermakov S, Gerstenfeld EP, Svetlichnaya Y, Scheinman MM. Use of flecainide in combination antiarrhythmic therapy in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2017 Apr;14(4):564-569. doi: 10.1016/j.hrthm.2016.12.010. Epub 2016 Dec 9.
Results Reference
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Pilot Randomized Trial With Flecainide in ARVC Patients
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