Conditions: Arrhythmogenic Right Ventricular Cardiomyopathy
Keywords: arrhythmogenic right ventricular cardiomyopathy ARVC Flecainide ventricular arrhythmias implantable cardioverter-defibrillator
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 22
Healthy volunteers: no

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.

Arms:
arm 1: 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 2: 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.

Interventions: intervention 1: Flecainide Pill intervention 2: Placebo
Intervention descriptions: intervention 1: Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each intervention 2: Flecainide pill or placebo 100 mg administered twice a day for 4 weeks each

Protocol document:
Prot_SAP_000.pdf: 
Version 2.0   December 4, 2018         RSRB00073590 
 
Page 1 of 26 
 
 
 
Effects of Flecainide on Cardiac Arrhythmias in 
 ARVC Patients 
 
 
 
Sponsor: 
University of Rochester 
 
Clinical Trials.gov: 
NCT 03685149 
 
Funding Body: 
 
NHLBI 
 
Indication: 
 
Patients with ARVC and ventricular arrhythmias 
 
Intervention: 
 
Flecainide 
 
Study Type:  
 
Randomized clinical trial 
 
Principal Investigator: 
 
Wojciech Zareba, MD, PhD, FACC, FESC 
Clinical Cardiovascular Research Center 
University of Rochester Medical Center 
265 Crittenden Blvd., CU 420653  
Rochester, NY 14642 
 
 
Study Manager: 
 
Kathryn Pyykkonen, R.N., MS 
Clinical Cardiovascular Research Center 
University of Rochester Medical Center 
265 Crittenden Blvd., CU 420653  
Rochester, NY 14642 
 
 
Protocol Version/Date: 
 
Version 2.0 / December 4, 2018 
 
 
 
 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 2 of 26 
 
Abbreviations 
 
ARVC  –  
arrhythmogenic right ventricular cardiomyopathy 
 
CMRI – 
cardiac magnetic resonance imaging 
 
DCC 
– 
Data Coordinating Center  
 
ECG  –  
electrocardiogram 
 
ICD  
–  
implantable cardioverter-defibrillator 
 
IDS  
–  
Investigational Drug Services 
 
VF  
–  
ventricular fibrillation 
 
VPBs  –  
ventricular premature beats 
 
VT  
–  
ventricular tachycardia 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 3 of 26 
 
Table of Contents 
 
1. PURPOSE OF THE STUDY AND BACKGROUND 
6 
1.1.  Background 
6 
    1.1.1. Arrhythmogenic Right Ventricular Cardiomyopathy 
6 
    1.1.2. Antiarrhythmic Pharmacological Treatment in ARVC   
7 
    1.1.3. Flecainide 
8 
    1.1.4. Significance of Pilot Project 
9 
    1.2. Purpose of the Study 
10 
2. STUDY DESIGN 
10 
    2.1. Overview 
10 
    2.2. Rationale for Study Design 
10 
    2.3. Rationale for Dosage 
10 
3. CHARACTERISTICS OF THE RESEARCH POPULATION 
10 
    3.1. Subject Characteristics 
10 
    3.2. Inclusion and Exclusion Criteria 
11 
    3.3. Discussion of Subject Population 
12 
4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
12 
    4.1. Method of Subject Identification and Recruitment 
12 
    4.2. Process of Consent 
12 
5. METHODS and PROCEDURES 
12 
     Design of the Trial (Figure 4) 
12 
     Schedule of Activities (Table 2) 
13 
  5.1. Visits 
13 
       5.1.1. Visit 0: Subject Screening and Consent   
13 
     5.1.2. Visit 1: Randomization  
 
14 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 4 of 26 
 
    5.1.3. Visit 2: Phone visit 
14 
    5.1.4. Visit 3: Phone visit 
14 
    5.1.5. Visit 4: In person visit in home or in clinic 
15 
    5.1.6. Visit 5: Phone visit 
15 
    5.1.7. Visit 6: Phone visit 
15 
    5.1.8. Visit 7: Phone visit 
15 
    5.1.9. Visit 8: In person visit in home or in clinic 
15 
    5.1.10. Visit 9: Phone visit 
16 
    5.1.11. Visit 10: Phone visit 
16 
   5.2. Treatment Dosage and Administration 
16 
   5.3. Efficacy Assessments 
16 
   5.4 Safety Assessments 
16 
   5.5. Assessment of Subject Compliance 
17 
   5.6. Costs to the Subject 
17 
   5.7. Payment for Participation 
 
17 
   5.8. Return of Individual Research Results 
17 
6. CONCOMITANT AND DISALLOWED MEDICATIONS 
 
17 
7. SUBJECT WITHDRAWALS 
 
17 
8. STUDY DRUG ADMINISTRATION/ASSIGNMENT 
 
17 
    8.1. Study Drug 
 
17 
    8.2. Dosage of Study Drug 
 
18 
    8.3. Subject Enrollment/Randomization 
 
18 
    8.4. Accountability of Investigational Supplies 
 
18 
    8.5. Subject Withdrawal of Study Drug 
 
18 
    8.6. Emergency Drug Disclosure 
 
18 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 5 of 26 
 
9. DEVIATIONS 
18 
10. SAFETY AND REPORTABLE EVENTS 
19 
     10.1. Adverse Event Definition 
 
19 
     10.1.1. Serious Adverse Event 
 
19 
     10.1.2. Unexpected Adverse Drug Experience 
 
19 
     10.2. Recording Adverse Events 
 
19 
     10.3. Responsibilities for Reporting Serious/Unexpected Adverse Events 
 
20 
11. RISK/BENEFIT ASSESSMENT 
 
20 
     11.1. Potential Risks  
20 
     11.1.1 Potential Risks to Patients Undergoing Treatment with Flecainide 
20 
     11.1.2  Blood Draw 
21 
     11.1.3  ECG, Zio Patch and Holter Monitor 
21 
     11.1.4 Loss of Confidentiality 
21 
     11.1.5 Pregnancy 
21 
     11.2. Protection Against Risks 
 
21 
     11.3. Potential Benefits to Subjects 
 
21 
     11.4. Alternatives to Participation 
 
21 
12. CONFIDENTIALITY OF DATA AND INFORMATION STORAGE  
 
22 
13.  RESEARCH INFORMATION IN MEDICAL RECORDS 
 
22 
14. DATA ANALYSIS AND MONITORING 
22 
     14.1. Sample Size Determination 
 
22 
     14.2. Planned Statistical Analysis 
 
23 
     14.3. Data and Safety Monitoring  
23 
  15. REFERENCES 
 
24 
 
 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 6 of 26 
 
1.   PURPOSE OF THE STUDY AND BACKGROUND 
 
1.1.   Background 
 
1.1.1. Arrhythmogenic Right Ventricular Cardiomyopathy  
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy 
characterized by fibrofatty replacement primarily of right ventricular muscle. The resultant 
heterogeneous structure of the RV myocardium results in ventricular arrhythmias, including 
ventricular premature beats (VPBs), nonsustained or sustained ventricular tachycardia (VT) or 
ventricular fibrillation (VF). ARVC is uncommon disorder (1 in 5000 individuals) but may account 
for up to 20% of cases of sudden death among young individuals (Marcus et al. 1982, Calkins 
2013, Corrado 2017).  As shown in Figure 1 from the Johns Hopkins and the Dutch ARVC 
registries described by Bhonsale et al. (2015), about 60% pf ARVC patients develop life-
threatening arrhythmic event or SCD by the age of 30 years.  Figure 2 from an Italian cohort 
described by Mazzanti et al. (2016), about 20% died from cardiovascular causes by the age of 30 
years. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3 from the North American ARVC Registry, which enrolled newly diagnosed ARVC 
patients, showed that about 40-50% of men and women with ARVC and implanted ICD developed 
arrhythmic events or did die within 2 years after implant of the device. The risk of fast VT, VF or 
Figure 2: The risk of cardiovascular death in 198 
ARVC patients (Mazzanti, et al. 2016). 
Figure 1: The risk of sustained arrhythmias or SCD 
in 200 ARVC patients with single and 15 patients 
with double mutations (Bhonsale 2015). 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 7 of 26 
 
death is higher in males than females: 27% vs. 11%, respectively at 2 years (Choudhary et al. 
2016). The John Hopkins and Dutch registries showed significantly higher lifetime risk of 
sustained arrhythmias or SCD in 312 males than in 256 females (Bhonsale et al. 2015). 
 
 
 
 
 
 
 
ARVC is caused by mutations in the genes encoding for desmosomal proteins which are 
found in about 50% of patients (Groeneweg et al. 2015). In the remaining 50%, genes are 
unknown. Desmosomal genes include: plakophilin-2 (PKP2), plakoglobin, desmoplakin, 
desmoglein-2, and desmocollin-2 but mutations in several non-desmosomal genes including 
phospholamban and TMEM43-encoding transmembrane protein 43 have also been reported to 
cause ARVC (Bhonsale et al. 2015, Groeneweg et al. 2015). In the Johns Hopkins and the Dutch 
ARVC registry, among 575 ARVC patients with known mutations 463, (80%) carried a single copy 
of a PKP2 mutations (Bhonsale et al. 2015).   
 
Prevention of sudden cardiac death with implantable cardioverter defibrillator (ICD) is the 
primary management in ARVC. Several studies of ARVC patients who received an ICD showed 
appropriate interventions during follow-up in about 50% of patients (Dalal et al. 2005, Corrado et 
al. 2010, Bhonsale et al. 2011, Link et al. 2014). Of these, approximately 40% were considered 
life-saving based on the presence of rapid VT/VF with a rate of >240 bpm. Predictors of 
appropriate therapy included previous VF arrest, syncope, severe RV dilation, LV dysfunction, 
young age, and definite disease by Task Force criteria. However, ICD therapy does not reduce 
the frequency of recurrent arrhythmias and antiarrhythmic pharmacological therapy or catheter 
ablation of VT is prescribed to diminish the risk of arrhythmic events and death. Frequent shocks 
are associated with psychological effects and decreased quality of life and every effort needs to 
be made to reduce their frequency.    
 
1.1.2. Antiarrhythmic Pharmacological Treatment in ARVC   
 
Beta-blockers are currently recommended for all patients with ARVC, for both prevention 
of arrhythmias and reduction of right ventricular wall stress (Corrado et al. 2015). In patients with 
ventricular arrhythmias, antiarrhythmic drug therapy offers the potential to ameliorate symptoms, 
although there is no proof that it confers protection against sudden cardiac death (Ermakov and 
Scheinman 2015, Corrado 2017). Analysis of the effects of antiarrhythmic medications in 95 
patients from the North American ARVC Registry (Marcus G et al. 2009) showed that 61% 
received beta-blockers, and these medications were not associated with an increased or 
decreased risk of ventricular arrhythmias. Sotalol was associated with a greater risk of any 
clinically relevant ventricular arrhythmia as defined by sustained ventricular tachycardia or ICD 
therapy (hazard ratio [HR]: 2.55, p=0.045), but this was not statistically significant after adjusting 
Figure 3: The risk of VT/VF or death in ARVC patients 
with ICD’s by sex (Choudhary, et. al. 2016). 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 8 of 26 
 
for potential confounders. An increased risk of any ICD shock and first clinically relevant 
ventricular arrhythmia while the patients were taking sotalol remained significant after 
multivariable adjustment. Amiodarone seemed to be more effective but there were only 10 
patients receiving this medication. An independent analysis of a large cohort from Italy (Mazzanti 
et al. 2016) showed that none of the arrhythmic medications had a beneficial effect on the rate of 
events when comparing matched periods before and after administered drugs (Table 1). There is 
no good data indicating that common antiarrhythmic medications reduce VT/VF in ARVC patients. 
The same is true for catheter ablation in the analysis shown in Table 1; although some data show 
that catheter ablation might reduce VTs in select patients (Riley et al. 2010, Santangeli et al. 
2015). Therefore there is a great need to explore the efficacy of other antiarrhythmic medications. 
Experimental data on flecainide are promising. 
 
 
 
 
 
 
1.1.3. Flecainide 
Flecainide is a class 1C antiarrhythmic drug that blocks sodium channels. Flecainide is 
used to suppress cardiac tachyarrhythmias including paroxysmal atrial fibrillation and 
supraventricular tachycardia. Flecainide is also used to treat LQT3 patients and patients with 
Ca2+-mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). Flecainide can 
have proarrhythmic effects after myocardial infarction (Echt et al. 1991). These divergent actions 
result from its physiological and pharmacological actions at multiple, levels of cellular organization 
(Salvage et al. 2017). These properties of flecainide were studied in murine genetic models with 
modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function 
(Watanabe et al. 2009). Flecainide accesses its transmembrane Nav1.5 channel binding site 
during activated, open states, producing a use-dependent antagonism. Closing either activation 
or inactivation gates traps flecainide within the pore. An early peak INa related to activation of 
Nav channels followed by rapid de-activation, causes action potential upstrokes and their 
propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav1.5 
channels, such as in the Brugada syndrome that may be exacerbated by flecainide. In contrast, 
the pro-arrhythmic effects attributed to prolonged action potential recovery by abnormal late INaL 
following gain-of-function modifications of Nav1.5 channels in LQT3 are reduced by flecainide. 
Anti-arrhythmic effects of flecainide that reduce triggering in CPVT mediated by sarcoplasmic 
reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing 
[Ca2+]i by a reduced [Na+]i and/or direct open state antagonism of the RyR2-Ca2+ channel. The 
consequent [Ca2+]i alterations could also modify action potential propagation velocity and 
therefore arrhythmic substrate through its actions on Nav1.5 channel function. This is consistent 
with the paradoxical differences between flecainide actions on Na+ currents, AP conduction and 
arrhythmogenesis under circumstances of normal and increased RyR2 function. 
Table 1: Matched- Periods Analysis for the Efficacy of Antiarrhythmic Drugs and Transcatheter 
Ablation (Mazzanti, et.al. 2016). 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 9 of 26 
 
In a small randomized trial flecainide was effective in reducing ventricular arrhythmias in 
patients with catecholaminergic polymorphic ventricular tachycardia, a condition linked to RyR2 
mutations causing increased SR release and triggered arrhythmias (Kannankeril 2017). This 
study reported a significant reduction of all forms of ventricular arrhythmias recorded during 
exercise in CPVT patients. ARVC patients show high prevalence of catecholamine-facilitated 
focal VT that is associated with ventricular premature beats observed at diagnosis and with 
induced sustained VT (Philips et al. 2013). Ventricular arrhythmogenicity during isoproterenol 
testing was further proven by Dr. Haissaguerre’s group from Bordeaux who demonstrated that 
induction of sustained and nonsustained VT episodes by isoproterenol was highly sensitive 
(91.4%) for ARVC diagnosis in 41 patients with the disorder and predictive of follow-up events 
(Denis et al. 2014).  
  
Experimental data using a novel murine model with cardiac-specific tamoxifen induced 
PKP2 deficiency indicate that enhanced triggered activity and increased sarcoplasmic reticulum 
(SR) calcium release via RyR2 channels could contribute to adrenergic-induced arrhythmias in 
an experimental model of ARVC (Cerrone et al. 2017, Van Opbergen et al. 2017). This study also 
reported that flecainide effectively prevented the arrhythmias observed in the experimental 
animals. Separate preclinical and anecdotal clinical reports also suggest that flecainide, probably 
through a block of the RyR2 receptor is a promising antiarrhythmic approach in ARVC. The 
arrhythmia burden was tested in 6 animals in the presence of a single dose of 40 mg/kg of 
flecainide (Cerrone et al, 2012). In contrast with results in untreated animals, flecainide-treated 
PKP2-cKO mice showed an absence of ISO-induced arrhythmia burden in the total recording 
period of 20 minutes. These results further support the notion that arrhythmias in PKP2-cKO 
animals may result from dysregulation of intracellular calcium cycling via increased RyR2-
dependent calcium release. 
  
Recent analysis of 8 ARVC patients with recurrent VT/VF events, who were treated with 
flecainide after several attempts with other antiarrhythmic medications, showed that 6 out of 8 of 
these patients had arrhythmias eliminated (Ermakov and Scheinman 2017). It is important to 
stress that patients with variants other than PKP2 and those cases with no known mutation 
responded to flecainide in this small series. 
Clinical data from the Johns Hopkins Registry (Orgeron et al. 2017), in 312 ARVC patients 
with ICDs showed that patients with ventricular flutter or VF had frequent VPBs ≥1000 /24 hours, 
with hazard ratio of 4.39 (p=0.016). Other predictors included syncope (HR: 1.85; p=0.021), age 
≤30 years at presentation (HR: 1.76; p=0.036), and male sex (HR: 1.73; p=0.046). Therefore, 
treatment with flecainide in patients with frequent VPBs will address a high-risk subset of patients. 
 
 
1.1.4. Significance of Pilot Project 
 
There is no known effective antiarrhythmic treatment in ARVC patients. Flecainide is a 
promising option, but there are no clinical trials to prove its efficacy and safety in ARVC patients. 
The pilot study will assess the effect of flecainide on cardiac arrhythmias detected by long-term 
ECG monitoring and will provide preliminary data that might lead to a larger study with  stringent 
endpoints consisting of ICD-documented VT, VF or death during long-term follow-up. Assessing 
safety of this therapy is of major importance in view of the results of the CAST trial that showed 
increased mortality in patients with ischemic heart disease treated with antiarrhythmic drugs 
including flecainide (Echt et al. 1991). This is the reason we are taking precautions of including 
only ARVC patients with ICDs and excluding patients with significant left ventricular dysfunction 
and significant heart failure, who constitute a small minority of ARVC patients. Importantly, as 
documented in the secondary analyses from the CAST trial, proarrhythmic effects of flecainide in 
studied patients with depressed or preserved ejection fraction was eliminated by concomitant 
administration of beta-blockers (Kennedy et al. 1994: Kennedy 1997). If the pilot study documents 
a significant reduction in ECG-recorded arrhythmias and if a subsequent trial show long-term 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 10 of 26 
 
effectiveness of this therapy, it would be a major therapy in the treatment of ARVC patients.   
  
1.2.   Purpose of the Study 
 
The primary specific aim of this pilot trial is to determine whether flecainide administration 
is associated with a significant reduction in the number of ventricular premature beats (VPBs) in 
ARVC patients with ICDs. 
 
The secondary aims are to: 
1) Assess safety of flecainide administration with particular emphasis on pro-arrhythmic 
response measured by: 
a. VPBs on ECG monitoring 
b. Nonsustained and sustained VT/VF episodes documented on ICD interrogation 
c. Effects of flecainide on QRS morphology and duration. 
2)  Assess the effects of flecainide on the number of VT runs in 7-day ECG recordings. 
3)  Assess the effects of flecainide on the frequency of atrial premature beats in 7-day ECG 
recordings. 
4)  To demonstrate feasibility of enrollment of rare arrhythmia ARVC patients in a randomized 
study in preparation for the planned future large clinical trial with VT/VF as the primary 
endpoint. 
 
 
 
 
2. STUDY DESIGN 
 
2.1. Overview 
 
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 in a 
blinded randomized order. 
 
2.2. Rationale for Study Design 
 
The cross over design of this study is suitable for the ARVC population, as the disease is 
chronic and the proposed intervention is not curative for the disease. The innovation of this trial 
is the concept of randomized trial in ARVC patients to test antiarrhythmic therapy. To date there 
has not been a randomized trial in ARVC patients to evaluate any therapy including ICD therapy, 
ventricular tachycardia ablation, or pharmacological drugs. As indicated, prior publications 
regarding pharmacological therapies including antiarrhythmic therapies have shown conflicting 
results.  
 
2.3. Rationale for Dosage 
 
Based on clinical experience and safety profile of flecainide a uniform dose of 100 mg of 
flecainide bid will be used. This dose is recommended in FDA-approved prescription information.  
This also was initial dose in the catecholaminergic polymorphic ventricular tachycardia trial 
although the median dose was 150mg bid (Kannankeril 2017).  In the study “Safety and efficacy 
of flecainide in subjects with Long QT-3 syndrome with delta KPQ mutation” (Moss et al. 2005) 
an average 100 mg per day dose produced significant effects on late sodium current that caused 
significant QTc shortening. 
 
3. CHARACTERISTICS OF THE RESEARCH POPULATION 
 
3.1. Subject Characteristics 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 11 of 26 
 
 
a) Number of Subjects: This trial will enroll 38 subjects at 10 enrolling sites who meet study 
inclusion and exclusion criteria as described in Section 3.2.  
b) Gender and Age of Subjects:  Male or female subjects aged 18 years or older.  
c) Racial and Ethnic Origin:  There are no restrictions on race or ethnicity in this study. 
 
3.2. Inclusion and Exclusion 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, may be included after 5 day washout period with subsequent 24-hour 
Holter obtained after washout period.  
- 
Persons prescribed sotalol may 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. 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 12 of 26 
 
3.3. Discussion of Subject Population 
         There is no known effective antiarrhythmic treatment in ARVC patients. Flecainide is a 
promising option, but there are no clinical trials to prove its efficacy and safety in these patients. 
The proposed pilot study to assess the effect of flecainide on cardiac arrhythmias detected by 
long-term ECG monitoring will provide preliminary data. Assessing safety of this therapy is of 
major importance in view of the results of the CAST trial that showed increased mortality in 
patients with ischemic heart disease after myocardial infarction treated with antiarrhythmic drugs 
including flecainide (Echt et al. 1991). To assure the safety of subjects the study is including only 
ARVC patients with ICDs and excluding patients with significant left ventricular dysfunction and 
significant heart failure, who constitute a small minority of ARVC patients. 
 
 
4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
 
4.1. Method of Subject Identification and Recruitment 
Subjects will be recruited from US enrolling centers.  
 
 
4.2. Process of Consent 
        The site investigator and/or study coordinator will consent subjects in this study. The consent 
document will be used as a guide for the verbal explanation of the study and will be the basis for 
a meaningful exchange between the investigator and the potential subject. The subject’s 
signature provides documentation of agreement to participate in a study, but is only one part of 
the consent process. The consent document will not serve as a substitute for discussion and the 
potential subject will be invited to ask any questions or concerns that will be answered by the 
study team members. Once a participant indicates that he or she does not want to take part in 
the research study, this process stops. The potential subject will be given sufficient opportunity to 
consider whether or not to participate. Refusal to take part or withdraw from the study at any time 
will not interfere with the future medical treatment of the potential subject. 
 
 
5. METHODS AND PROCEDURES 
 
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 
shown below requires a 10-week treatment with each patient receiving flecainide 100 mg bid for 
28 days and placebo for 28 days in a blinded randomized order. The Figure 4 and Table 2 below 
show the study design and the schedule of activities.  
 
 
 
 
    Flecainide 
         Washout                         Placebo      
Washout 
  
 
 
    
   
 
 
 
Screening/ 
Baseline  
R 
V3 
    
     V4         
            X      
 V6 
 
    V8 
 
           C 
 
  
   
 
    
 
          Placebo  
        Washout  
       Flecainide  
    Washout 
Weeks 
-4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
R  –  randomization  
 
V3 and V6  -  remote ICD Interrogation 
X  –  crossover, ICD interrogation  V4 and V8 –  in home with ECG, blood draw, 7 day ZIO-Patch 
             C  –  closeout, ICD interrogation 
 
 
 
 
Figure 4: Design of the trial. 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 13 of 26 
 
Table 2. Schedule of Activities. 
 
 
 
 
Visit 
0a 
Visit 
1a 
Visit 2 
Visit  
3 
Visit  
4 
Visit  
5 
Visit  
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit 
10 
 
Screen 
Ran-
domize 
Drug 
Initia-
tion 
 
 
 
Second 
Drug 
Bottle 
 
 
 
Close-
out 
Start Medication 
Weeks 
-4-0 
weeks 
-4-0 
weeks 
0 
1  
week  
+  2 
days 
3 
weeks 
+  2 
days 
4 
weeks 
+ 2 
days 
5 
weeks 
+ 2 
days 
6 
weeks 
+ 2 
days 
8 
weeks 
+ 2  
days 
9 
weeks 
+ 2 
days 
10 
weeks 
+ 2 
days 
In person visit 
Yes 
in 
clinic 
No 
No 
By 
phone 
 
No 
by 
phone 
In 
home 
or in 
clinicd 
No 
by 
phone 
No 
by 
phone 
No 
by 
phone 
In  
home 
or in 
clinicd 
No 
by 
phone 
No 
by 
phone 
Study Periods 
 
 
Period 1 
Period 2 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test b 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
Holter Monitor c 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample 
 
 
 
 
 
 
 
 
 
 
 
7-day ECG Monitor 
 
 
 
 
 
 
 
 
 
 
 
Remote ICD interrogation 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
 
 
 
 
 
 
 
 
 
 
 
Drug 
Dispense/Accountability  
 
 
 
 
 
 
 
 
 
 
 
Stop and return study drug 
and ZIO-Patch  
 
 
 
 
 
 
 
 
 
 
 
Study Closeout 
 
 
 
 
 
 
 
 
 
 
 
 
a - Visits 0 and 1 could be done on the same day.  
 
b - Pregnancy test must be obtained prior to randomization 
c – Holter Monitor for subjects have had a washout of antiarrhythmic therapy 
d - Visit at home will be done by specialized services with: ECG recording and blood draw; ZIO-Patch could be self-applied by 
subject or by study staff member. These visits could take place in a clinic if this is what subject and investigator are agreeable to.  
 
 
5.1. Visits 
       
5.1.1. Visit 0: Subject Screening and Consent   
 
Each potential subject will have inclusion and exclusion criteria verified by study personnel 
prior to approaching a potential subject for consent.  The consent process begins with the protocol 
described to them by one of the physicians or research coordinators at the enrolling site. Potential 
subjects will sit down with the coordinator or physician and have the opportunity to ask questions. 
Those who meet inclusion/exclusion criteria will then be asked to sign consent for study 
participation. At this time they will sign an “informed consent” form that is fully approved by the 
local IRB following local IRB consent administration regulations. It is the responsibility of the 
investigator to ensure that subjects are eligible to participate in the study prior to enrollment and 
throughout the study. Once informed consent has been obtained, all screening tests and 
procedures have been assessed and study eligibility has been confirmed, subjects will be 
assigned a unique subject identification number.  The enrolling site will enter data in the web base 
system and the system will assign the subject ID after study eligibility criteria are met. The scheme 
for assigning subject ID is as follow: first 2 numbers are assigned for enrolling site and will not 
change for duration of the study. Next two numbers are specific to a randomized subject in the 
enrolling site.  


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 14 of 26 
 
 
The principal investigator ensures that informed consent from each potential research 
participant will be obtained by an IRB approved consent designee and documented. The following 
persons may obtain consent:  the principal investigator, sub-investigators, or study team members 
listed on the IRB application form as a consent designee. Each individual who will interact with 
potential research participants to obtain consent will submit evidence of human subject 
compliance training per local IRB regulations.  
 
 
After written informed consent is obtained, a medical history and an ECG will be obtained 
from the subject. Any woman of childbearing age must have a negative pregnancy urine or blood 
test prior randomization, unless the woman is surgically sterile or post-menopausal (no menstrual 
periods for more than one year). Investigators will verify that subjects must use a medically 
acceptable method of birth control prior to study entry and while participating in the study. 
 
 
Subjects are expected to be on one of the following beta-blockers unless contraindicated: 
metoprolol, propranolol, atenolol, nadolol, carvedilol or bisoprolol. Subjects on antiarrhythmic 
medications including: sotalol, mexilitene, flecainide, quinidine, procainamide, propafenone, 
disopyramide, dronedarone, or phenytoin will require washout lasting a minimum of 5 days and a 
subsequent 24-hour Holter recording demonstrating at least 500 VPBs prior to being considered 
for randomization.  Study sites are provided with dedicated Holter recorders to be used if needed. 
Patients should return Holter recorders in person or by mail to the enrolling site personnel who 
will upload Holter files into the University of Rochester Box.com system for analysis. Enrolling 
centers will be informed about the results of 24-hour Holter analysis within 2 business days. 
Subjects not meeting eligibility criteria of at least 500 VPBs in 24-hour Holter after washout of 
medication used prior to the study drug initiation will be withdrawn and replaced.   
 
5.1.2. Visit 1: Randomization (Visit 1 could take place on the same day as Visit 0):  
 
During this study visit:  
 
Study personnel will confirm subject’s eligibility if not possible during Visit 0. No patient 
contact is needed if subject remains eligible.   
 
Study personnel will randomize subject via computer entry of the study data which will 
trigger the University of Rochester IDS to ship study drug, diary,  ZIO-Patch with 
instructions, blood drawing kit, and prepaid return envelope for next day delivery via 
Federal Express to subject. The Zio-Patch is identified only by a serial number and will be 
sent to the manufacturer to retrieve information regarding ECG findings.   
 
For subjects requiring a 24-hour Holter recording after washout from antiarrhythmic 
medication, eligibility will need to be reconfirmed based on number of VPBs found on 
holter monitoring 
 
 If subject is found to have less than 500 VPBs in 24-hour Holter, the subject will be 
informed that he/she will be withdrawn from the study.   
 
 
 
 
5.1.3. Visit 2: Phone Visit (within 7 days from Visit 1) 
 
The following tasks will be performed and documented at the Visit 2:  
 
Enrolling site staff member will confirm receipt of study shipment and review contents with 
subject.  
 
Review study drug prescribing regimen, diary and emphasize importance of compliance 
with subject. Instruct patient to begin taking study drug and record the date of the subject’s 
first dose of study medication. 
 
 5.1.4. Visit 3: Phone visit (One week after initiating study drug) 
  
During this follow-up visit: 
 
An ICD interrogation (with a manual transmission by patient, if system is not automatic) 
from remote device monitoring system should be obtained. 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 15 of 26 
 
 
Study drug prescribing regimen, diary and importance of compliance will be reviewed with 
subject. 
 
Adverse events will be assessed and reported. 
 
  5.1.5. Visit 4: In person visit in home or in clinic (Three weeks after initiating study drug)  
 
During this follow-up visit: 
 
A standard 12-lead ECG recording will be performed.  
 
Blood sample will be drawn for flecainide levels. A teaspoon (5ml) of blood is needed for 
this sample. This blood sample will be sent to a specialized lab. Paper copy of ECG will 
be uploaded to the Box.com at the University of Rochester.   
 
A ZIO-Patch (a small, adhesive, water-resistant one lead ECG recorder) will be applied to 
the chest for a continuous 24-hour monitoring over 7 days. ZIO-Patch could be self-applied 
or applied by study staff member. At the end of the 7 days the patch must be removed 
and returned to the University of Rochester 
 
Review study drug prescribing regimen, diary and importance of compliance will be 
reviewed with subject. 
 
Adverse events will be assessed and reported. 
 
5.1.6. Visit 5: Phone visit (Four weeks after initiating study drug) 
 
During this follow-up visit study: 
 
Patient will be reminded to:  
o stop study drug from first bottle (begin wash out period) 
o remove ZIO-Patch 
o return the medication bottle, diary and ZIO-Patch in a pre-paid mailer to the 
University of Rochester. 
 
Adverse events will be assessed and reported.  
 
5.1.7. Visit 6: Phone visit (Five weeks after initiating study drug) 
      During this follow-up visit: 
 
Enrolling site will confirm receipt of study shipment and review contents with the subjects. 
Shipment will include: second bottle of study drug, diary, Zio-Patch with instructions, blood 
drawing kit and prepaid return envelope for next day delivery via Federal Express.  
 
Study drug prescribing regimen, diary and importance of compliance will be reviewed with 
subject. 
 
Instruct patient to begin taking study drug and record the date of the subject’s first dose of 
study medication from second bottle. Adverse events will be assessed and reported. 
 
5.1.8. Visit 7: Phone visit (Six weeks after initiating study drug) 
During this follow-up visit: 
 
An ICD interrogation (with a manual transmission by patient, if system is not automatic) 
from remote device monitoring system will be obtained.  
 
Study drug prescribing regimen, diary and importance of compliance will be reviewed with 
subject. 
 
Adverse events will be assessed and reported. 
 
5.1.9. Visit 8: In person visit in home or in clinic home visit (Eight weeks after initiating 
 
study drug) 
 
During this follow-up visit: 
 
A standard 12-lead ECG recording will be performed.  
 
Blood sample will be drawn for flecainide levels. A teaspoon (5ml) of blood is needed for 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 16 of 26 
 
this sample. This sample will be sent to a specialized lab for analysis and paper copy of 
ECG will be sent to the University of Rochester. 
 
A ZIO-Patch (a small, adhesive, water-resistant one lead ECG recorder) will be applied 
to the chest for a continuous 24-hour monitoring over 7 days. ZIO-Patch could be self-
applied or applied by study staff member. At the end of the 7 days the patch must be 
removed and returned to the University of Rochester 
 
Study drug prescribing regimen, diary and importance of compliance will be reviewed with 
subject. 
 
Adverse events will be assessed and reported. 
 
  5.1.10. Visit 9: Phone visit (Nine weeks after initiating study drug) 
 
During this follow-up visit study: 
 
Patient will be reminded to:  
o stop study drug from second bottle 
o remove ZIO-Patch 
o return the medication bottle, diary and ZIO-Patch in a pre-paid mailer to the 
University of Rochester. 
 
Adverse events will be assessed and reported.  
 
5.1.11. Visit 10: Phone visit (Ten weeks after initiating study drug) 
During this follow-up visit: 
 
An ICD interrogation (with a manual transmission by patient, if system is not automatic) 
from remote device monitoring system will be obtained.  
 
Adverse events will be assessed and reported. 
 
Subject will be informed by study personnel regarding subsequent medical management 
regarding antiarrhythmic medications to be taken after the closeout of the study as per 
decision of enrolling center physician.  
 
Close out the study participation of the subject.  
 
 
5.2. Treatment Dosage and Administration 
 
Each subject will take 1 blinded capsule of study drug (flecainide or a placebo) dose BID 
per randomization scheme for 28 days. After 28 days there will be a 7-day washout period. At the 
end of the washout period, each subject will then take 1 blinded capsule of study drug (flecainide 
or placebo) for the next 28 days.  
 
5.3. Efficacy Assessments 
 
During this pilot clinical trial, efficacy of flecainide on cardiac rhythm will be assessed by 
7-day ECG monitoring with ZIO-Patch to determine overall burden of premature ventricular 
contractions. In addition, remote ICD monitoring of the subjects previously implanted ICD device 
will be used to account for episodes of ventricular tachycardia ventricular fibrillation.  
 
 5.4. Safety Assessments 
The assessments that will be performed to evaluate safety include medical history, 
standard 12-lead ECG, implanted device interrogation and the use of the 7-day ZIO-Patch monitor 
and will be quantified by:   
 
a) VPBs on 7-day ECG monitoring to determine the possibility of proarrhythmia defined 
as a 3-fold increase in number of VPBs;  
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 17 of 26 
 
b) Total burden of nun-sustained and sustained (ICD treated and untreated) VT episodes 
on interrogation of ICDs evaluated after the first week and after the fourth week of study 
drug administration with a 5-fold increase in number of VT episodes defining 
proarrhythmia.  
 
c) QRS prolongation on ECG defined as >40ms in comparison to baseline and the new 
presence of the Brugada pattern of the ECG. We expect 17-29% prolongation of the QRS 
but prolongation >30% (40ms) will be unusual. The appearance of cove-type Brugada 
pattern will be monitored. 
 
5.5. Assessment of Subject Compliance 
 
Study drug compliance will be emphasized during each contact with the study subject. 
Compliance will also be assessed by count of returned study drug and plasma concentrations of 
flecainide.  
 
5.6. Costs to the Subject 
 
Study drug, the ZIO-Patch monitor, ICD interrogation, ECG during in person visit and 
serum flecainide level will be paid for by study funds. 
 
 
 5.7. Payment for Participation 
Subjects will not be paid for participation. 
 
 5.8. Return of Individual Research Results 
Research results will not be provided to subjects.   
 
 
6. CONCOMITANT AND DISALLOWED MEDICATIONS 
Subjects will be allowed to take any prescribed beta-blocker including: propranolol, 
metoprolol, atenolol, nadolol, carvedilol, and bisoprolol. Disallowed antiarrhythmics medications 
include: sotalol, quinidine, procainamide, disopyramide, lidocaine, phenytoin, mexilitene, 
propafenone, dofetilide, ibutilide, amiodarone, dronedarone, verapamil, diltiazem. Subjects and 
their physician treating them for ARVC must agree to discontinue use of these medications to 
participate in this study for their safety. These medications could be administered after 
participation of a subject is completed per physician discretion.  
 
 
7. SUBJECT WITHDRAWALS 
Subjects will be advised in the written informed consent forms that they have the right to 
withdraw from the study at any time without prejudice. Subjects may be withdrawn as lost to 
follow-up by the investigator if they do not follow-up after 4 documented attempts to contact the 
subject. These subjects will not undergo any additional study activities prior to withdrawal. 
Subjects not meeting eligibility criteria of at least 500 VPBs in 24-hour Holter after washout of 
medication used prior to study drug initiation will be  withdrawn and replaced.   
 
8. STUDY DRUG ADMINISTRATION/ASSIGNMENT 
 
8.1. Study Drug 
 
This study is IND exempt per FDA; meeting the criteria set forth in 21 CFR 312.2(b) and 
320.31(b). The University of Rochester Investigational Drug Service (IDS) will prepare and 
dispense the study medication. All capsules of study drug will be identical in appearance (same 
size and color). Blinded capsules will be prepared via over-encapsulation. Active doses will 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 18 of 26 
 
consist of 2 x 50 mg flecainide tablets placed inside larger opaque colored capsules and backfilled 
with lactose. Placebo doses will consist of the same opaque colored capsules filled with inert 
powder (lactose). Study subjects will be instructed to swallow all capsules whole and not to open 
them. Each subject will be dispensed 56 blinded doses per treatment period, per randomization 
(2 doses/day x 28 days = 56 doses per period). The University of Rochester Investigational Drug 
Service (IDS) will receive the subject randomization assignment and prepare and ship study drug 
directly to the subject for next day delivery via Federal Express. At the time of crossover and at 
the study closeout, bottles will be collected for study drug accountability.  Subjects will be provided 
a pre-paid mailer to return unused study drug to the University of Rochester IDS. 
 
8.2. Dosage of Study Drug 
 
The active dosage of study drug is two 50 mg tablets of flecainide over encapsulated.  The 
matching placebo will be filled with inert lactose. 
 
8.3. Subject Enrollment/Randomization 
 
The University of Rochester IDS will package the capsules into blinded labeled bottles. 
Site personnel will randomize subjects by using a computer by entry of subject data to confirm 
eligibility in the study electronic data capture system. If all conditions are satisfied in the computer, 
the subject is randomized by checking a field on the eligibility form.  The site will then send via 
facsimile subject contact information to the University of Rochester IDS.  University of Rochester 
IDS will dispense study medication per the randomization assignment and ship study drug via 
Federal Express for next day delivery. 
 
8.4. Accountability of Investigational Supplies 
 
At the time of crossover and at the study closeout, the study subject will ship the study 
drug containers back to the University of Rochester IDS for study drug accountability.  
 
 
8.5. Subject Withdrawal of Study Drug 
 
This is intention to treat trial.  If the subject decides not to take study drug, the subject may 
remain in the study and continue study procedures for the duration of their participation.  
 
8.6 Emergency Drug Disclosure 
 
In the event of a clinical emergency, provisions have been made for the enrolling site 
Principal Investigator to obtain quick disclosure of treatment assignment for an individual subject 
in the study.  A clinical emergency is defined as any clinical event or laboratory test that the 
enrolling investigator (in consultation with Dr. Hugh Calkins from The John Hopkins University the 
Clinical Director and Co-PI of this study) determines requires immediate disclosure of the 
assigned treatment group (flecainide versus placebo) to which the subject has been assigned in 
order to treat the adverse event. Emergency disclosure is not required to determine study drug 
causality of a serious or non-serious adverse event. 
 
Disclosure of treatment assignment does not require a subject to be withdrawn from the 
study. The subject may remain in the study, and be provided the necessary treatment required 
for their condition as prescribed by their private physician.  
   
 
9. DEVIATIONS 
 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the Data 
Coordinating Center (DCC) and the reviewing IRB of any deviation from the investigational plan 
to protect the life or physical well-being of a subject in an emergency, and those deviations which 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 19 of 26 
 
affect the scientific integrity of the clinical investigation. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing local 
requirements, if sooner than 5 working days.  
 
All deviations from the investigational plan, with the reason for the deviation and the date 
of occurrence, must be documented and reported to the DCC using the EDC system. Sites may 
also be required to report deviations to the IRB, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, 
appropriate corrective and preventive actions (including notification, enrolling site re-training, or 
discontinuation) will be put into place by the DCC. 
 
 
10. SAFETY AND REPORTABLE EVENTS 
 
10.1. Adverse Event Definition 
 
An adverse event is any symptom, sign, illness, or experience that develops or worsens 
during the course of the study whether or not considered drug-related. An adverse event occurring 
in the course of the use of a drug product in professional practice; an adverse event occurring 
from drug overdose whether accidental or intentional; an adverse event occurring from drug 
abuse; an adverse event occurring from drug withdrawal; and any failure of expected 
pharmacological action. All serious and unexpected adverse events must be reported per 
definition in Section 9.2. Diagnostic and therapeutic invasive and non-invasive procedures 
(including surgeries) should not be reported as adverse events. However, the medical condition 
for which the procedure was performed should be recorded if it meets the criteria for an adverse 
event. 
 
10.1.1. Serious Adverse Event 
 
A serious adverse event is defined as any adverse medical experience that results in any 
of the following outcomes: 
• death; 
• is life-threatening; 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in permanent impairment of a body structure, a body function or cancer; 
• requires medical or surgical intervention to prevent permanent impairment or damage; 
• is due to overdose; 
• leads to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
10.1.2. Unexpected Adverse Drug Experience 
 
This is defined as an adverse drug experience that is not listed in the current labeling for 
the drug product. This includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event because of greater severity or 
specificity. For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the labeling only referred to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the labeling only listed cerebral vascular accidents. "Unexpected," as used in this 
definition, refers to an adverse drug experience that has not been previously observed (i.e., 
included in the labeling) rather than from the perspective of such experience not being anticipated 
from the pharmacological properties of the pharmaceutical product. 
 
10.2. Recording Adverse Events 
 
At each subject contact the site study staff will assess adverse events per definition in 
Section 10.1 by recording all voluntary complaints of the subject and by assessment of clinical 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 20 of 26 
 
and laboratory features.  At each study visit, the subject should be questioned directly regarding 
the occurrence of any adverse experience since his/her last contact.   
 
All adverse events, whether observed by the Investigator, elicited from or volunteered by 
the subject, should be documented on or following randomization date and within 5 calendar days 
of date reported to the enrolling site.  Ventricular tachyarrhythmias will be documented in the ICD 
interrogations. Each adverse event will include a brief description of the experience, the date 
reported to the enrolling site, the date of onset, the date of resolution, the duration and type of 
experience, the severity, and relationship to subject condition or study drug, contributing factors, 
and any action taken.  Event status if not resolved will be tracked at each follow-up with final 
status indicated at the conclusion of study participation e.g., resolved, ongoing, unresolved. 
 
10.3. Responsibilities for Reporting Serious and Unexpected Adverse Events 
 
 The Investigator will record all adverse events per Section 10.1 definition that occur during 
the study period in the appropriate source documents and/or AE case report form with 15 calendar 
days of the date reported to the enrolling site for serious events and 15 days for other adverse 
events. The study period for reporting adverse events (e.g., from the time of randomization to final 
study visit) will be 10 weeks, the local IRB will be notified by the enrolling site per local IRB 
regulations. The Investigator will comply with local regulations regarding the reporting of adverse 
events.  Adverse events reported by enrolling sites will be promptly reported to Data Coordinating 
Center Institutional Review Board, NIH, and FDA per local regulations. Similar to other clinical 
trials conducted by University of Rochester investigators, adverse events will be immediately 
reported to the Data Coordinating Center (DCC) via dedicated web-based case report forms to 
the PI (Dr. Zareba). The DCC will be forwarding relevant reports to the Chair of DSMB for review 
and Chair will determine whether individual case will require immediate assessment by full DSMB 
committee or it could be assessed during electively scheduled DSMB meeting. The main point of 
assessment by DSMB will be to judge whether given adverse event could be related to study 
drug. 
 
 
 
11. RISK/BENEFIT ASSESSMENT 
 
 
11.1. Potential Risks 
 
11.1.1. Potential Risks to Patients Undergoing Treatment with Flecainide  
Flecainide is an antiarrhythmic drug approved by the Food and Drug Administration in the 
US since 1982 to suppress cardiac arrhythmias and is predominantly used for atrial arrhythmias. 
Flecainide was studied in the CAST trial (Echt et al. 1991) in patients after myocardial infarction 
with ventricular arrhythmias and was associated with a higher incidence of mortality or non-fatal 
cardiac arrest (19/323) as compared with its matching placebo (7/318). The most serious adverse 
reactions reported for flecainide in patients with ventricular arrhythmias were new or exacerbated 
ventricular arrhythmias which occurred in 6.8% of patients and new or worsened congestive heart 
failure which occurred in 3.9% of patients. In some patients, flecainide treatment has been 
associated with episodes of unresuscitatable ventricular tachycardia or ventricular fibrillation. 
There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. A total of 
1.2% of patients developed sinus bradycardia, sinus pause, or sinus arrest.   The frequency of 
most of these serious adverse reactions probably increases with higher trough plasma levels, 
especially when these trough levels exceed 1.0 μg/mL, unlikely to occur with our propose dose of 
100 mg bid. 
Patients with structural heart disease, treated with flecainide for supraventricular 
arrhythmias, may be at increased risk for proarrhythmia and cardiac adverse events. The use of 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 21 of 26 
 
flecainide in these patients has been associated with life-threatening and occasionally fatal 
ventricular arrhythmias. Therefore, in these patients, especially in the presence of impaired left 
ventricular function with ejection fraction ≤ 40%, flecainide should be used with extreme caution, 
preferably after other antiarrhythmic drugs have been tried or considered inappropriate. Because 
flecainide has a mild negative inotropic effect, it may cause or worsen congestive heart failure, 
particularly in patients with cardiomyopathy, pre-existing severe heart failure (NYHA functional 
class III or IV) or ejection fractions ≤ 40%. Flecainide should therefore be used cautiously in 
patients who are known to have a history of congestive heart failure or myocardial dysfunction. 
When used per current FDA approved prescription information flecainide is considered a safe 
drug.  
The use of flecainide in this study had been approved by FDA with the Investigational New 
Drug (IND) exempt. The study team will carefully monitor studied patients regarding any side 
effects of the study drug. One of important secondary aims of this study is to evaluate safety of 
flecainide administration in ARVC patients and our design involving only patients with ICD 
implanted provides a safety measure in case of proarrhythmia.  
The most commonly reported non-cardiac reactions experienced by patients with ventricular 
arrhythmias taking 200 mg/day were dizziness 11%, visual disturbance 5.4% (includes blurred 
vision, diplopia, visual field effects, photophobia), headache 4.5%, nausea 4.9% and dyspnea 
5.2%.  
 
11.1.2. Blood Draws: Blood draws may cause pain, redness, bruising or very rarely infection at 
the site of the needle stick.  Rarely some people faint.   
 
11.1.3. ECG, ZIO-Patch and Holter Monitoring (if needed): Other than possibly experiencing 
some minor skin irritation from the electrodes there are no anticipated risks related to complete 
the electrocardiogram, ZIO-Patch or holter monitor.  
 
11.1.4. Loss of confidentiality: As this study involves the use of identifiable, personal 
information, there is a chance that a loss of confidentiality will occur. The researchers have 
procedures in place to lessen the possibility of this happening. All personal information obtained 
from subjects is removed and subjects are given a unique study ID number. Access to study 
records is limited and any information that may potentially identify a subject will not be used in 
publications or reports.  
 
11.1.5. Pregnancy: If a subject or their partner becomes pregnant during this study, there are 
unforeseeable risks to the unborn baby. 
 
11.2. Protection against Risks 
To minimize the risks of flecainide administration in ARVC patients, all enrolled subjects 
must have an implanted functioning defibrillator.  Their cardiac left ventricular ejection fraction 
must be > 40% by any cardiac imaging modality.  These subjects may continue concomitant use 
of beta blocker therapy, as pro-arrhythmic effects of flecainide in studied patients with depressed 
or preserved ejection fraction was eliminated by concomitant administration of beta-blockers 
(Kennedy et al. 1994: Kennedy 1997). 
 
11.3. Potential Benefits to Subjects 
There is no direct benefit to the subjects.  
 
11.4. Alternatives to Participation 
 
If a subject does not want to participate in the study, they will receive standard medical care 
for their condition  


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 22 of 26 
 
 
 
12. CONFIDENTIALITY OF DATA AND INFORMATION STORAGE  
 
Efforts will be made to maintain confidentiality of study data.  All study data will be coded 
with an unidentifiable study code.  The study coordinator for each enrolling site will locally maintain 
an internal key linking the subject’s name with study data which will not be shared outside of the 
enrolling site.  Subjects’ personal information will be kept confidential and will not be released 
without his/her written permission, except as described in this section or as required by local law. 
Subject’s personal information may be shared, to the extent necessary, among the research staff, 
with the Institutional Review Board and for research oversight as dictated by local regulations.   
  
All information and data collected concerning subjects or their participation in this 
investigation will be considered confidential by the DCC. No social security numbers or direct 
identifiers will be collected by the DCC. Study data collected during this investigation may be used 
by the DCC for the purposes of this investigation, publication, to support future research and/or 
other business purposes. HIPAA authorization will be obtained from each subject by every 
enrolling site per local regulations and enrolling sites are expected to follow all local regulations 
related to data collection.  
  
All data will be submitted using a password protected electronic data capture system with 
access limited to only those authorized by the Principal Investigator at each enrolling site per an 
electronic access request document with delegation signed by the Principal Investigator. All study 
data will be coded with a study subject number that is assigned at the time of treatment 
randomization and cannot be linked to the patient’s identify except by internal records maintained 
at the individual enrolling sites. Source document records to support event adjudication or core 
laboratory analysis will be redacted of all PHI before being sent to the coordinating center and 
only the subject ID will be recorded to link the subject to this data.  The electronic data will be 
directly extracted from web system for data collection.  
 
13.  RESEARCH INFORMATION IN MEDICAL RECORDS 
 
Indication of study participation in medical records will be left to local enrolling site 
standards of documentation of study participation 
 
  
14. DATA ANALYSIS AND MONITORING  
 
14.1. Sample Size Determination 
 
Enrolling 38 subjects and allowing for up to 10% drop-out due to withdrawal or death, we 
expect at least n=34 fully evaluable subjects in the study. As shown in Table 2 below, this sample 
size will provide >90% power to detect a relative reduction of 40% in VPB burden, using a two-
sided 0.05 level paired t-test, assuming the correlation between VPB is at least 0.5. If the 
correlation is 0.7, the power to detect a more modest 30% relative reduction will be 84%. 
 
Power 
Relative Reduction in VPB 
Correlation between VPB burden 
84% 
30% 
0.7 
62% 
30% 
0.5 
99% 
40% 
0.7 
90% 
40% 
0.5 
 
 
Detecting a relative reduction of 30-40% in VPB frequency (flecainide vs placebo) is 
equivalent to detecting a shift of 0.515-0.737 units in log2 (VPB), which has an estimated 
standard deviation (SD) of 1.28 based on our pilot data. If the correlation between VPB 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 23 of 26 
 
measures (before and after crossover) were at least 0.5, then the SD of the change in log2 
(VPB) would be at most 1.28, whereas if the correlation were 0.7 the SD of the change would be 
0.99. An evaluable sample size of n=34 patients provides 90% power to detect a 40% reduction 
in VPB frequency using a 2-sided 0.05 level paired t-test applied to log2 (VPB), assuming the 
correlation is 0.5. Accounting for 10% loss to follow-up, we will randomize n=38 patients. Power 
of the proposed linear mixed effects model analysis will be slightly higher, since it can 
accommodate partial information from any subjects who might be lost to follow-up. 
 
14.2. Planned Statistical Analysis 
 
The effect of flecainide on log2(VPB) will be analyzed using a linear mixed effects analysis 
of variance model with fixed effects for treatment and period and a random effect for subject. The 
estimated treatment effect, with a 95% confidence interval (CI), will be exponentiated to back-
transform to the original scale, resulting in an estimated relative reduction in VPB along with 95% 
CI. The mixed effects model incorporates available data from all randomized subjects and 
accommodates missing data in an appropriate way under the “missing at random” assumption. 
The analyses will be repeated including only subjects who complete both treatment periods, but 
these analyses will be considered as secondary sensitivity analyses. It is anticipated that the 
withdrawal rate in this trial will be minimal and that the two methods of analysis will yield consistent 
results. Similar methods will be used to analyze secondary outcome variables. Adverse events 
will be tabulated by treatment, severity, and perceived relationship to study drug. 
 
14.3. Data and Safety Monitoring 
A data and safety monitoring board (DSMB) will be appointed to independently monitor 
the conduct and the outcome of the trial. The DSMB will be responsible for monitoring the safety 
and well-being of the patients participating in this study and ensuring the ethical conduct of the 
trial. The safety endpoints consist of ECG and ICD-derived measures of ventricular 
arrhythmogenicity. The main focus of DSMB activity will be to monitor events obtained from ICD 
interrogations obtained after 1 week and after 4 weeks of each treatment, data from 7 day ECG 
monitoring and clinical adverse events that could be related to the study medication. Data on 
clinical events including adverse events, HF hospitalizations, ventricular tachyarrhythmias 
requiring ICD therapy, and death will also be collected and provided to the DSMB for evaluation 
of risks associated with the drug therapy. 
In the above capacities, the DSMB will be advisory to the Executive Committee 
responsible for overseeing the design, conduct, and data collection/analysis of the trial. The 
Executive Committee for the trial consists of: the trial Principal Investigator, the Co-Principal 
Investigator the Biostatistician and two site investigators. 
The board will be comprised of 3 independent members: (1) a statistician with experience 
in clinical trials; (2) 1 cardiologist with expertise in drug clinical trials; and (3) 1 electrophysiologist 
with expertise in device implantation and experience antiarrhythmic drugs. The DSMB will meet 
before trial commencement and 2 times in year 1 and three times in year 2.  It is anticipated that 
these meetings will take place via conference call. One of the clinical cardiologists will be selected 
to chair the committee and will serve as the principal representative of the group. 
 
 
 
 
 
 
 
 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 24 of 26 
 
REFERENCES 
 
Bhonsale A, James CA, Tichnell C, et al. Incidence and predictors of implantable cardioverter 
defibrillator therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy 
undergoing implantable defibrillator implantation for primary prevention. JACC 2011;58:1485-96. 
 
Bhonsale A, Groeneweg JA, James CA, et al. Impact of genotype on clinical course in 
arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur 
Heart J 2015;36:847–55. 
 
Calkins H. Arrhythmogenic right-ventricular dysplasia. Curr Probl Cardiol 2013;38:103-123 
 
Cerrone M, Noorman M, Lin X, et al. Sodium current deficit and arrhythmogenesis in a murine 
model of plakophilin-2 haploinsufficiency. Cardiovasc Res 2012; 95:460-8. 
 
Cerrone M, Montnach J, Lin X, et al. Plakophilin-2 is required for transcription of genes that control 
calcium cycling and cardiac rhythm. Nature Communications 2017;106.  
 
Choudhary N, Tompkins C, Polonsky B, et al. Clinical presentation and outcomes by sex in 
arrhythmogenic right ventricular cardiomyopathy: findings from the North American ARVC 
Registry. J Cardiovasc Electrophysiol 2016;27:555-62.  
 
Corrado D, Calkins H, Link MS, et al. Prophylactic implantable defibrillator in patients with 
arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or 
sustained ventricular tachycardia. Circulation 2010;122:1144–52. 
 
Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular 
cardiomyopathy/dysplasia: an International Task Force consensus statement. Circulation 2015; 
132: 441-53 
 
Corrado D, Link MS, Calkins H. Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 
2017;376:61-72. 
 
Dalal D, Nasir K, Bomma C, et al. Arrhythmogenic right ventricular dysplasia: A United States 
experience. Circulation 2005;112:3823-32. 
 
Denis A. Sacher F, Derval N et al. Diagnostic value of isoproterenol testing in arrhythmogenic 
right ventricular cardiomyopathy. Circ Arrhythm Electrophysiol. 2014;7:590-597  
 
Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, 
flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-
8. 
 
Ermakov S, Scheinman M. Arrhythmogenic Right Ventricular Cardiomyopathy – Antiarrhythmic 
Therapy. Arrhythm Electrophysiol Rev. 2015;4:86-9 
 
Groeneweg JA, Bhonsale A, James CA, et al. Clinical presentation, long-term follow-up, and 
outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family 
members. Circ Cardiovasc Genet 2015;8:437–46. 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 25 of 26 
 
Kannankeril PJ, Moore JP, Cerrone M et al. Efficacy of flecainide in the treatment of 
catecholaminergic polymorphic ventricular tachycardia. a randomized clinical trial. JAMA 
Cardiology 2017;2:759-66. 
 
Kennedy HL, Brooks MM, Barker AH, et al.Beta-blocker therapy in the Cardiac Arrhythmia 
Suppression Trial. CAST Investigators. Am J Cardiol. 1994 Oct 1;74(7):674-80. 
 
Kennedy HL. Beta-blocker prevention of proarrhythmia and proischemia: clues from CAST, 
CAMIAT, and EMIAT. Cardiac Arrhythmia Suppression Trial. Canadian Amiodarone Myocardial 
Infarction Arrhythmia Trial. European Myocardial Infarct Amiodarone Trial. Am J Cardiol. 
1997;80:1208-11. 
 
Link MS, Laidlaw D, Polonsky B, Zareba W, McNitt S, Gear K, Marcus F, Estes NA 3rd. Ventricular 
arrhythmias in the North American multidisciplinary study of ARVC: predictors, characteristics, 
and treatment. J Am Coll Cardiol 2014;64:119-25. 
 
Marcus FI, Fontaine GH, Guiraudon G, et al. Right ventricular dysplasia: a report of 24 adult 
cases.   Circulation 1982;65:384-98. 
 
Marcus GM, Glidden DV, Polonsky B, et al. for Multidisciplinary Study of Right Ventricular 
Dysplasia Investigators. Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular 
cardiomyopathy: a report from the North American ARVC Registry. J Am Coll Cardiol. 
2009;54:609-15.  
 
Mazzanti A, Ng K, Faragli A, et al. Arrhythmogenic right ventricular cardiomyopathy: clinical 
course and predictors of arrhythmic risk.J Am Coll Cardiol 2016;68:2540-2550 
 
Orgeron GM, James CA, Te Riele A et al. Implantable cardioverter-defibrillator therapy in 
arrhythmogenic right ventricular dysplasia/cardiomyopathy: predictors of appropriate therapy, 
outcomes, and complications. J Am Heart Assoc. 2017;6:e006242. 
 
Philips B, Madhavan S, James C et al. High prevalence of catecholamine-facilitated focal 
ventricualr tachycardia in patients with arrhythmogenic right ventricualr dysplasia/cariomyopathy. 
Circ Arrhythm Electrophysiol 2013;6:160-166. 
 
Riley MP, Zado E, Bala R et al. Lack of uniform progression of endocardial scar in patients with 
arrhythmogenic right ventricular dysplasia/cardiomyopathy and ventricular tachycardia. Circ 
Arrhythm Electrophysiol. 2010;3:332-338. 
 
Salvage SC, Chandrasekharan KH, Jeevaratnam K et al. Multiple targets for flecainide action: 
implications for cardiac arrhythmogenesis. British Journal of Pharmacology 2018;175:1260.  
 
Santangeli P, Zado ES, Supple G, et al. Longterm outcome with catheter ablation of ventricular 
tachycardia in patients with arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythm 
Electrophysiol 2015;8:1413–21 
 
Tambocor prescription information. https://www.rxlist.com/tambocor-drug.htm#description 
 


Version 2.0   December 4, 2018         RSRB00073590 
 
Page 26 of 26 
 
Van Opbergen CJ, Delmar M, van Veen TA: Potential new mechanisms of pro-arrhythmia in 
arrhythmogenic cardiomyopathy: Focus on calcium-sensitive pathways. Neth Heart J. 25:157-
169, 2017.   
 
Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholaminergic polymorphic 
ventricular tachycardia in mice and humans. Nat Med. 2009;15(4):380-383.