Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS): A Pilot Study
Phase: PHASE4
Conditions: Ventricular Premature Beats, Contractions, or Systoles, Cardiomyopathies
Sponsor: Hunter Holmes Mcguire Veteran Affairs Medical Center

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Prospective Assessment of Premature Ventricular Contractions 
Suppression in Cardiomyopathy (PAPS): A Pilot Study  
 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
 
Sponsored by: 
 
National Institute of Health (NIH) 
 
National Heart Lung and Blood Institute (NHLBI) 
 
 
 
Principal Investigators 
 
Jose F. Huizar, M.D. (Contact PI & Translational Research, McGuire VA Medical Center) 
 
Carlos Morillo, M.D., (Trialist, University of Calgary) 
 
Teresa De Marco, M.D.  (Heart Failure, University of California San Francisco) 
 
Kenneth A. Ellenbogen, M.D. (Electrophysiologist, Virginia Commonwealth University) 
 
Edward Gerstenfeld, M.D. (Holter Core Laboratory, University of California San Francisco) 
 
Gregory Hundley, M.D. (Magnetic Resonance Core Laboratory, Virginia Commonwealth University) 
 
John Gorcsan III, M.D. (Echo Core Laboratory, Washington University, St. Louis)  
 
Adam Sima, Ph.D. (Biostatistician, Virginia Commonwealth University) 
 
 
 

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Contact information 
 
 
Role 
Contact 
 
Clinical Contacts 
Pamela Summers, BS, CCRP 
Research Coordinator 
McGuire VA Medical Center / McGuire Research Institute 
1201 Broad Rock Blvd, 3rd floor, Richmond, VA 23249 
Phone: 804-675-6831; Email: pamela.summers@va.gov 
 
Donna Sargent, R.N.,BSN,CCRC 
Clinical Coordinator 
McGuire VA Medical Center / McGuire Research Institute 
1201 Broad Rock Blvd, 3rd floor, Richmond, VA 23249 
Phone: 804-675-5466; Email: donna.sargent@va.gov 
 
Jose F. Huizar, M.D. Principal Investigator (Contact) 
Associate Professor of Medicine & Director, Arrhythmia and Device Clinic 
McGuire VA Medical Center / McGuire Research Institute 
1201 Broad Rock Blvd, 3rd floor, Richmond, VA 23249 
Phone: 804-675-5466; Email: jose.huizar2@va.gov; jose.huizar@vcuhealth.org 
 
Core 
Laboratories 
• 
Echocardiography Core Laboratory  
John Gorcsan III, M.D.    
Washington University in St. Louis, St. Louis, MO 
Email: gorcsan@wustl.edu 
 
• 
Magnetic Resonance Core Laboratory  
Gregory Hundley, M.D.   
Virginia Commonwealth University,Richmond, VA 
       Email: greg.hundley@vcuhealth.org 
• 
Holter Core Laboratory  
Edward Gerstenfeld, M.D.  
University of California San Francisco, San Francisco, CA. 
Email: edward.gerstenfeld@ucsf.edu 
 
Data, Safety and 
Monitoring Board 
 
Chair - James C. Fang, M.D. (Heart Failure & Cardiac Transplantation) 
The University of Utah 
50 North Medical Drive, Salt Lake City, Utah 84132 
Phone 801-581-7715; Email: james.fang@hsc.utah.edu 
 
Thomas A. Dewland, M.D. (Cardiac Electrophysiologist) 
Knight Cardiovascular Institute / Oregon Health & Science University 
Portland, Oregon 
Phone: (503) 494-7400; Email:  dewland@ohsu.edu 
 
Ryan J. Tedford, M.D. (Heart Failure & Cardiac Transplantation) 
Medical University of South Carolina / Division of Cardiology 
Charleston, SC  
Email: tedfordR@musc.edu 
 
 

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Adjudication 
Event Committee 
 
 
Chair - John P. Boehmer, M.D. (Heart Failure) 
Penn State Hershey Heart & Vascular Institute 
500 University Drive, Hershey, PA 17033 
Phone:     Email: jboehmer@psu.edu 
 
Joshua M. Cooper, M.D. (Cardiac Electrophysiologist) 
Temple University Health System 
3401 N. Broad Street, Philadelphia, PA 19140 
Phone:  215-707-7526:  Email: joshua.Cooper@tuhs.temple.edu 
 
Sean Pinney, M.D. (Heart Failure & Transplantation) 
Mount Sinai Health System 
One Gustave Levy Place, New York, NY 10029 
Phone 212-241-7300; Email: sean.pinney@mountsinai.org 
 
 
 
Vendors / 
Services 
 
- 
IRhythm Technologies Inc., San Francisco, CA  
Judith C. Lenane, RN, MHA (Chief, Clinical Officer & EVP, Operations) 
 
- 
Research Electronic Data Capture (REDCap)  
Tim Aro, Ph.D. Manager, Clinical Research Informatics 
Center for Clinical and Translational Research, VCU (Richmond, VA) 
 
 
 
 

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Protocol Synopsis 
 
PROSPECTIVE ASSESSMENT OF PVC SUPPRESSION IN CARDIOMYOPATHY (PAPS):  
A Pilot Study 
 
Part I - PAPS pilot randomized trial 
 
Study / 
Objectives 
 
 Assess the feasibility of enrolling, randomizing treatment strategies and retaining 
participants with frequent PVCs and associated CM. 
Interventions 
 
3-month observation period followed by either radiofrequency ablation (RFA) or 
antiarrhythmic drugs (AADs).  
All interventions (RFA and all proposed medications) are FDA approved and are 
currently standard of care for subjects with frequent PVCs. 
 
Study Design 
 
Multicenter randomized prospective study 
Eligible subjects 
Subjects with frequent PVCs (equal to or greater than 10% burden) and 
cardiomyopathy with calculated left ventricular ejection fraction (LVEF) ≤ 45%. 
 
Planned number 
of subjects 
 
This study will enroll between 36-39 subjects 
 – 3 subjects per center (enrollment completed within 18 months). 
Number of 
participating 
sites/ countries 
At least 12 centers in the United States and one in Canada 
Primary 
Endpoint(s) 
 
1. Improvement of LVEF after PVC suppression at 12-month follow-up. This is 
chosen as the primary-endpoint due to the known prognostic value of LVEF. The 
lower the LVEF, the higher the risk of sudden cardiac death and heart failure1-3. 
This will compare the overall improvement or change in LVEF between RFA and 
AAD groups. This end-point will support that either RFA or AADs have an overall 
better outcome due to significant improvement of LV function with potential 
impact on morbidity and mortality associated with PVC-CM. 
2. Responders to PVC suppression strategy at 12-month follow-up. Assessment 
of the number of responders (delta LVEF ≥ 10%) after PVC suppression 
strategies (RFA or AADs) will assess the effectiveness of RFA and AADs to 
reverse or improve cardiomyopathy induced by frequent PVCs. Evidence that 
either RFA or AADs is superior to improve or even reverse LV dysfunction in 
subjects with high burden PVCs could have significant impact of morbidity and 
mortality including future heart failure and ventricular arrhythmias, and also may 
avoid ICD implantation.   
 
Additional 
Endpoint(s) 
 
1. Efficacy of RFA vs AADs groups to achieve successful PVC suppression at 12-
month follow-up, defined as a reduction of PVC burden ≥80% (regardless of 
LVEF change). Understanding the success rate of PVC suppression between 
RFA and AADs will help better determine the best treatment to those subjects 
with high PVC burden.  
2. Composite end-point of adverse events at 12-month follow-up, including 
worsening in NYHA functional class (I-IV), number of HF and cardiac-related 
admissions, RFA complications and AAD adverse effects and cardiovascular 
death.  
3. Composite end-point of arrhythmia burden at 12-month follow-up, including 
PVC recurrence, non-sustained (< 30sec) and sustained (> 30sec) ventricular 
arrhythmias and arrhythmic sudden cardiac death.  
 

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Follow up 
Schedule 
 
 
Subjects will be screened via chart review. If the inclusion criteria is met, subject 
will be asked to participate in the study during Visit 1 (Week 0)  
Each enrolled subject will be followed at the following visits: 
- 
Week 0 –, Enrollment, informed consent and clinical evaluation 
- 
Week 9 – ECG and ambulatory ECG recording 
- 
Week 12 – Clinical evaluation and echocardiogram 
- 
Week 12-15 – Initiation of intervention (RFA or AADs) 
- 
Week 21 – Clinical evaluation 
- 
Every 3 months after RFA or AADs (week 38, 50 and 64) – Clinical 
assessment with occasional testing (echocardiogram and ambulatory 
ECG recording) 
- 
Week 64 – Complete protocol. 
 
All visits and testing are clinically indicated and considered standard of care. 
Most of these subjects receive this follow up regardless of participation in the 
study. 
Study Duration 
 
Study duration is approximately 36 months.  
Each subject will be followed for at least 15 months, which includes a 3-month 
observation period and 12months after intervention is initiated. 
- 
Enrollment and subject follow up of all subjects is estimated to be 
completed within 3 years. 
 
 
Key Inclusion 
Criteria  
 
 
- 
LV dysfunction (calculated LVEF ≤45% based on Echo) within 150 days of 
Enrollment (Day 0) 
- 
Average PVC burden ≥ 10 % by at least a 24-hr ambulatory ECG monitor 
(within 150 days of Enrollment (Day 0) 
 
 
 

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Key Exclusion 
Criteria 
 
 
- 
Age < 18 years old 
- 
Current amiodarone use or within last 2 months 
- 
Current use of any antiarrhythmic drug class I or III 
- 
Contraindication to use amiodarone or any other class III antiarrhythmic  
- 
Severely symptomatic PVCs (defined as incapacitating palpitations or pre-
syncope) and unable to complete a 3-month observation period 
- 
Severe/ significant CAD with planned revascularization in the near future 
- 
Complete AV block and pacemaker dependent 
- 
Pacemaker or ICD with > 10% of right ventricular pacing 
- 
Severe valvular heart disease or planned valvular/cardiac surgery 
- 
Uncontrolled or untreated endocrinopathies 
- 
Uncontrolled HTN systolic (BP > 180mmHg or diastolic >110 mmHg) 
- 
Hypertrophic cardiomyopathy 
- 
Systemic infiltrative and immune disorders 
- 
Family history of dilated CM in a first degree relative 
- 
Alcohol abuse or illicit drug use 
- 
Contraindication to short-term acute anticoagulation (due to possible 
randomization to RFA) 
- 
Atrial fibrillation and flutter with Rapid VR with possible tachycardia-induced 
cardiomyopathy 
- 
Pregnant or lactating women 
- 
Possible infectious etiology of cardiomyopathy 
- 
Previous PVC ablation 
 
Statistical Methods 
Primary 
hypothesis 
 
1) A large-scale randomized PAPS clinical study is feasible with minimal barriers 
of enrollment, treatment crossover and drop out due to a unique design including 
a short observation period and PVC suppression strategy in all participants. 
2) The rate of responders (defined as improvement of LVEF ≥ 10% points) with HF 
medical therapy alone during observation period will be less than 15% in subjects 
with CM associated with frequent PVCs. In contrast to HF medical therapy alone, 
RFA and AADs will have a responder rate of at least 35% in the same population. 
Furthermore, RFA will have a greater 1-year response rate when compared to AAD 
therapy. 
3) RFA will have a lower rate of composite adverse events (worsening NYHA 
class, HF admission, treatment side effects & complications, and death), 
arrhythmia burden and a better long-term tolerance than AADs.  
 
Sample Size 
 
This has been estimated solely on primary end-point of improvement in LV ejection 
fraction between PVC suppression strategies (RFA vs. AADs groups). Assuming 
that subjects would have a LVEF level of 25% (SD=5%) in each of the groups at 
baseline and LVEF levels of 40% and 35% (SD=10%) in the RFA and AAD groups 
at 12 months, respectively. A within subject correlation of 0.25 was assumed along 
with an inter-site standard-deviation of 1%. This model was fit assuming that, on 
average, 10% of the subjects would drop out randomly. Approximately 140 total 
subjects (70 per group) should be enrolled to reject the null hypothesis that the 
mean LVEF between RFA and AAD groups are equal with probability (power) 0.8 
and Type I error probability of 0.05. As a pilot study we have determined to enroll 
at least 20% (30 subjects) of preliminary sample size estimation to understand 
feasibility and key aspects of subject enrollment, randomization and retention to 
 properly power a large-scale randomized PAPS study. Sample size is increased  

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by 15% (6 additional subjects, between 36-39 subjects total – 19 to 20 subjects in 
each treatment group) to take into account possible spontaneous improvement of 
LV dysfunction during 3-month observation period between treatment strategies. 
 
Part II - Prevalence of PVC- Cardiomyopathy in the overall ambulatory Holter population 
Study / 
Objectives 
 
Estimate the prevalence of cardiomyopathy (CM, LVEF ≤ 45%) and frequent 
premature ventricular contractions (PVCs ≥10%) in the overall population receiving 
ambulatory ECG Holter monitors. 
 
Primary 
hypothesis 
 
The prevalence of CM (LVEF ≤ 45%) and frequent PVCs (≥10% burden) is largely 
under recognized in subjects undergoing ambulatory ECG Holters. 
Study Design 
and duration 
 
Multicenter prospective and retrospective population-based database of all 
subjects undergoing ambulatory ECG monitor during 24-month period. 
Eligible subjects 
All-comers undergoing at least a 24-hr ambulatory ECG monitor for any clinical 
indication 
 
Planned number 
of subjects 
A total of 20,000 ambulatory ECG monitors  
– 1,500 subjects per center (to be completed within 24 months). 
 
Planned number 
of participating 
sites/ countries 
At least 12 centers in the United States and one in Canada 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1. Title Page ……………………………………………………………………………….. 1 
2. Contact Information…………………………………………………………………….. 2 
3. Protocol Synopsis ……………………………………………………………………… 4 
4. Table of Contents ……………………………………………………………………… 8 
5. List of Abbreviations…………………………………………………………………….   9 
6. Project Summary / Abstract …………………………………………………………... 10 
7. Specific Aims …………………………………………………………………………… 11 
8. Introduction …………………………………………………………………………….. 13 
9. Significance …………………………………………………………………………….. 14 
Impact of proposed PAPS pilot study ……………………………………….. 15 
10. Innovation ……………………………………………………………………………….. 15 
11. Study Design Part I…………………………………………………..………………….  16 
A. Study population and eligibility …………………………………………………. 16 
➢ 
Definitions ……………………………………………………..…………... 16 
➢ 
Inclusion / Exclusion criteria (Table 1) ……………………………….… 17 
➢ 
Timeline of tests and interventions (Table 2) …………………………. 18 
➢ 
PVC-CM Registry…………………………………………………….20 
B. Scheduled Visits………………………………………………….………………... 20  
➢ PAPS study design algorithm (Figure 1) ……………….. 22 
C.  Clinical Assessments and tests ………………………………………………….23 
D. Description of the intervention(s)/treatment(s)…………………………………..24 
E. Primary and Secondary outcomes (Table 3) .………………………………25- 26 
F. Data interpretation and analysis   ………………………………………………. 26 
G. Data Collection …………………………………………………………………… 28 
H. Limitations ………………………………………………………………………… 28 
I. Statistical analysis and Sample size estimate ………………………………… 29 
J. Ethical / Regulatory Affairs ……………………………………………………… 30 
K. Timeline (Table 4) ……………………………………………………………….. 31 
L. Enrollment ………………………………………………………………………… 31 
 
12. Study Design Part II……………………………………………….…………………….  32 
A. Study population and eligibility …………………………………………..……. 32 
B. Data Management / Collection ……………………..………………………….. 32 
C. Data Interpretation ………………………………………………………………. 32 
D. Ethical / Regulatory Affairs ………………………………………………...…… 32 
 
13. Enrollment, Retention and Follow up Plans ………….……………………………… 33 
14. Protection of Human Subjects ………………………………………………….…….. 34 
15. Data Safety Monitoring Plan ………………………………………………………….. 41 
a. Form – Report of Significant Events ………………………………………… 44 
b. Form – Serious Adverse Events …………………………………………….. 45 
c. Form – Adverse Events ………………………………………………………. 46 
16. Inclusion of Women and Minorities ………………………………………………….. 47 
17. Inclusion of Children …………………………………………………………………... 47 
18. Resource Sharing Plan ……………………………………………………………….. 48 
19. References ……………………………………………………………………………… 49 
 

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List of Abbreviations 
AADs 
Antiarrhythmic Drugs 
AE 
Adverse Events 
AV 
Atrio-venticular 
BNP 
Brain Natriuretic Peptide 
CAD 
Coronary Artery Disease 
CCB 
Calcium Channel Blockers 
CCTR 
Clinical Center for Translational Research 
CM 
Cardiomyopathy 
CMR 
Cardiac Magnetic Resonance 
CRF 
Case Report Form 
CRP 
C-reactive Protein 
DSMB 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECV 
Extracellular volume fraction 
EPS 
Electrophysiologic study 
ESR 
Erythrocyte sedimentation rate 
FS 
Fractional Shortening 
HF 
Heart Failure 
HTN 
Hypertension 
ICD 
Implantable cardioverter defibrillator 
LA 
Left atrium 
LFTs 
LV 
Liver Function Tests 
Left Ventricle 
LVEF 
Left ventricular ejection fraction 
LVEDD 
Left ventricular end-diastolic dimension 
LVESD 
Left ventricular end-systolic dimension 
MR 
Magnetic resonance 
MV 
Mitral Valve 
NYHA 
New York Heart Association 
Obs 
Observation 
OMT 
Optimal Medical Therapy 
PAPS 
Prospective Assessment of PVCs Suppression 
PI 
Principal Investigator 
Pro-BNP 
Pro-brain Natriuretic Peptide 
PVC 
Premature Ventricular Contractions 
PVC-CM 
PVC-Cardiomyopathy 
QOL 
Quality of Life 
R 
Randomization 
REDCap 
Research Electronic Data Capture 
RFA 
Radiofrequency Ablation 
SAE 
Severe Adverse Events 
SCD 
Sudden Cardiac Death 
SD 
Standard Deviation 
TSH 
VCU 
Thyroid Stimulating Hormone 
Virginia Commonwealth University 
VR 
Ventricular response 
Zio 
Ziopatch (IRhythm) ambulatory ECG Holter monitor 
 
 
 
 
 

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PROSPECTIVE ASSESSMENT OF PVC SUPPRESSION IN CARDIOMYOPATHY (PAPS):  
 
A Pilot Study 
 
PROJECT SUMMARY / ABSTRACT 
 
 
Premature ventricular contractions (PVCs) coexist in subjects with heart failure (HF) and LV 
dysfunction. Frequent PVCs have been shown to induce a reversible cardiomyopathy (PVC-CM). Yet, it is 
unclear why some subjects develop PVC-CM, while others do not. Retrospective and observational studies 
have shown improvement of LV function after PVC suppression via radiofrequency ablation (RFA). Thus, 
appropriate diagnosis and treatment of subjects with PVC-CM is believed to carry significant benefits, 
improving quality of life (QOL), HF symptoms / admissions and life expectancy. Currently, these subjects 
are offered RFA, antiarrhythmic drugs (AADs) or no treatment depending on physician’s experience and 
resources. Thus, there is clear need for a large clinical trial comparing these treatment strategies. Yet, we 
need to better understand the prevalence of PVC-CM, feasibility and limitations of such a trial.   
Research Design and Methods. We propose a clinical pilot study, enrolling between 36-39 subjects with 
frequent PVCs (burden ≥10%) and CM (LVEF ≤45%) and randomize them to either: 1) RFA or 2) AADs. 
Prior to treatment, a baseline cardiac MR will be requested if clinically indicated followed by a 3-month 
observation period . We plan to follow changes in LV function/scar, PVC burden/arrhythmias and 
clinical/functional status (QOL, HF symptoms and admissions, NYHA class) and adverse events 
throughout the observation period and compare with PVC suppression strategies (RFA or AAD). Similar 
comparison will be made between RFA and AAD treatment groups during a 12-month follow up using a 
Prospective Randomized Open, Blinded End-point (PROBE) study design. The treatment regimens will be 
compared in an intention-to-treat analysis. 
 
In addition, we plan to screen 20,000 consecutive ambulatory ECG Holter monitors of all participating 
centers (1,500 per participating center) to identify all subjects with probable diagnosis of PVC-CM (PVC 
burden >10% and LVEF <45%).  
 
This pilot study is intended to estimate the prevalence of this clinical entity and pave the way for a large 
full scale randomized trial to identify the best treatment strategy for subjects with PVC-CM. Treating and 
reversing this underestimated PVC-CM may improve subject’s health and subsequently decrease HF 
healthcare spending. 
 
 

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PROSPECTIVE ASSESSMENT OF PVC SUPPRESSION IN CARDIOMYOPATHY (PAPS): 
A Pilot Study 
 
SPECIFIC AIMS 
 
Rationale. Premature ventricular contractions (PVCs) are commonly associated with heart failure (HF) 
and cardiomyopathy (CM). Frequent PVCs have been shown to induce a reversible cardiomyopathy (PVC-
CM)4-7. Yet, it is unclear why some subjects develop PVC-CM, while others do not. Recent publications8,9 
have demonstrated an incidence of systolic HF of 62.8 (95% CI 61.2 to 64.4) per 1,000 subject years 
among those with PVCs during a 5-year period and an overall age- and sex-adjusted incidence of PVC-
CM of 2.6 per 100,000 (95% CI 1.6-3.5). Appropriate diagnosis and treatment of subjects with PVC-CM is 
believed to carry significant benefits, improving quality of life (QOL), HF symptoms / admissions and life 
expectancy. Currently, these subjects are offered radiofrequency ablation (RFA), antiarrhythmic drugs 
(AADs) or no treatment depending on physician’s experience and resources.4-6,10. Nevertheless, no 
randomized-prospective study exists to support the benefit of RFA. Thus, there is clear need for a large-
scale multicenter randomized clinical trial comparing these treatment strategies, which we plan to launch 
entitled “Prospective Assessment of PVC Suppression in Cardiomyopathy (PAPS) Study”. However, we 
need to better understand the prevalence of PVC-CM, feasibility and limitations of such a trial.   
Thus, we propose a PAPS pilot study using a multidisciplinary team approach to better estimate the 
potential affected subject population, limitations of enrollment, rate of clinical outcomes, potential crossover 
and drop out. This pilot study is key to better design and power the large-scale multicenter PAPS trial.  
 
Aim 1 (Part I). PAPS pilot randomized trial: to assess the feasibility of enrolling, randomizing treatment 
strategies and retaining participants with frequent PVCs and associated CM.  
 
Aim 2 (Part II). Estimate the prevalence of CM (LVEF ≤ 45%) and frequent PVCs (≥10%) in the overall 
population receiving ambulatory ECG Holter monitors. 
Hypotheses. Our main hypotheses of the PAPS pilot study are:  
1) A large-scale randomized PAPS clinical study is feasible with minimal barriers of enrollment, treatment 
crossover and drop out due to a unique design including a short observation period and PVC 
suppression strategy in all participants.  
2) The rate of responders (defined as improvement of LVEF ≥ 10% points) with HF medical therapy alone 
during observation period will be less than 15% in subjects with CM associated with frequent PVCs. In 
contrast to HF medical therapy alone, RFA and AADs will have a responder rate of at least 35% in the 
same population. Furthermore, RFA will have a greater 1-year response rate when compared to AAD 
therapy. 
3) RFA will have a lower rate of composite adverse events (worsening NYHA class, HF admission, 
treatment side effects & complications, and death), arrhythmia burden and a better long-term tolerance 
than AADs.  
4) The prevalence of CM (LVEF ≤ 45%) and frequent PVCs (≥10% burden) is largely under recognized 
in subjects undergoing ambulatory ECG Holters (Part II). 
Methods. To test our hypotheses, we propose: 1) a clinical pilot study to prove the feasibility of a large-
scale multicenter clinical trial (PAPS study) of subjects with probable PVC-CM, and 2) screen near 20,000 
consecutive ambulatory ECG Holter monitors of all participating centers to identify all subjects with 
probable diagnosis of PVC-CM (PVC burden ≥10% and LVEF ≤45%). The clinical pilot study will enroll 
between 36-39 subjects with frequent PVCs (burden ≥10%) and CM (LVEF ≤45%) and randomize them to 
either: 1) RFA or 2) AADs. Prior to treatment, a baseline cardiac MR will be performed if clinically indicated 
and be allowed a 3-month observation period . To assess the effects of PVC suppression, we plan to 
compare changes in LV function, rate of responders (defined above), PVC burden/arrhythmias and 
clinical/functional status (QOL, HF symptoms and admissions, NYHA class) and adverse events between 
observation period both PVC suppression strategies (RFA or AAD).  

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To identify the best PVC suppression strategy, we will perform similar comparisons between RFA and AAD 
treatment groups during a 12-month follow up using a Prospective Randomized Open, Blinded End-point 
(PROBE) study design. The treatment regimens will be compared in an intention-to-treat analysis. 
 
Our study is unique due to its multidisciplinary approach and design including: 1) observation/control 
period that allows us to assess for spontaneous improvement of PVCs and/or CM, and 2) active 
treatment to all subjects, which will allow for easier subject enrollment and retention with minimal drop 
out. 
In summary, the multicenter PAPS pilot study is intended to better estimate the prevalence of PVC-
CM, prove feasibility and rates of clinical outcomes. This pilot study with a multidisciplinary approach will 
pave the way for a large-scale randomized PAPS trial to identify the best treatment strategy for subjects 
with PVC-CM.   Treating and reversing PVC-CM with its associated HF morbidity and mortality will impact 
not only healthcare spending, but most importantly it will improve patient’s health, quality of life and long-
term prognosis.  
 
 

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PROSPECTIVE ASSESSMENT OF PVC SUPPRESSION IN CARDIOMYOPATHY (PAPS):  
 
A Pilot Study 
 
 
INTRODUCTION 
Premature ventricular contractions (PVCs) are commonly associated with heart failure (HF), 
cardiomyopathy (CM), ventricular arrhythmias and sudden cardiac death (SCD)4-7,11,12. Several studies 
have shown that the frequency of PVCs correlate at least modestly with the extent of LV dysfunction and 
ventricular dilation at the time of initial clinical presentation4,5,13-15. Moreover, case reports16,17 and 
retrospective studies 4,5,7,10,15,18-21 have found a reversal of CM after elimination of PVCs; leading to the 
description of a reversible CM referred to as “PVC-induced CM” (PVC-CM). Some of these studies have 
also noted independent predictors for PVC-CM such as high PVC frequency (PVC burden greater than 
10%), male gender and epicardial location7,22. Yet, some subjects do not develop a CM even with similar 
features. Thus, it is likely that other subject’s characteristics and/or PVC features play a role in the 
pathophysiology of PVC-CM. A challenge is to identify when PVCs are the etiology of a CM or just “innocent 
bystanders” in subjects with CM. Even if PVCs are the result of CM, PVCs may contribute and further 
worsen CM and HF symptoms10,23. 
 
PVCs in a 60-second 12-lead ECG are found in 1% to 4% of subjects without heart disease. However, 
the prevalence of PVCs is significantly higher in ambulatory ECG recordings, (40% and 75% of participants 
on 24- to 48-hour ambulatory Holter monitoring)6. This can be explained due to a significant variability of 
PVC frequency with time24. It is not surprising that a 2-week ECG ambulatory recording is ideal to 
determine more accurately the PVC frequency25.  
 
A recent retrospective analysis of the Cardiovascular Health study (CHS)12 in subjects with normal 
cardiac function demonstrated an adjusted odds ratio of 3.10 and hazard ratio of 1.48 and 1.31 to develop 
LV dysfunction, CHF and mortality in subjects within the highest PVC quartile (PVC burden 0.123 - 17.7%). 
This supports frequent PVCs as a significant and modifiable risk factor for HF and increased mortality. 
 
PVC-CM is probably underestimated. A recent retrospective study7 of 245 subjects with non-ischemic 
CM and frequent PVCs (mean PVC burden 20 ± 13%) demonstrated improvement of LV function in 67% 
of subjects after radiofrequency ablation (RFA). The mean improvement of LV function after RFA in most 
studies ranges from ≥ 12-15%7,22,26. Similarly, a prospective study of 66 subjects with LVEF <35% 
(ischemic and non-ischemic) with ICD indication and PVC burden >4% demonstrated that 24% of subjects 
had a complete normalization of LVEF after eliminating PVC via RFA, resulting in subsequent absence of 
an indication for ICD implantation in 38 and 42 subjects (57 and 63%) at 6- and 12-month follow up, 
respectively.26 
 
Currently, a PVC suppression strategy with RFA or antiarrhythmic drugs (AADs) is a widely accepted 
intervention to treat a CM that might be secondary to frequent PVCs. Nevertheless, no randomized-
prospective study has compared the effectiveness and benefit of different PVC suppression strategies. 
Furthermore, the clinical outcomes associated with PVC suppression strategies in PVC-CM and the PVC 
features (e.g. coupling interval, location, QRS duration) prone to induce CM are unknown. Current literature 
speculates that elimination of PVCs may be a modifiable risk factor for heart failure and cardiovascular 
events including death.12 
 
 
 
 
 
 
 

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SIGNIFICANCE 
Approximately, 6.6 million patients in the U.S. had heart failure (HF) in 2010 and more than one million 
hospital admissions were associated with HF in 2009. HF incidence in age group >45 years of age 
increases yearly with an estimated 650,000 new cases each year, approaching 10 cases per 1000 
population after 65 years of age2. PVCs are highly prevalent in subjects with CM and HF, and they have 
been recently identified as a potential cause of a reversible CM6. Most recent publications8,9 of large 
population-based cohorts have estimated an incidence of systolic HF of 62.8 (95% CI 61.2 to 64.4) per 
1,000 subject years among those with PVCs during a 5-year period and an overall age- and sex-adjusted 
incidence of PVC-CM of 2.6 per 100,000 (95% CI 1.6-3.5) with a similar age-adjusted incidence by gender 
(2.4 and 2.7 per 100,000 in females and males respectively). The true prevalence of CM and HF induced 
by PVCs is unknown, but it has been long suspected to be underestimated since the prevalence of PVCs 
increases with age and PVC-CM appears to develop in a time-dependent manner6. At 40 years of age, the 
lifetime risk of developing HF for both men and women is 1 in 52, and PVCs could well contribute to the 
development of some instances of CM and HF6. 
 
This project will address these two common chronic cardiac conditions, CM and ventricular ectopy 
(PVCs). Only retrospective/observational studies have supported that LV dysfunction or CM can be 
restored after elimination of frequent PVCs, so called PVC-CM5,10. However, there is no prospective 
randomized study that demonstrates PVC suppression using radiofrequency ablation (RFA) to be superior 
to standard medical therapy, yet most practitioners offer RFA to patients with high PVC burden.  
 
Since 1998, several case reports and retrospective and observational studies have shown 
that radiofrequency ablation (RFA) of frequent PVCs in patients with LV dysfunction can improve LV 
function. However, it is unclear who is susceptible to develop PVC-CM, but most importantly who will 
respond to PVC suppression. Furthermore, the best PVC suppression strategy (RFA vs. AADs) to improve 
LVEF and outcomes has not yet been elucidated. For that reason, clear guidelines of treatment of frequent 
PVCs with associated CM are not available and treatment can be quite variable between EP physicians. 
 
To better understand the difference of treatment in patients with CM and frequent PVCs, we conducted 
a 12-question survey with different clinical scenarios. A total of 155 cardiac electrophysiologists (EP) within 
the United States answered this survey. It was quite clear that the management of a single patient is quite 
different between electrophysiologists. For instance, a patient with LV dysfunction (LVEF 45%) with 
frequent asymptomatic PVCs (25% burden) would receive conservative management (HF therapy only) 
by 50% of physicians, whereas the remaining 18.8% and 29.9% of doctors would treat this patient with 
antiarrhythmic drugs or RFA, respectively. Yet if the same patient (20% PVC burden) had a lower LVEF of 
35%, 23% of EP physicians would continue to treat conservatively, while 64% and 12% of EP doctors 
would recommend RFA and AADs, respectively. Furthermore, if this patient had stable CAD, more 
physicians (35%, 12% absolute increase) would recommend conservative management, while 50% and 
17% of doctors would recommend RFA or AADs, respectively. 
 
Over the past few years it has become clear that comparative effectiveness trials to understand how 
to best treat subjects with frequent PVCs and CM are needed12,26. Thus, we propose a multicenter study 
to better understand the prevalence of frequent PVCs and CM, as well as conduct a clinical pilot study to: 
1) prove feasibility of a large-scale randomized clinical trial, 2) determine rate of improvement of LV function 
(responders), cardiovascular and adverse events in both RFA and AADs treatments and 3) determine the 
rate of spontaneous improvement of LV function (during observation period), Understanding the 
prevalence of PVC-CM will give us a better perspective of the magnitude of this clinical entity, while the 
prospective pilot study will allow us to properly design and power a large multicenter prospective 
randomized study, the Prospective Assessment of PVC Suppression (PAPS) study. 
 
 
 PVC-CM, as any CM, leads to HF admissions and implant of internal cardiac defibrillators and cardiac 
resynchronization devices6,27, which likely translates into increased healthcare costs. Therefore, 
appropriate diagnosis and treatment of PVC-CM will not only reverse LV dysfunction with its associated 
HF morbidity, mortality and healthcare spending, but most importantly improve subject’s health, quality of 

PAPS Pilot Study: Clinical Investigation Plan                                 Page 15 of 50, Version 8.0 (22-Apr-2019) 
life and long-term prognosis. A better understanding of the PVC features required to induced CM and the 
clinical impact of RFA and AADs could help us prevent and better target therapy in those subjects with 
PVC-CM6.  
 
 
Impact of proposed PAPS pilot study  
This study will not only generate data to demonstrate the need of a clinical trial, but also to better 
design our large–scale multicenter randomized clinical trial, the PAPS study.  
 
This grant application with a multidisciplinary approach intends to: 
1) Identify the prevalence of subjects with potential PVC-CM (≥10% PVC burden and LVEF ≤45%) in the 
overall population receiving Holters in participating tertiary high-volume centers.  
 
2) Identify demographics, rate and limitations of enrollment, rate of responders (defined as improvement 
of LVEF ≥ 10%; rationale found in Section: Approach – Study Design: Aim 2) during observation period 
and active PVC suppression, and potential crossover between PVC suppression arms (RFA and 
AADs).  
 
3) Understand the feasibility and better design and power a large multicenter trial (PAPS Study).  
 
Thus, the proposed pilot study will pave the way for a large-scale multicenter randomized PAPS study to 
identify the best treatment strategy for subjects with PVC-CM. 
 
 
 
 
 
 
INNOVATION 
 
Both RFA and AADs are current therapies used to suppress frequent PVCs. While other studies registered 
in clinicaltrials.gov compare RFA versus optimal HF medical therapy in a similar population,  
our study includes 3 types of innovations: 
1) Clinical innovation by a) identifying the prevalence of PVC-CM in a specific population and identify 
the safest and effective therapy to improve clinical outcomes, and b) comparing PVC strategies of RFA 
to AADs and include secondary end-points such as adverse events, arrhythmia burden and clinical 
outcomes (New York Heart Association class, quality of life, HF admissions, and need for ICD 
implants). 
2) Trial design innovation by incorporating a 3-month observational period, which allows: a) each 
subject to serve as his/her own control when we compare to PVC suppression strategy, whether RFA 
or AADs, and b) assess natural history and the rate of spontaneous resolution of PVCs and/or CM.  
3) Mechanistic innovation with cardiac magnetic resonance (CMR) imaging to ascertain baseline 
myocardial tissue characteristics (indicative of interstitial versus replacement fibrosis) and LV 
contraction patterns to identify potential mechanisms of lack of response despite PVC suppression. 
 
 
 
 
 
 
 
 
 
 
 

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 STUDY DESIGN – PART I 
 
PAPS pilot randomized trial: to assess the feasibility of enrolling, randomizing treatment 
strategies and retaining participants with frequent PVCs and associated CM.  
 
The lack of treatment guidelines of PVC suppression results in the use of different treatment strategies 
or no treatment at all of subjects with possible PVC-CM, which is solely based on personal physician’s 
experience and availability rather than outcomes. 
 
A. Study Population and Eligibility 
This is a prospective randomized pilot study including between 36-39 subjects with cardiomyopathy 
(CM) and high PVC burden with a likely diagnosis of PVC-CM6, where all subjects will be assigned to a 
1:1 random allocation to one of two un-blinded PVC suppression groups: 1) PVC radiofrequency ablation 
(RFA) vs. 2) antiarrhythmic drugs (AADs).  
 
Definitions:  
The diagnosis criteria for PVC-CM is based on LVEF ≤ 45% (by echocardiography) and average PVC 
burden ≥ 10% in an ambulatory ECG Holter monitor that meet the inclusion and exclusion criteria (Table 
1), regardless of severity and time of onset. LVEF and PVC burden must be within 150 days of Enrollment 
Visit (Day 0). 
Responders are defined as an LVEF increase greater than 10% points regardless of intervention.  
 
If screening confirms eligibility (LVEF ≤45% and PVC burden ≥ 10%), a baseline visit will be scheduled 
to obtain subject’s demographics and medical history, 12-lead ECG, Minnesota living with HF quality of 
life (QOL) questionnaire, NYHA functional class and cardiac magnetic resonance (CMR) if clinically 
indicated. Subjects that refuse enrollment, will be asked to participate in a PVC-CM registry to follow their 
response and crossover to different treatment strategies.  
If subjects meet inclusion criteria (Table 1) during screening, informed consent should be obtained. 
Stratified randomization to either RFA or AADs will be performed at the time of enrollment (baseline visit, 
week 0). Based on our preliminary data, we expect that around 30% of subjects will have a PVC burden 
>20%5. Thus, a stratified randomization based PVC burden (assessed by Holter) above and below 20% is 
needed to assure that subjects in both groups (RFA vs. AAD) are equally distributed between PVC burden 
above and below 20%. Stratified randomization will be performed using approved software available at the 
Coordinating Center only.   
If a subject is randomized to the RFA arm, a RFA procedure (Visit 1) should be scheduled at the time 
of randomization due to usual 8-week next available RFA appointment in most participating centers. Yet 
both, RFA and AAD interventions should only occur or be initiated after completion of a 3-month 
observation (Table 2 - Visit Tx-V1, week 12-15). 
A 3-month observation period will assess spontaneous variation of PVC burden and improvement or 
deterioration of LV function. During the final 3-month observation visit (Week 12), LVEF and Holter will be 
repeated to confirm eligibility if PVC burden and LVEF remains ≥10% and ≤45%, respectively.  
 
 
 
 
 
 
 
 

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Table 1. Inclusion and Exclusion Criteria. 
Inclusion Criteria 
1.  LV dysfunction (calculated** LVEF ≤45% based on Echo) within 150 days of Enrollment Visit  
(Day 0)  
2. Average PVC burden ≥ 10% by ambulatory ECG Holter monitor within 150 days of Enrollment Visit 
(Day 0) 
 
**If only the estimated LVEF is available at time of enrollment, request calculated LVEF within 
five days of enrollment 
 
 
Exclusion Criteria 
 
1. Age < 18 years old 
2. Current Amiodarone use or within last 2 months 
3. Current use of any antiarrhythmic drugs class I or III 
4. Contraindication to use amiodarone or any other class III antiarrhythmic 
5. Severely symptomatic PVCs (defined as incapacitating palpitations or pre-syncope) unable to 
complete a 3-month observation period 
6. Severe/significant CAD with planned revascularization in the near future 
7. Complete AV block and pacemaker dependent 
8. Pacemaker or ICD with > 10% of right ventricular pacing 
9. Severe valvular heart disease or planned valvular/cardiac surgery 
10. Uncontrolled or untreated endocrinopathies 
11. Uncontrolled HTN (systolic >180 mmHg or diastolic > 110 mmHg) 
12. Hypertrophic cardiomyopathy 
13. Systemic infiltrative and immune disorders 
14. Family history of dilated CM in a first-degree relative 
15. Alcohol abuse or illicit drug use 
16. Contraindication to short-term anticoagulation (due to possible randomization to RFA) 
17. Atrial fibrillation and flutter with Rapid VR with possible tachycardia-induced cardiomyopathy 
18. Pregnant or lactating women 
19. Possible infectious etiology of cardiomyopathy 
20. Previous PVC ablation 
 
 
 
If both PVC and/or LVEF criteria are not met after the observation period, the subject will be withdrawn 
from the study and treatment will be as recommended by primary provider. We will ask the subject to 
participate in a PVC-CM registry with assessment of PVC burden and LVEF as clinically indicated during 
the following 12-month study. When allowed by the IRB, informed consent will include an option for 
participation in this registry as a contingency in case subjects no longer meet criteria or decide to withdraw 
participation. These subjects will continue treatment as recommended by their local clinical 
electrophysiologist. 

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Table 2. Table of Study Procedures 
 
 
3-month Observation  
12-month Treatment Phase 
Obs–V1 
Baseline 
Obs–V2 
2-mo 
Obs–V3 
3-mo 
Tx–V1 
Baseline 
Tx–V2 
1-mo 
Tx–V3 
3-mo 
Tx–V4 
6mo 
Tx– V5 
9-mo* 
Tx – V6 
12-mo 
Timeline in Weeks 
(range of days) 
Week 0 
(Day 0) 
Week 9 
(51-63) 
Week 12  
(84-96) 
Week 12-15 
(84-105) 
Week 21 
(141-153)  
Week 26 
(176-188) 
Week 38 
(260-272) 
Week 50 
(344-356) 
Week 64  
(441-454) 
Informed consent  
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Collection of demographic 
data 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
X 
X 
X 
X 
X 
Functional status/NYHA class 
X 
 
X 
 
X 
X 
X 
X 
X 
QOL Minnesota HF 
Questionnaire 
X 
 
X 
 
X 
X 
X 
X 
X 
Current / change of 
medications 
X 
 
X 
 
X 
X 
X 
X 
X 
12-lead ECG 
X* 
X* 
X 
 
X* 
X* 
X* 
X* 
X* 
Ziopatch 
X 
X‡ 
X€ 
X 
X 
X 
Echo  
X£ 
X‡ 
X 
X* 
X 
BNP / ProBNP levels 
ESR & CRP 
X*£ 
 
X* 
 
X* 
X* 
X* 
X* 
X* 
Urine pregnancy test (if 
applicable) 
X 
 
X 
X 
X 
X 
X 
X 
X 
CMR 
X* 
TSH (if assigned to 
amiodarone) 
 
 
X 
 
 
 
X 
 
X 
LFT (AST) (if assigned to 
amiodarone) 
 
 
X 
 
 
 
X 
 
X 
Treatment randomization  
X 
 
 
 
 
 
 
 
 
Initiation of RFA or ADD 
 
 
 
X 
 
 
 
 
 

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Collection of unsolicited AEs 
From Obs-Visit 1 until Tx-Visit 6 
Footnote:  *, visit/intervention if clinically indicated. 
‡ LVEF results of 2D-echocardiogram and Ziopatch have to be available at the time of Observation Visit 3 (Obs-V3). € If PVC burden >10%, subject should be 
considered to either adjust antiarrhythmic therapy (AAD group) or second ablation procedure (RFA group) based on their randomization group. ESR, Erythrocyte 
sedimentation rate; CRP, C-reactive protein.  £ Must   be done within 150 days of Enrollment Visit (Day 0)  

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Crossover between PVC suppression strategies is not encouraged. We request that crossover only be 
considered after 6 months of initiation of treatment, for which an intention-to-treat analysis will be 
performed. However, if crossover occurs before 6 months of initiation of treatment, subjects will be 
withdrawn from the study and included in the PVC-CM registry if the subject provided consent.  
Every effort will be made to have females enter this study. Medically accepted birth control is 
required to enter this study. This may include, but is not limited to, birth control pills, IUD’s, condoms, 
diaphragms, implants, being surgically sterile, or being in a post-menopausal state.  However, no birth 
control method completely eliminates the risk of pregnancy and potential risk of miscarriage, birth 
defects, other medical complications or unforeseen risks to subject or to the unborn baby (i.e. embryo or 
fetus) is possible if pregnancy occurs during the study. Any female of childbearing age must have a 
negative pregnancy test before entering the study.  
A pregnancy test will be obtained on females of childbearing age that are assigned to the RFA 
treatment prior to procedure due to fluoroscopy exposure. In contrast, a pregnancy test will be performed 
on a monthly basis on those randomized to the antiarrhythmic treatment arm to confirm the lack of 
pregnancy throughout the 12-month follow up. If a female on the antiarrhythmic arm becomes pregnant 
during the 12-month follow up we will consider stopping antiarrhythmics and the subject will be withdrawn 
from the study. 
Thus, subjects that no longer meet criteria after the 3-month observation period, those that crossover 
before 6 months of treatment initiation or become pregnant during the study will be included in the PVC-
CM registry if the subject provided consent. Subjects that refuse participation in this portion of the study 
(Part I) will also be included in the PVC-CM registry if they provide consent.  
A.1. PVC-CM registry. This registry will consist of patients that: 1) refuse to participate in the randomized 
treatment protocol, 2) no longer meet criteria after 3-month observation, 3) crossover before 6 months of 
treatment initiation, or 4) become pregnant during the study. When allowed by the IRB, informed consent 
will include an option for participation in this registry as a contingency in case subjects no longer meet 
criteria, become pregnant, crossover treatment arms or decide to withdraw from the study.  A separate 
informed consent to participate in this registry will be provided only for those patients that refuse 
participation in the randomized treatment study (main study). Data will be collected at Baseline (day subject 
refuses enrollment in the randomized study), 6 and 12 months for these subjects. Alternately, subjects 
included in this PVC-CM registry who screen fail or withdraw early for any reason,will have data collected 
only by chart review at 6 and 12 months after withdrawing from the study. Data to be collected will include 
demographics, past medical history, treatment interventions including outcomes and related complications, 
NYHA functional status, 12-lead ECG, ambulatory ECG Holter including heart rate, PVC burden and 
arrhythmia burden, echocardiographic data including LVEF, medications and cardiac-related hospital 
admissions. The purpose of this registry is to assess different treatment options offered to patients with 
this medical condition in the “real world” as well as the clinical response to these treatments. 
 
B. Scheduled Visits 
When a subject is first identified during a visit or when reviewing a 24-48 hour or 2-week ambulatory 
ECG monitor (Zio Patch), we request that sites briefly screen the subject by reviewing the inclusion/ 
exclusion criteria of the protocol. Assessment of calculated LVEF (obtained by transthoracic 
echocardiogram) and PVC burden is acceptable as long as it has been obtained within the prior 150 days. 
If the subject meets both, then the subject should be scheduled for a Baseline Visit (Observation – Visit 1).  
Subjects enrolled in the study will have visits as outlined in Table 2 and Figure 1. There are some 
circumstances where the screening and Observation Visit 1 may occur the same day. 
i. Observation – Visit 1.  After inclusion/exclusion criteria is confirmed, the study protocol will be 
explained to the subject and informed consent should be obtained. If the subject agrees to participate, the 
following data should be collected using appropriate forms (see Data collection forms), including general 
info and demographics, current medical therapy, physical exam, NYHA functional class and Minnesota HF 
quality of life questionnaire (QOL). Physical examination and NYHA functional class can be completed 

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based on a prior visit (up to 120 days prior). A 12-lead electrocardiogram and cardiac MR should be 
requested if clinically indicated. Alternatively, we will request that sites provide images of prior ECG or 
CMR if performed within the prior 120 days. Sites should obtain a copy of the transthoracic echo (during 
screening Visit) and mail it to the Echo Core laboratory led by Dr. John Gorcsan III, M.D.The Echo report 
should be uploaded to REDCap. Finally, a 2-week Zio Patch (IRhythm ambulatory ECG device) should be 
placed on the subject to obtain a long-term PVC burden. The subject will mail the device to IRhythm for 
analysis. Instructions will be provided to all centers on the placement of this device.  
During this 3-month observation period, all subjects are allowed to titrate medical therapy to be 
optimized or continue on optimal medical therapy throughout the study. We define optimal medical therapy 
as maximal tolerated/recommended target doses of beta blockers (carvedilol 25mg twice daily, metoprolol 
succinate / tartrate 200mg daily or bisoprolol 10mg daily), angiotensin converting enzyme (ACE) inhibitors 
(lisinopril 20-40mg daily, ramipril 10mg daily, enalapril 10-20mg twice daily or quinapril 40mg twice daily) 
or angiotensin receptor blockade (ARB, valsartan 160mg twice daily or candesartan 32mg daily), 
aldosterone antagonists (spironolactone 25mg daily or eplerenone 25mg daily) and loop diuretics if 
indicated to achieve dry weight28. Entresto (sacubitril 49-97mg/valsartan 51-103mg bid) could be used if 
clinically indicated. Except for non-dihydropyridine calcium-channel blockers (CCB, amlodipine and 
felodipine), diltiazem, verapamil, and nifedipine (dihydropyridine CCB) are not allowed during the study 
due to negative inotropic effect. Class Ia AADs will not be allowed during study due to risk of pro-
arrhythmia.  
During this visit, randomization to either antiarrhythmic drugs (AADs) or radiofrequency ablation (RFA) 
will be obtained. If the subject is assigned to the RFA arm, we request that the RFA procedure be 
scheduled at 3-months from this visit (Treatment – Visit 1). All subjects should be optimized or  continue 
current medical therapy without change. If the subject is randomized to antiarrhythmic therapy (see Section 
C: Description of the intervention/treatment), this should be withheld until the 3-month observation period 
is completed.  
ii. Observation – Visit 2. During this visit, subjects are asked to return to have a repeat Zio Patch (2-
week ECG monitor) and ECG (if clinically indicated). Similarly, subjects will be instructed to mail back the 
Zio Patch to IRhythm, for assessment of PVC burden. At this time, a transthoracic echocardiogram should 
be scheduled in preparation for Observation – Visit 3.  
 
iii. Observation – Visit 3. Similar to Visit 1, appropriate data collection forms should be used to collect 
current medical therapy, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 12-
lead ECG should be obtained if clinically indicated. Transthoracic echocardiogram should be performed to 
assess LVEF and a copy mailed to the Echo Core laboratory led by Dr. John Gorcsan III, M.D. The local 
PI and designated site staff will be able to log in to iRhythm’s ZioReports to obtain the Zio Patch report that 
should include a 2-week PVC burden.  
If PVC burden remains ≥ 10% and LVEF ≤ 45%, then the subject will either initiate antiarrhythmic drugs 
or undergo RFA procedure (see Section C: Description of the intervention/treatment) and will continue on 
protocol as scheduled. However, if these criteria are no longer met, the subject is considered a screen 
failure and is withdrawn from the study. In such a case, the treatment decision is solely at the discretion of 
the electrophysiologist caring for subject.  Nevertheless, this subject will be included in a PVC-CM registry 
if consent was provided (described above Section A.1). 
 
 
i) Treatment – Visit 1. This is considered the baseline visit where PVC suppression strategy 
assignment is initiated (either RFA or AADs). If the subject is randomized to RFA, we will request that sites 
complete the RFA data collection form which includes information during the RFA procedure as well as 
recovery, complications and hospital stay. EPS will be performed on their baseline medications, except for 
antiarrhythmic drugs class II (beta blockers) which will be held at least 5 half-lives prior to procedure. Beta 
blockers should be resumed after RFA.  
iv.  However, subjects randomized to AADs can have this visit combined with Observation-Visit 3. In 
addition, subjects in the antiarrhythmic (AAD group) will require a baseline TSH and LFTs (AST only) if 
amiodarone is chosen.   

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v. Treatment – Visit 2. Using appropriate data collection forms, we will ask that sites obtain current 
medical therapy information, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 
12-lead ECG should be obtained if clinically indicated. A repeat Zio Patch should be placed to re-assess 
adequate PVC suppression after RFA or initiation of AADs. The local PI and designated site staff will be 
able to log in to iRhythm’s ZioReports) 3 weeks later to obtain a Zio Patch Report with repeat PVC burden 
after intervention. If PVC burden is suppressed by more than 80%, intervention is considered successful 
and the subject should continue with treatment visits as scheduled,  
However, if PVC burden does not decrease by more than 80%, intervention is considered a failure. In 
such a case, the subject should be considered for a second RFA procedure or a different antiarrhythmic 
drug depending on the randomization group that the subject was assigned (see Section C: Description of 
the Intervention/treatment). We discourage crossover of treatment arms since this will result in automatic 
withdrawal from the study.   Nevertheless, subjects that withdraw from the study will be included in a PVC-
CM registry if the subject provided consent. (described above Section A.1). 
 
 
 
vi. Treatment – Visit 3. Appropriate data collection forms should be used to collect current medical 
therapy information, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 12-lead 
ECG should be obtained if clinically indicated. A transthoracic echocardiogram should be performed to 
assess LVEF and a copy mailed to the Echo Core laboratory led by Dr. John Gorcsan III, M.D. A repeat 
Zio Patch should be placed to re-assess PVC burden. Local PI and designated site staff will be able to log 
in to iRhythm’s ZioReports 3 weeks later to obtain a Zio Patch Report if desired for any clinical decision.  
 
vii. Treatment – Visit 4. Appropriate data collection forms should be used to collect current medical 
therapy information, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 12-lead 
Figure 1. PAPS study design. A 3-month Observation (Obs) period allows each subject to serve as their own 
control to assess benefits of PVC suppression. All subjects will be randomized (R) to either RFA or AADs. OMT, 
optimal medical therapy. QOL, quality of life questionnaire; NYHA, New York Heart Association class; LVEF, LV 
ejection fraction; Zio, ambulatory ECG Ziopatch Holter, CMR, Cardiac MRI (*, visit/intervention if clinically 
indicated). 

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ECG should be obtained if clinically indicated. If clinically indicated, a transthoracic echocardiogram should 
be performed to assess LVEF and a copy mailed to the Echo Core laboratory led by Dr. John Gorcsan III, 
M.D. A repeat Zio Patch should be placed to re-assess PVC burden. The local PI and designated site staff 
will be able to log in to iRhythm’s ZioReports 3 weeks later to obtain a Zio Patch Report if desired for any 
clinical decision. In addition, subjects in the antiarrhythmic (AAD group) will require a follow-up TSH and 
LFTs if amiodarone is part of the current treatment.   
 
viii. Treatment – Visit 5. Using appropriate data collection forms, we will ask that sites obtain current 
medical therapy information, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 
12-lead ECG should be obtained if clinically indicated. If a transthoracic echocardiogram is performed for 
any reason prior to this visit, we will ask that sites mail a copy to the Echo Core laboratory (Dr. John 
Gorcsan III, M.D.). 
 
ix. Treatment – Visit 6. Using appropriate data collection forms, we will ask that sites obtain current 
medical therapy information, NYHA functional class and Minnesota HF quality of life questionnaire (QOL). 
12-lead ECG should be obtained if clinically indicated. A final, transthoracic echocardiogram should be 
performed to obtain assessment of LVEF and images should be sent to the Echo Core laboratory (John 
Gorcsan III, M.D.). A repeat Zio Patch should be placed to re-assess PVC burden. The local PI will be able 
to log in to iRhythm’s ZioReports to obtain a Zio Patch Report if thought to be needed for treatment 
decisions.  In addition, subjects in the antiarrhythmic (AAD group) will require a follow-up TSH and LFTs if 
amiodarone is part of the current treatment.   
 
C. Clinical Assessment and tests 
Regardless of group assignment, all subjects will undergo clinical evaluation and a series of 
clinically indicated tests and interventions as outlined in Table 2 and Figure 1. 
c. 1. 12-lead ECG will be performed at each center and sent to the ECG/Holter core lab (led by Dr. 
Edward Gerstenfeld, UCSF, San Francisco, CA) where a cardiologist blinded to treatment group will 
provide a final interpretation. Scheduled ECG is requested as noted in Table 2 if clinically indicated. We 
will assess QRS duration and QT interval of non-PVC beats and PVC features such as location, QRS 
duration and coupling interval or prematurity.  
c 2. Ambulatory Holter monitor (Zio Patch, iRhythm, Inc). This Holter monitor will be  provided directly by 
iRhythm, Inc. to participating centers. Subjects will mail the device back directly to iRhythm where it will 
be analyzed and results will be provided to each center. This monitor will provide automatic assessment 
of daily PVC burden remaining blinded to the group assignment. Custom software designed by Dr. 
Gerstenfeld will be used to measure PVC coupling interval, coupling interval variability, and number of 
PVC morphologies. This will allow us to assess important PVC features during the observation period 
and treatment arms. Reports will be sent to the ECG/Holter core lab (noted above) for final interpretation. 
Similar to the ECG, the reader will be blinded to the group assignment. The ambulatory Holter monitor 
will allow us to assess long-term PVC burden and morphology and compare efficacy to achieve 
successful PVC suppression (defined as PVC reduction ≥ 80%) between RFA and AAD groups. 
Furthermore, it will provide information such as PVC recurrence, and the presence of non-sustained 
and/or sustained ventricular tachycardia. 
c. 3. Transthoracic Echocardiogram. Scheduled 2D-Echocardiograms should be requested as noted on 
Table 2 if clinically indicated. Echocardiograms will be performed using a commercial system with a 
5MHz standard cardiac probe with at least 70-80 frames per second. Echocardiography will be 
considered adequate if echocardiographic windows allow assessment of the following parameters, 
otherwise, echo contrast should be performed. LV function will be assessed by quantifying the calculated 
LVEF (Simpson’s formula), fractional shortening (FS), LV end-systolic and diastolic dimensions (LVESD, 
LVEDD), LV thickness, left atrial (LA) size, mitral valve (MV) function, LV compliance (E/A ratio and E/E’ 
ratio), and dyssynchrony29. Interventricular dyssynchrony will be evaluated by RV and LV 
electromechanical delay (time from onset of QRS to the onset of pulmonary and aortic systolic flow, 
respectively). LV mechanics / dyssynchrony will be assessed by 1) septal to posterior wall delay, 2) PW-
TDI maximum systolic motion delay between septal, anterior, posterior and lateral wall, and 3) 2D 

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speckle tracking strain analysis (radial, circumferential and longitudinal strain)18. A copy of the 
echocardiogram images should be sent to the Echo core laboratory (led by Dr. John Gorcsan, III) for final 
interpretation by a cardiologist blinded to the randomization arm. Assessment of LVEF by 
echocardiography will be repeated during observation and treatment phases in order to assess changes 
in LV function during observation period and between PVC suppression strategies. 
c.4. Cardiovascular magnetic resonance (CMR). If clinically indicated, a delayed enhancement CMR 
will be performed at each center following a single protocol (approved by CMR core laboratory Director: 
Dr. Gregory Hundley, Richmond, VA) and sent to the CMR core lab for final interpretation. Similarly, 
CMR core lab and participants will remain blinded to group assignment. CMR will be obtained at baseline 
if clinically indicated to assess LV volumes, mass, ejection fraction, and mid-wall circumferential strain; 
overall myocardial T1, T2, and extracellular volume fraction (ECV); and scar location and extent using 
late gadolinium enhanced methods according to previously published techniques30,31. Associations 
between each CMR assessment and improvement in LV function (responders) will be determined after 
PVC suppression strategy. Interstitial myocardial fibrosis and outcomes between early- vs. late-coupled 
PVCs in an attempt to support a mechanistic aim in final PAPS study. The CMR will be considered 
clinically indicated to exclude other types of cardiomyopathy, and all sites have agreed to order CMR on 
enrolled subjects. 
c.5. Minnesota living with heart failure quality of life (QOL) and NYHA functional class questionnaires to 
be used in the PAPS study will be approved by Dr. Teresa DeMarco (Heart failure core lab). These 
questionnaires will be provided to each center to be answered by each subject in their local institution. 
This will allow us to assess heart failure symptoms and change in quality of life and functional status 
during the observation period and between both treatment groups. Questionnaires will be sent directly to 
the Heart failure core lab. All QOL and NYHA questionnaires will be evaluated and graded by an event 
adjudication committee (independent of the steering committee, see Section G. Ethical / Regulatory 
Affairs). If clinically indicated, we will request to provide brain natriuretic peptide (BNP) levels as well as 
CRP and ESR as per schedule on Table 2. Participants who are evaluated by study staff and suspected 
to be depressed will be referred to a primary care provider to facilitate the evaluation. 
c. 6. Complications, heart failure admissions and adverse events. All events including mortality, hospital 
admissions and heart failure exacerbations and treatment-related complications will be documented on 
each subject throughout the observation and treatment periods. Each center will report any adverse 
events to the Coordinating Center (McGuire VA Medical Center, Richmond VA) within 24-48 hours of the 
occurrence or knowledge of the event. All SAE/hospital admissions, procedure complications and events 
will be evaluated and assigned by an event adjudication committee (see Section G. Ethical / Regulatory 
Affairs and documents: Human subjects and Data Safety Monitoring plan for details). 
 
 
 
Participating centers will provide all available clinical data to respective core labs (echocardiogram, 
cardiac MR and Holter) and Coordinating Center (McGuire VA Medical Center) through REDCap with a 
case number without identifiers and treatment randomization as outlined in the Manual of Operations and 
Standard Operating Procedures manual. 
Of note, subject participation and results of this study will not change diagnostic testing (e.g. 
electrophysiologic studies for other indications) and medical management including medical therapy 
(unless safety drug interactions are clear) and indicated procedures (e.g. left heart catheterization). ICD 
implantation is not encouraged (but not prohibited) during the study as the CM may improve or even resolve 
after RFA of PVCs as recently shown by Penela et al.26. 
 
D. Description of the intervention(s)/treatment(s). 
Prior to intervention, all subjects should complete a 3-month observation period consisting of a total 
of 3 visits. Subjects that are not able to wait or be observed for this period of time should not be considered 
for this study. Subjects will be randomized to intervention at the baseline visit of observation. Crossover 
between different treatment arms (RFA vs. AADs) is not encouraged and will not be allowed before 6-
month follow-up duration of the treatment period, unless considered critical for the subject’s well-being. 
 

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ii) Treatment or intervention arms will consist of: Antiarrhythmic drug (AAD) therapy. AAD therapy 
of choice is amiodarone due to its proven safety in subjects with LV dysfunction. Amiodarone loading dose 
of 10 grams is recommended, followed by maintenance dose of 200-400mg daily to achieve successful 
PVC suppression. We define successful PVC suppression only if ≥ 80% absolute reduction in PVC burden 
is achieved after a drug or intervention4,24.  Alternatively, sotalol and/or propafenone could be considered 
at the discretion of the electrophysiologist (sotalol dose of at least 120mg twice daily, propafenone 150-
300mg tid) if there is a significant concern of safety profile of amiodarone. Finally, other AADs (class Ic) 
are acceptable if there is a clear preference by the clinical electrophysiologist while a rationale is requested 
for such choice. Overall, we suggest avoiding class Ia antiarrhythmic drugs due to the prior documented 
risk of pro-arrhythmia, however, they could be considered in subjects with an implantable or external 
defibrillator (Lifevest). Optimal heart failure medical therapy should be continued in combination with AAD 
throughout the 12-month follow-up. Throughout the 12-month follow up period, subjects will have a total of 
5 visits to assess changes in clinical status, arrhythmia burden including PVCs and LVEF as outlined in 
Table 2 and Figure 1. In addition, subjects receiving amiodarone as antiarrhythmic (AAD group) will require 
a baseline TSH and LFTs and should be repeated every 6 months.   
A 2-week ambulatory ECG Holter (Zio Patch, IRhythm, Inc.) will be obtained 4-6 weeks after initiation 
of AAD to assess whether PVC suppression was successful (defined above). If successful PVC 
suppression is not achieved, we will ask sites to consider either an increase in the antiarrhythmic dose or 
change of antiarrhythmic as noted above. A repeat 2-week ambulatory Holter monitor will be done 4 weeks 
after adjustment of AAD to re-assess PVC suppression. 
 
Radiofrequency Ablation (RFA) of PVCs. RFA will be performed after completion of 3-month observation 
period). EPS will be performed on their baseline medications, except for antiarrhythmic drugs class II (beta 
blockers) which will be held at least 5 half-lives prior to procedure. Beta blockers should be resumed after 
RFA.  
 
EPS and RFA will be performed using standard techniques and protocols similar to those subjects 
that do not participate in this clinical study. Multipolar electrode diagnostic catheters will be inserted. If no 
ectopy is present at baseline, isoproterenol may be infused at rates up to 10mcg/min. If the ectopy is 
infrequent despite adrenergic stimulation, pace mapping will be performed at a pacing cycle length 
determined by coupling interval of the spontaneous ventricular ectopy5. RV or LV PVCs will be mapped/ 
ablated at the discretion of the electrophysiologist. Coronary angiography and/or intracardiac echo will be 
performed as needed. RFA will be performed at the site of earliest endocardial activation or best pace 
map. RFA applications will be delivered for at least 30 seconds if adequate power at the electrode-tissue 
interface is achieved. RFA will be continued for at least 60-120 seconds in sites where PVCs are abolished 
within 30 seconds. After ablation of the PVCs, isoproterenol will be administered at 2-10 mcg/min as 
required to shorten sinus CL to 500ms to confirm that PVCs are not inducible by adrenergic stimulation. In 
the event of polymorphic PVCs, all morphologies are to be targeted for ablation 5. Subjects will be observed 
overnight in a telemetry bed and discharged home the next day, as it is current standard of care.  
During enrollment and immediately after RFA, baseline medical therapy (including ACE 
inhibitors/ARB, beta blockers) should be optimized or continued throughout the 12-month follow-up period. 
Practitioners will be asked to document any changes in medical therapy including rationale. All events, 
side effects as well as change or decrease of doses will be documented and rationale explained. Similar 
to the AAD group, subjects will have 5 follow-up visits (Visit 2 – 6, Table 2 and Figure 1) to assess changes 
in clinical status, arrhythmia burden including PVCs and LVEF.  
A 2-week ambulatory ECG Holter (Zio Patch, IRhythm, Inc.) will be obtained 4-6 weeks after RFA 
to assess whether PVC suppression was successful (defined above). If successful PVC suppression is not 
achieved, subjects will be offered a second PVC-RFA procedure 3 months after initial randomization. 
Redo-RFA will be performed with a similar approach as the first intervention; however, epicardial mapping 
will be encouraged if considered appropriate. This subgroup of subjects will have a repeat 2-week Holter 
monitor within 2-4 weeks after redo-RFA to document successful or failure of PVC suppression. All events 
and complications in the PVC suppression arm related to RFA will be documented.   
 
E. Primary and secondary outcome measures. 
The outcomes are divided in primary and secondary end-points (Table 3). 
The primary end-points will consist of: 

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1.  Improvement of LVEF after PVC suppression at 12-month follow-up. This is chosen as primary-end 
point due to the known prognostic value of LVEF. The lower the LVEF, the higher the risk of sudden cardiac 
death and heart failure1-3. This will compare the overall improvement or change in LVEF between RFA and 
AAD groups. This end-point will support that either RFA or AADs have an overall better outcome due to 
significant improvement of LV function with potential impact on morbidity and mortality associated with 
PVC-CM. 
2. Responders to PVC suppression strategy at 12-month follow-up (See rationale under Section 
“Definitions” in 3rd paragraph of Aim 2). Assessment of the number of responders (delta LVEF ≥ 10%) 
after PVC suppression strategies (RFA or AADs) will assess the effectiveness of RFA and AADs to reverse 
or improve cardiomyopathy induced by frequent PVCs. Evidence that either RFA or AADs is superior to 
improve or even reverse LV dysfunction in subjects with high burden PVCs could have significant impact 
of morbidity and mortality including future heart failure and ventricular arrhythmias, and also may avoid 
ICD implantation.   
 
The secondary end-points will consist of:  
1. Efficacy of RFA vs AADs groups to 
achieve successful PVC suppression at 
12-month 
follow-up, 
defined 
as 
a 
reduction 
of 
PVC 
burden 
≥80% 
(regardless 
of 
LVEF 
change). 
Understanding the success rate of PVC 
suppression between RFA and AADs will 
help better determine the best treatment 
to those subjects with high PVC burden.  
2. Composite 
end-point 
of 
adverse 
events at 12-month follow-up, including 
worsening in NYHA functional class (I-IV), 
number 
of 
HF 
and 
cardiac-related 
admissions, RFA complications and AAD 
adverse effects and cardiovascular death. 
This adverse event composite end-point 
is chosen to understand the overall 
complications and adverse effects/events 
related to RFA and AADs. Worsening of 
NYHA functional class will be defined as when/if the subject’s functional status worsens by one NYHA 
class. Hospital admissions will be defined as any visit to ED or hospital admissions related only to a 
cardiovascular event such as heart failure, angina, pre/syncope and palpitations. 
3. Composite end-point of arrhythmia burden, including PVC recurrence, non-sustained (< 30sec) and 
sustained (> 30sec) ventricular arrhythmias and arrhythmic sudden cardiac death at 12-month follow-up. 
This composite end-point of arrhythmia burden is chosen in order to understand the difference in 
arrhythmia recurrence between RFA and AAD therapy. PVC recurrence will be defined as reduction of 
PVC burden ≤ 80% at 6- and 12-months when compared to baseline (pre-treatment) PVC burden. 
 
F. Data interpretation and analysis 
Barriers / limitations of enrollment, randomization and retention of participants in this clinical pilot study.
 
Subjects are referred to tertiary centers for RFA of PVCs in subjects with associated CM in the 
hope to reverse LV dysfunction if the underlying cause is related to PVC-CM. Thus, it is important to 
understand that the observational period and randomization is acceptable and will not compromise 
enrollment. Subjects that meet inclusion and exclusion criteria will be asked to participate. We plan to 
understand the comfort level of subjects participating in this clinical study. We will assess the rate and 
rationale for declining participation or withdrawal from this study. Those individuals that decline or withdraw 
will be asked to provide one of the following rationale: 1) uncomfortable with observation/waiting period, 2) 
uncomfortable with AAD therapy, 3) unable/unwilling to commit for a long term follow up, 4) uncomfortable 
participating in any type of research, 5) other reasons including those not related to the study itself. 
Table 3. End-points for PAPS Pilot study  

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Subjects that refuse enrollment, will be asked to participate in a PVC-CM registry to follow their response 
and crossover to different treatment strategies (described above Section A.1)..  
We hypothesize that subjects and/or physicians will not object to participate due to the 3-month 
observation period since most tertiary referral centers have significant procedure wait times for which 
usually they are scheduled between 8- to 12-weeks after clinical decision of PVC suppression is made. 
We have involved all participating centers, who agree that this is a common and acceptable scenario during 
which the observation period proposed could take place. In contrast to other clinical studies where RFA is 
being compared to placebo, we speculate that randomization of RFA vs. AADs will not be an enrollment 
limitation since all subjects will undergo a PVC suppression strategy. This pilot study will allow us to prove 
feasibility of the PAPS study with the current study design including a 3-month observation period and 
treatment randomization. 
 
Rate of spontaneous recovery of CM and PVCs suppression during the 3-month observation period and 
assess the recurrence of CM and PVCs during a 12-month follow up.  
 
Due to a known temporal variability of PVC burden over time24,32, it is unclear how often spontaneous 
variability of PVCs would lead to observing what appears to be spontaneous resolution of PVCs (e.g.,  
without any intervention), which could in theory result in spontaneous improvement of LV dysfunction if 
CM is secondary to frequent PVCs.  
 
We will assess and compare the PVC burden and LVEF between the time of enrollment and at the 
end of the 3-month observation period. This pilot study will allow us to understand the degree and rate of 
spontaneous improvement of LVEF and reduction of PVCs (control phase) to properly power a large 
multicenter PAPS study. Subjects that do not meet both inclusion criteria (LVEF ≤45% and PVC burden 
≥10%) at the end of the observation period willbe considered a screen failure, and will be included in a 
PVC-CM registry if consent has been provided. Based on preliminary data, we believe that less than 10% 
of subjects will have spontaneous improvement of LVEF >45% and PVC <10%. Registry subjects will have 
PVC and LVEF assessment every 6 months for the remaining 12 months to understand the recurrence of 
CM and PVCs (see Section A.1).  
 
Rate of responders to PVC suppression  
 
Besides improvement in LV systolic function, no study has been designed to demonstrate clinical 
benefits with either RFA or AADs. Clinical benefits are implied based solely on the improvement of LVEF. 
Based on prior retrospective and observational studies, the rate of responders (improvement of LVEF) to 
PVC RFA is estimated at 50-65%7,22,26. Unfortunately, there is no recent data on antiarrhythmics due to 
the lack of recent studies. Our preliminary data from the CHF-STAT study demonstrates a response rate 
of 28% (Preliminary Data Section).   
 
We plan to further identify the rate of responders after PVC suppression by obtaining the following 
primary end-points: 1) improvement in LVEF (determined by delta LVEF = final LVEF – baseline LVEF) 
and 2) “responders” to PVC suppression (defined as change in LVEF ≥ 10%). In addition, we will obtain 
QOL and NYHA functional class questionnaires (secondary end-point described above). Each subject will 
serve as its own control, since all data obtained will be compared between the end of 3-month observation 
period (control phase - prior to randomization) vs. 3-month after PVC suppression strategy, regardless of 
treatment randomization (RFA and AAD). We hypothesize that a PVC suppression strategy (RFA or AAD) 
is better than optimal HF medical therapy alone to improve LV function, HF symptoms, heart failure 
admissions, and avoid the need for defibrillator. The PAPS pilot study will help us determine the rate of 
responders to PVC suppression strategy in order to properly estimate sample size and power the large 
randomized PAPS study. 
 
Determine the efficacy to achieve successful PVC suppression and rate of adverse events between RFA 
and AAD treatment arms.  
 
The best PVC suppression strategy (RFA vs. AADs) in subjects with PVC-CM is not known due to the 
lack of head-to-head comparison. Moreover, The rate of responders, successful PVC suppression (defined 
as 80% PVC reduction), adverse events and treatment crossover between these 2 treatment arms is 
unknown. We plan to assess and compare clinical benefits (QOL, NYHA class, HF symptoms, morbidity 
and mortality, avoidance of device implants) and secondary end-points (composite adverse events, 

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composite arrhythmia burden and efficacy of PVC suppression) between RFA and AADs in a large 
randomized PAPS study.   
 
After treatment randomization in the proposed PAPS pilot study, all data will be compared between 
RFA and AAD throughout the 12-month follow up to determine the change in PVC burden, clinical 
outcomes including adverse events and treatment crossover between both distinct treatments. We 
hypothesize that RFA is better than AADs to improve LV function, HF symptoms, while decreasing heart 
failure admissions, arrhythmia burden, heart failure admissions, and avoid the need for a defibrillator.  
 
This pilot study will allow us to determine the rate of successful PVC suppression (greater than 80% 
PVC reduction), adverse events and 6-month treatment crossover between both RFA and AADs, which in 
turn will allow us to properly design and power the large randomized PAPS study. 
G. Data collection 
Using a subject questionnaire and through medical records, we will obtain and record baseline 
demographics, including age, gender, race, ethnicity, duration of cardiomyopathy and prior LVEF, history 
of atrial fibrillation, and medical therapy including dosing prescription. All procedures and tests to be 
performed during the observation and treatment period (RFA vs. AADs group) are outlined in Figure 1 and 
Table 2.  
Data will be collected and recorded directly by the research coordinator and local investigator and as 
per protocol. A unique identifier will be given to each subject. All participating institutions will be required 
to complete and submit all data directly to the Coordinating Center via a secure encrypted data capture 
system (REDCap). In addition, we will request all centers to scan a copy of all completed questionnaires 
and forms through REDCap. All participating sites will comply with all applicable laws, regulations and 
provisions related to the subject’s privacy and data confidentiality (see details in Protection of Human 
Subjects). 
Data quality and consistency of intervention (RFA of PVCs) will be facilitated and monitored by 1) 
standardized subject’s research study forms to be completed by all centers, 2) review of subject’s 
data/forms as study visits are completed, 3) complications/adverse events, and 3) effectiveness of PVC 
suppression by Data Safety Monitoring Board (DSMB) and during PAPS investigators annual meeting. In 
contrast, the quality of echocardiogram, Zio Patch Holter monitors and CMR will be monitored by Echo, 
Holter and CMR core laboratories, respectively. 
 
H. Limitations 
The following limitations may arise during the development of this project: 
1. Subjects with progression from mild and moderate to severely symptomatic PVCs (incapacitating 
palpitations and dizziness) will be encouraged to complete the 3-month observation period since PVC 
suppression will initiate immediately thereafter. Subjects are excluded if symptoms preclude completion of 
the 3-month observation. 
2. Limited or poor suppression of PVC suppression in randomized treatment (RFA or AAD) arm. These 
subjects are encouraged to remain on the assigned arm. However, crossover to the alternate treatment 
arm can be considered after 6 months only if considered medically indicated. If crossover were to occur 
before 6 months, immediate notification and final evaluation with echocardiogram and ambulatory ECG 
Holter monitor (Zio Patch) should be obtained prior to crossover, and the subject will be excluded from 
study and followed in a PVC-CM registry if consent was provided (described above Section A.1).  
3. PVC variability or spontaneous resolution of PVCs may limit pre vs post procedure comparison. PVC 
burden has significant temporal variability and it may be a major limitation in the study of arrhythmias24,32. 
Schmidt 24 demonstrated that an 80% absolute reduction of PVC burden is required to show a true drug 
effect. To minimize daily PVC variability, PVC evaluation in this study will be performed using a 2-week 
ambulatory ECG Holter monitor (Zio Patch, IRhyhtm, Inc.) which is shown to be a better indicator of long-
term PVC burden33.  
4. LV function assessment in ventricular bigeminy. Assessment of LVEF during frequent PVCs represents 
a challenge for all imaging modalities34. Modified acquisition and post-processing methods have been 
developed to correct for R-R interval variability expected with frequent PVCs 35. In the event that the subject 
has persistent ventricular bigeminy at the time of the scheduled echocardiography, the LV function 
assessment should be postponed for a few hours or a later date when PVCs are less prominent (at least 
ventricular quadrigeminy).  

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5. Non-indicated clinical visits, ECGs and cardiac imaging. Due to limited funds provided by R34, the 
protocol relies mostly on clinically indicated follow up visits and cardiac imaging for subjects with HF and 
frequent PVCs undergoing PVC suppression strategy. Table 2 and Figure 1 detail the visits and procedures 
recommended for this study. However, some visits, testing and imaging may be considered outside of 
standard of care (noted on asterisk). It is left to the local PI to attempt to obtain/request these tests if 
considered clinically indicated. This pilot study will also help us determine the number of visits, tests and 
imaging (echocardiograms and cardiac MR) that is clinically indicated to better plan a budget for the large-
scale PAPS study.  
6. ICD implantation for primary prevention is not encouraged during the study as the CM may improve or 
even resolve after RFA of PVCs as recently shown by Penela et.al26 . If an ICD is present or the practitioner 
decides to implant an ICD prior to completion of the study; programming to VVI 40 or other pacing algorithm 
should be considered to ensure minimal ventricular pacing.  
 
I. Statistical analysis and sample size estimate 
All results will be reported according to the CONSORT guidelines. Specifically, all study data will be 
summarized by means and standard deviations or frequencies and percentages. Fisher’s exact tests and 
Wilcoxon rank-sum tests will be used to compare demographic and baseline injury severity information 
between the treatment regimens to ensure proper randomization. The unadjusted relative risk between 
each potential predictors at each time point will be calculated36. An extended model will consider the 
change in the relative risk values over time while also assessing if the relationship between outcome and 
predictor depended on the baseline PVC burden. Similar analyses will be performed for each of the 
secondary outcomes. Lastly, the adverse events will be summarized separately for each treatment group 
using frequencies and percentages. Similar summaries will be provided for each of the PVC burden levels. 
The software SAS/STAT® Software (SAS Institute, Inc. Cary, NC) will be used for all statistical analysis.  
 
Avoidance of bias 
In order to avoid a high proportion of a single ethnic or racial group, we decided to involve multiple high-
volume centers across the country. All participating centers will send all clinically indicated data 
(echocardiograms, CMR, ECG, and Holters) to the respective core laboratory, where the cardiologist will 
be blind to the assigned group, giving a final interpretation. All 2-week ambulatory ECG Holter monitors 
will be contracted to a single company (ZioPatchTM, IRhythm Technologies, Inc.) and evaluated by the 
Holter core lab (Dr. Gerstenfeld) to prevent differences in PVC detection algorithms. Finally, stratified 
randomization will ensure an equal distribution of subjects between PVC burden above and below 20%. 
 
Sample size justification. 
This has been estimated solely on primary end-point of improvement in LV ejection fraction after PVC 
suppression. We are planning to compare the improvement in LVEF between PVC suppression strategies 
(RFA vs. AADs groups). Due to the multiple random effects, a simulation study was conducted to estimate 
the number of subjects required for this study. Specifically, data was simulated according to a linear mixed-
effects model with an unstructured error structure with a random site effect. It was assumed that subjects 
would have a LVEF level of 25% (SD=5%) in each of the groups at baseline and LVEF levels of 40% and 
35% (SD=10%) in the RFA and AAD groups at 12 months, respectively. A within subject correlation of 0.25 
was assumed along with an inter-site standard-deviation of 1%. This model was fit assuming that, on 
average, 10% of the subjects would drop out randomly. Approximately 140 total subjects (70 per group) 
should be enrolled to reject the null hypothesis that the mean LVEF between RFA and AAD groups are 
equal with probability (power) 0.8 and Type I error probability of 0.05. As a pilot study we have determined 
the need to enroll at least 20% (30 subjects) of preliminary sample size estimation to understand feasibility 
and key aspects of subject enrollment, randomization and retention to properly power a large-scale 
randomized PAPS study. Sample size is increased by 15% (6-9 additional subjects, 36-39 subjects total – 
between 19-20 subjects in each treatment group) to take into account possible spontaneous improvement 
of LV dysfunction during the 3-month observation period between treatment strategies. 
 
 
 
 

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J. Ethical / Regulatory Affairs 
The study will be submitted for review to your IRB of record and registered on clinicaltrials.gov prior 
to commencement of study activity. 
 
Event Adjudication Committee 
We will establish a committee to evaluate each hospitalization event to determine its relationship to HF 
and/or the PVC suppression treatment arm. The committee consists of three physicians: 2 heart failure 
cardiologists (Drs. Sean Pinney and John Boehmer) and 1 cardiac electrophysiologist (Dr. Joshua Cooper) 
(see letters of support). Throughout the study and the adjudication process, the committee members will 
remain blinded to treatment allocation, as well as other information that may disclose allocation (TSH, 
LFTs).  
 
Risk Benefit assessment  
All PVC suppression strategies (RFA and AADs), proposed in this grant application are approved by 
the Heart Rhythm Society and FDA for the treatment of ventricular arrhythmias, respectively. Subjects 
assigned to the RFA arm may have a small risk of minor or major complications related to RFA of PVCs. 
However, these risks associated with RFA of PVCs are acceptable and RFA of PVCs continues to be 
performed in clinical practice even though there is limited data to support benefit from this intervention. 
Risks associated with RFA are small (1-2%) including but not limited to stroke, myocardial infarction, 
coronary artery injury, bleeding, cardiac tamponade, pneumothorax, atrioventricular block with subsequent 
need for permanent pacemaker, and even death. Similarly, antiarrhythmic drugs (AAD) may have long-
term risks/adverse effects based on the antiarrhythmic chosen (e.g. amiodarone has significant long-term 
effects including lung disease such as decrease in lung diffusion capacity, optical neuritis, abnormal thyroid 
and liver function, and pro-arrhythmic effects; see Section C in Protection of Human Subjects document 
for details). Yet, these treatment options are currently standard of care frequently offered to this subject 
population with knowinn complications and these adverse events. To minimize the potential risks with 
AADs, all subjects should be considered for additional safety laboratory analyses during treatment as 
recommended per guidelines based on AAD chosen (amiodarone - TSH, LFTs, PFTs, eye exam). 
A pregnancy test will be obtained on females of childbearing age that are assigned to the RFA 
treatment prior to procedure due to fluoroscopy exposure. In contrast, a pregnancy test will be performed 
on a monthly basis on those randomized to the antiarrhythmic treatment arm to confirm the lack of 
pregnancy throughout the 12-month follow up period. If a female on antiarrhythmic arm becomes 
pregnant during the 12-month follow up period, we will consider stopping antiarrhythmics and the subject 
will be withdrawn from the study. 
The IRB should be notified of any serious adverse events (SAE) within 24 hours of such event or 
knowledge of the event. Additionally, the PAPS National Research Coordinator should be notified within 
24 hours of the event or knowledge of the event. The investigator must decide whether each incident meets 
the definition of a SAE.  
 
Data Safety Monitoring Plan and Board 
Serious adverse events and subject monitoring will be performed as stipulated in the Data Safety 
Monitoring Plan (DSMP). As required by NIH, this multicenter trial will also have a Data Safety Monitoring 
Board (DSMB) that will monitor the safety of the study. The DSMB will consist of 2 heart failure specialists 
(Drs. James Fang and Ryan Tedford) and a cardiac electrophysiologist (Dr. Thomas Dewland) (see letters 
of support). Further details of DSMP and responsibilities of IRB and DSMB as stated in the Section: 
Protection of Human Subjects and Data Safety Monitoring Plan.  
 
 
 
 
 
 
 
 
 

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K.  Timeline 
The timeline to enroll between 36-39 subjects in this prospective randomized clinical pilot study is 
summarized in Table 4. IRB submission and coordination will occur within the first few months. Enrollment 
at each center will start as soon as central or local IRB approval is granted and proper training has been 
completed. We expect an average enrollment of 3 subjects per center completing recruitment and follow-
up in 18 and 36 months, respectively.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
L.  Enrollment 
We will engage clinicians/consultants to identify all subjects with frequent PVCs and mild to severe 
CM, regardless of duration, symptoms and heart failure during the following visits: 1) primary care and 
cardiology clinics, 2) device clinic referral for ICD implantation; 3) non-invasive laboratory with documented 
LV dysfunction by transthoracic echocardiogram and a minimum of >10 PVC/hour on average on at least 
a 24-hour Holter; 4) HF clinic with systolic LV dysfunction with frequent PVCs; 5) hospital admission to 
cardiac telemetry due to HF symptoms and PVC frequency of ≥ 10 PVC / hour. However, it is likely that 
most subjects will be identified through Part II, where we will screen all ambulatory Holters for PVC ≥10% 
and LVEF ≤45%. Refer to document Enrollment for further details. 
 
 
 
Table 4. Timeline of PAPS Pilot study  

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 STUDY DESIGN – PART II 
 
Estimate the prevalence of CM (LVEF ≤ 45%) and frequent PVCs (≥ 10%) in the overall population 
receiving ambulatory ECG Holter monitors. 
To prove the feasibility of a large randomized clinical trial (PAPS study), we plan to better estimate 
the prevalence of patients with PVC burden ≥10% and associated CM (LVEF ≤ 45%) in all consecutive 
adult patients undergoing at least a 24-hr ambulatory ECG monitor (Holter). 
A. Study Population and eligibility 
All consecutive adult patients prospectively and retrospectively who have undergone or will 
undergo local ambulatory ECG Holters (at least 24 hr )will be scrutinized for the presence of PVC ≥10% 
and LVEF ≤ 45% by reviewing a recent LVEF assessment (echocardiogram, MUGA or cardiac MR within 
6 months of Holter date). If no LVEF is available, LVEF assessment should be considered to rule out 
associated CM as this would be clinically indicated. The enrollment goal is 1,500 unique subjects per center 
in the first 2 years for a total of near 20,000. Waiver of consent and waiver of HIPAA is requested for this 
portion of the study.   
Retrospective and prospective data collection of this Holter data will allow each center to identify 
patients with potential diagnosis of PVC-cardiomyopathy, which could potentially be candidates for 
treatment randomization (Part I) if inclusion/exclusion criteria is met.  Sites will collect Holter data 
retrospectively starting with Holters placed in July 2018 and forward. 
B. Data Management / Collection  
We will request that all centers provide PVC burden and LV ejection fraction in all-comers that 
undergo placement of an ambulatory ECG Holter regardless of duration (at least 24 hours).  
Only, if PVCs are >10% on Holter, will centers  provide further data including: 
- 
Ambulatory Holter: mean heart rate, number of different PVC morphologies, PVC coupling interval. 
- 
Echocardiographic data: LV end-diastolic and end-systolic dimension, LA size, if available. 
- 
Upload a 12-lead ECG with representative PVC if available. 
 
Once information is collected and entered in REDCap, each subject will receive a unique case 
number.  
 
C. Data Interpretation 
By reviewing Holters and LVEF in all subjects undergoing Holters, we will be able to estimate the 
prevalence of CM (LVEF ≤ 45%) and frequent PVCs (PVC burden ≥10%) in this specific population. We 
will calculate the prevalence of PVC-CM by dividing the number of subjects with frequent PVCs and CM 
by the overall subjects receiving Holters. As noted in our preliminary data, we speculate that the prevalence 
of both CM and frequent PVCs is 0.6% in subjects undergoing Holters. If our hypothesis is proven correct, 
we could demonstrate the potential magnitude of this clinical entity and the feasibility of the large-scale 
multicenter PAPS study by having 3 subjects with a potential PVC-CM diagnosis per 500 Holters. 
D. Ethical / Regulatory Affairs 
 
The study will be conducted according to Good Clinical Practice Guidelines, the Declaration of 
Helsinki and US 21 CFR. Due to inaccessibility to some subjects, a waiver of informed consent and a 
waiver of HIPAA will be requested as some subjects may not be accessible for consent.  
There is a possibility that during the screening of ambulatory ECG Holters and echocardiograms, 
we may find subjects with possible undiagnosed PVC-CM. Ethically, we would then be obligated to notify 
the primary care provider and/or cardiologist of a potential undiagnosed PVC-CM leaving it up to them to 
pursue further referral/interventions.  
 
 

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ENROLLMENT, RETENTION AND FOLLOW UP PLANS 
 
This population is the interest of our research study since PVCs are frequently found, and in 
general these subjects are not considered a “hard-to-reach” population. PVC-CM does not appear to 
have a gender predisposition, but the difference by race or ethnic groups is unknown. Refer to document: 
Inclusion of Women and Minorities, where we address different approaches to include all races and 
ethnic groups. All participating centers are high-volume ablation institutions. We estimate each center 
treats at least 3 subjects within 2 years with a diagnosis of PVC-CM. Thus, participating centers should 
be able to enroll between 36-39 subjects to complete this 3-year pilot trial. Therefore, we are confident 
that recruitment goals will be met. We will engage clinicians and consultants to identify all subjects with 
frequent PVCs and mild to severe CM, regardless of duration, symptoms and heart failure during the 
following visits: 1) primary care and cardiology clinics, 2) device clinic referral for ICD implantation; 3) 
non-invasive laboratory with documented LV dysfunction by transthoracic echocardiogram and a 
minimum of ≥10 PVC/hour on average on at least a 24-hour Holter; 4) HF clinic with systolic LV 
dysfunction with frequent PVCs; 5) hospital admission to cardiac telemetry due to HF symptoms and 
PVC frequency of ≥ 10 PVC / hour and most importantly by 6) screening of consecutive ambulatory 
Holter monitors (PAPS Pilot study - Part II). 
 
Once identified, potential study subjects will be asked to participate in the PAPS study by 
engaging primary care providers to explain to affected subjects the relevance of participating and/or 
engaging and disseminating information regarding this important clinical trial.  
  
 The enrollment and follow up plan will consist of different visits (see Research Strategy, Table 2 
and Figure 1). Screening will consist of review of inclusion/exclusion criteria  
Baseline visit (Observation-Visit 1). If the subject meets inclusion/exclusion, then a baseline visit will be 
scheduled to obtain subject consent and if agreeable obtain NYHA assessment, quality of life 
questionnaire, ECG and perform randomization to either 1) RFA or 2) AADs groups.  If the subject is 
randomized to RFA, the subject should be scheduled 12-weeks ahead during which the 3-month 
observation period will take place. If the subject is randomized to the AAD group, we will ask that 
initiation of AAD  be  delayed, as there is a possibility of spontaneous resolution during a 3-month 
observation period. 
The observation period consists of 3 visits, while the treatment period consists of a total of 5-6 visits 
depending on whether successful PVC suppression is achieved with the very first intervention (Table 2).  
 
We plan to retain enrolled subjects by active engagement by different strategies including:  1) 
informing primary care and heart failure providers of the relevance of this study due to the lack of 
evidence of best treatment strategy, 2) scheduled follow ups, which will allow us to present and update 
all enrolled subjects in regard to the objective of the study, progress of the study as well as the 
importance of understanding the cardiovascular effects of PVCs; and 3) encourage and engage all 
subjects during all scheduled visits, answering all questions in regard to the study and health condition in 
an effort to minimize drop out and noncompliance and successfully complete follow up.   
 
We believe that this comprehensive enrollment and engagement plan will: 1) help us enroll and 
retain research subjects that are representative of the population with cardiomyopathy associated with 
frequent PVCs, and 2) achieve trust from our subjects. 
 
 

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PROTECTION OF HUMAN SUBJECTS 
 
This human research study involves an NIH-Defined Phase III clinical trial, which we will conduct 
according to Good Clinical Practice Guidelines, the Declaration of Helsinki and US 21 CFR. 
 
Risks to Human Subjects  
 
a. Human Subjects Involvement, Characteristics, and Design  
Involvement of human subjects in the work outlined in the Research Strategy section.  
Premature ventricular contractions (PVCs) are frequently found in cardiomyopathy (CM) and heart 
failure (HF). Recently, high PVC burden has been associated with a reversible left ventricular (LV) systolic 
dysfunction, so-called PVC-induced CM (PVC-CM). Animal models have proven the concept that frequent 
PVCs can induce CM, which is reversed after eliminating PVCs. A current clinical conundrum is to 
recognize when PVCs are responsible for the development of a CM or secondary to a CM. Furthermore, 
it is unclear why the majority of subjects with frequent PVCs have a benign course, whereas up to one 
third develop CM.  
Radiofrequency ablation (RFA) is an accepted intervention to restore LV function in CM potentially 
induced by PVCs, based solely on limited small retrospective studies. RFA can have risks as any other 
invasive procedure. Antiarrhythmic drugs (AAD) therapy is an alternative therapy offered to eliminate PVCs 
if subjects or physicians feel appropriate; however, no randomized-prospective study exists to understand 
the clinical outcomes and benefit of RFA when compared to AAD therapy.  Appropriate diagnosis and 
treatment of PVC-CM could impact HF morbidity, mortality and healthcare spending.  
These clinical relevant questions cannot be addressed in animal models. Thus, we propose this 
prospective multicenter randomized trial of subjects with CM and high PVC burden with a likely diagnosis 
of PVC-CM. This pilot study intends to provide the basis to design and power a large clinical randomized 
trial to assess reversal of CM associated with frequent PVCs between RFA and AADs and compare clinical 
benefits (improvement in quality of life, NYHA class, heart failure symptoms and decrease in hospital 
admissions) between RFA and AADs in PVC-CM.  
 
Characteristics of the subject population, including their anticipated number, age range, and health 
status if relevant.  
We will include subjects of any race, ethnic group, gender and adult age (18 years or older) with 
frequent PVCs (defined as PVC burden ≥ 10% by at least a 24-hr ambulatory Holter) ) and LV dysfunction 
(LVEF ≤ 45%) without any clear reversible cause of CM (Study Design – Part I: Table 1). All subjects that 
meet inclusion/exclusion criteria will be offered participation in this study regardless of gender, age or 
ethnic background.  We will attempt to have diversity in age, gender and ethnicity in our study by involving 
the general population treated in different University Hospitals, even though, there is no evidence that age, 
gender or ethnic groups will respond differently to treatment arms. While most subjects will be 
asymptomatic (no palpitations), the degree of heart failure symptoms will be variable (none to moderately 
severe). Based on sample size estimates, the full scale PAPS study will require 140 subjects randomized 
to either RFA (70 subjects) or AAD therapy (70 subjects) to assess differences between RFA and AAD 
treatments (see Sample size justification Section in Study Design – Part I). However, we propose a pilot 
study of 36-39 subjects (20% of subjects) to determine acceptability of treatment randomization of RFA 
versus AADs, rate of spontaneous recovery of CM and PVCs, responders, adverse events and treatment 
crossover, and to assess the feasibility of enrolling, randomizing and retaining participants. This pilot study 
will allow us to better design and power the large prospective PAPS study.  
In addition, we propose to screen all consecutive subjects undergoing at least a  24-hr, ambulatory 
ECG Holter for frequent PVCs (≥ 10% burden) and LVEF ≤ 45%. This has the intention to better estimate 
the prevalence of PVC and CM in this specific population.   
No vulnerable populations, such as fetuses, neonates, pregnant women, children, prisoners, 
institutionalized individuals, or others who may be considered vulnerable populations will be enrolled in 
our study.   
Sampling plan, recruitment and retention strategies and criteria for inclusion or exclusion of any 
subpopulation.  

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A signed informed consent will be obtained from each participating subject. Inclusion and 
exclusion criteria are the same for all subjects regardless of gender, age, race or ethnic group (See 
details in document: Study Design – Part I: Table 1).  We plan to recruit study subjects using different 
strategies and settings, but primarily by: 1) Engaging clinicians and consultants to identify subjects during 
visits to Primary care and cardiology clinics, Device and arrhythmia clinic, Non-invasive cardiac 
laboratory, heart failure clinic, and hospital admissions; 2) local heart failure service, and most 
importantly 3) screening of ambulatory ECG Holters that will allow us to identify subjects with frequent 
PVCs (Design Study – Part II).  Due to inaccessibility to some subjects with previous Holters, a waiver of 
informed consent and a waiver of HIPAA will be requested for subjects in Part II as they may not be 
accessible for consent. 
 
   
As a retention strategy, we will request each participating center to remain engaged with active 
study subjects through local heart failure groups and monthly emails or phone calls.  
 
Procedures for assignment to a study group. As related to human subject’s protection, describe 
and justify the selection of an intervention’s dose, frequency and administration.  
This is a prospective randomized-controlled study of subjects with CM and high PVC burden with 
a likely diagnosis of PVC-CM, where individual subjects will be assigned with a 1:1 random allocation to 
one of two un-blinded parallel groups (Figure 1): 1) PVC radiofrequency ablation (RFA) vs. 2) AADs. Since 
we expect about 30% of subjects will have a PVC burden >20%, we plan a stratified randomization based 
on PVC burden above and below 20% reported by at least a 24-hour Holter. Stratified randomization will 
assure equal distribution of subjects between PVC burden above and below 20%. Stratified randomization 
will be performed only at the Coordinating Center using biostatistics software and/or service 
(randomization.net). This stratified randomization will assure that both groups (RFA vs. AADs) are equally 
distributed between PVC burden above and below 20%.  
A few small studies suggest that an overall PVC burden more than 20% may affect LV function and 
NYHA functional class. In contrast, PVC burden of less than 10% is less likely associated with impairment 
of LV function. Interestingly, a few studies with PVC burden as low as 10 PVCs per hour have shown some 
degree of improvement in LV ejection fraction after PVC suppression. Based on limited data, we chose 
≥10% PVC burden as inclusion criteria for our study, as we believe these are subjects with a higher 
likelihood of a diagnosis of PVC-CM.  
As proposed in this study, we have an observation period that would allow us to assess and 
compare no active intervention (3-month observation) vs. PVC suppression (treatment phase). Moreover, 
our study design will allow us to compare two PVC suppression strategies: 1) RFA versus 2) AADs. 
Successful PVC suppression is defined as a decrease in 80% of PVC burden after 2-4 weeks of procedure. 
Single RFA of PVCs has been shown to be successful in more than 80% of cases. As in current practice, 
we plan to repeat a second RFA after 4-6 weeks on those subjects with unsuccessful RFA (less than 80% 
decrease in PVC burden after RFA group). Since all subjects will start or continue optimal medical therapy 
regardless of treatment randomization, they will be followed approximately every 3 months in order to 
assure compliance and assess potential side effects.  
 
Collaborating sites and role of collaborating investigators in performing the proposed research.  
1. We have involved at least 9 nationally-renowned high-volume electrophysiology centers across 
the United States to participate in this study) 
 
Each local investigator (co-investigator) will be responsible for obtaining consent, following the 
research plan as outlined, reporting severe and non-severe adverse events within 24-48 hours of 
knowledge of the event, protecting subject’s rights and welfare, securely storing and submitting accurate 
subject data, notifying the Coordinating Center of all IRB correspondence. Central IRBs will be arranged 
for most institutions except VA Medical Centers. Each local site is responsible for protecting the safety and 
welfare of research subjects at their sites. All institutions will have in place instructions to store subject’s 
files and records in a secure locked location. Any questions from local investigators/collaborators and 
coordinators in regard to subject enrollment, follow-up and/or termination should be addressed directly to 
the National Research Coordinator.  
Each center will submit Case Report forms via a secure encrypted data capture system (REDCap) 
and/or scan/fax or special carrier service. A contractual agreement with REDCap (Research Electronic 

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Data Capture) will be established in order to perform encrypted electronic data capture of research 
subject’s data throughout this 3-year national multicenter clinical trial. REDCap is a scalable, secure, 
enterprise-level application. Planning, configuration and end-user support for REDCap is provided by the 
VCU Clinical Center for Translational Research (CCTR). The REDCap platform at VCU is approved by 
VCU/VCUHS ISOs, has been extensively vetted and approved for capture of sensitive data (e.g. PHI), and 
is approved/recommended by the VCU IRB.  The CCTR clinical research informatics group will provide 
project-specific training to all end users regarding access, permissions, reporting, data quality checks, 
audit trail, self-help options, database design considerations, export and reporting capabilities, etc. The 
software is delivered via 256 bit SSL-encryption, and features: 1) an intuitive interface for the creation of 
case report forms (CRFs) and validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) procedures for importing data from external sources; the ability to relate CRFs to study 
events and schedule them via a calendar function; and 4) automated export procedures for seamless data 
downloads to common statistical packages (SPSS, SAS, STATA, R).  
The Coordinating Center will store and protect subject’s files and records in a secure locked 
location, while all electronic data will be secured in a secure (password-protected) encrypted server. 
 
b. Sources of Materials  
We will record baseline subject demographics, including age (date of birth), gender, race, ethnicity 
duration of cardiomyopathy, calculated LVEF, history of atrial fibrillation, and medical therapy including 
dosing prescription. We will obtain a 12-lead ECG, Minnesota living with Heart failure QOL questionnaire 
and NYHA functional class, ambulatory ECG Holter, echocardiogram and cardiac MR (if clinically 
indicated) as per protocol. All details related to the observation period and treatment arms of RFA or 
antiarrhythmic drug (AAD) therapy will be recorded. Details related to RFA of PVCs will be obtained, 
including PVC morphology and location, different PVC morphology, number or RFA/cryo lesions, radiation 
exposure, peri- and post-ablation complications, fluoroscopy time, procedure duration and days of 
hospitalization related to RFA. Similar data will be collected from subjects randomized to the AAD arm if 
applicable. We will obtain case report forms (containing data above) from the Coordinating Centers as well 
as from the participating centers. This data will be sent via electronic data capture and/or fax in complete 
case report forms.  
 
Data will be collected directly from the subject, research coordinator and local investigator as per 
protocol. This will be recorded by the investigator and/or research coordinators. All participating sites will 
comply with all applicable laws, regulations and provisions related to information privacy and data security 
in regard to individually identifiable private information. Local institutions will have only access to individual 
identifiable private information. A unique identifier will be given to each subject to identify subjects in the 
event that the study provides information that may affect the subject’s willingness to continue participation 
in the study and that would require sites to reach the research subject.  
Each local investigator (collaborator) will be required to obtain consent, follow the research plan as 
outlined, report severe and non-severe adverse events within 24-48 hours of becoming aware of the event, 
protect subject’s rights and welfare, securely store and submit accurate subject data, notify the 
Coordinating Center of all local IRB correspondence (if applicable). Each local site is responsible for 
protecting the safety and welfare of research subjects at their sites. All institutions will have in place 
instructions to store subject’s files and records in a secure locked location. 
All participating institutions will be required to complete and submit all data directly to the 
Coordinating Center via a secure encrypted data capture system (REDCap, as described above) and/or 
scan/fax or special carrier service. The Coordinating Center will not require nor accept blood specimens 
from research subjects. All participating and coordinating institutions will have in place directives to store 
subject’s files and records (including identifiable private information) in a secure locked location.  
 
c. Potential Risks  
 
The study will be conducted according to Good Clinical Practice Guidelines, the Declaration of 
Helsinki and US 21 CFR. Current clinical practice offers radiofrequency ablation (RFA) plus optimal 
medical therapy to the population of interest (frequent PVCs associated with cardiomyopathy) supported 
only on retrospective and non-randomized observational studies with a relatively short (3-6 months) follow 
up period. Alternative treatments include use of antiarrhythmics and/or optimal medical therapy alone. 
Risks associated with RFA include cardiac tamponade, bleeding, stroke, AV block, myocardial infarction 

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and even death. Risks related to antiarrhythmic drugs include common significant drug-to-drug interactions 
and side effects depending on specific drugs, which commonly leads to poor compliance. Amiodarone for 
instance, as the primary proposed antiarrhythmic drug in this pilot study, can have significant side effects 
such as dizziness/lightheadedness, pro-arrhythmic (ventricular tachycardia, torsade de Pointes), thyroid 
disorders, elevated liver enzymes, optic neuritis, pneumonitis and lung disease depending on dosing. In 
contrast, optimal medical therapy alone is not considered to add any additional risks to the current illness, 
however, it is unclear if by not eliminating PVCs (either with RFA or antiarrhythmics) we are potentially 
withholding a beneficial intervention. Our study proposes to randomize these subjects to two groups: 1) 
RFA and 2) AAD only after a 3-month observation period (control). The risks of the subjects participating 
in this research proposal are considered small primarily because most of these subjects would undergo 
RFA as frequent yet unproven therapy. A 3-month observation period (control) is an ethical intervention 
since 1) no randomized controlled study has been performed to assess if RFA is better than optimal 
medical therapy 2) this elective procedure usually is scheduled 8-12 weeks after diagnosis in most high 
volume medical centers, and 3) it is unclear if PVCs would decrease with time and without intervention 
with subsequent improvement of LV function without the need for invasive procedures. Finally, our study 
would not impose any psychological, financial or legal issues.  
 
Serious adverse events (SAE) will be monitored for all subjects during their participation in this 
study. The central IRB will be notified of any serious adverse events within 24 hours of our knowledge of 
such event. Additionally, SAEs should be reported to the Coordinating Center within 24 hours of the site 
becoming aware of the event (see details below Sections: Protection against risks and Data Safety 
Monitoring).   
 
Adequacy of Protection against Risks  
a. Recruitment and Informed Consent  
Describe plans for the recruitment of subjects and the process for obtaining informed consent.  
 
The study will be conducted according to Good Clinical Practice Guidelines, the Declaration of 
Helsinki and US 21 CFR. We plan to identify study subjects using different methods and settings: 1) 
Engaging clinicians and consultants to identify subjects during visits to Primary care and cardiology clinics, 
Device and arrhythmia clinic, Non-invasive cardiac laboratory, heart failure clinic, and hospital admission; 
2) local heart failure service and 3) subjects identified with frequent PVCs and CM during ambulatory ECG 
Holter screening (PAPS Pilot study – Part II).  We plan to include only adults (greater than 18 years of age) 
Children will not be included as addressed in Section: Inclusion of Children (see below). 
 
Potential study subjects will be further introduced to the proposed study by engaging primary care 
providers to explain to affected subjects the relevance of participating and/or engaging and 
disseminating information regarding this important clinical trial.  
 
Once introduction to the health issue of cardiomyopathy and frequent PVCs occurs, the principal 
investigator, collaborators and/or research coordinators will personally approach the potential subject in a 
1:1 setting to further discuss the option of participating in this study. Personnel obtaining consent should 
explain in detail the aims and methodology of the study and potential benefits and risks associated with 
the study (described below). Only after the subject is allowed to ask questions and they are all addressed, 
will the subject be asked to sign informed consent if he/she is in agreement with participating in the study. 
We will recommend to all participating sites to preferably consent the subject in the presence of a relative 
and/or witness. Signed written informed consent will be obtained from all subjects before protocol-specific 
procedures are carried out. Subjects will be informed of their right to withdraw from the study at any time. 
 
b. Protections against risk  
 
In order to minimize potential risks, the proposed project will require IRB approval at all participating 
institutions. The professional qualifications and resources (including time, equipment, support services) of 
principal investigators and collaborators and research teams will be required to protect and minimize 
potential harm to participants. Research personnel must have received appropriate training, and clinicians 
involved in the research must maintain appropriate professional credentials and licensing privileges.  
The Human Subjects CITI Online training including Biomedical Research Investigators and Key 
Personnel (Basic Course Module) would be required to minimize risks to privacy and confidentiality of 

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data of Human research participants. Completion of the CITI training is required of all research team 
members prior to participating in the proposed study. 
Furthermore, a Data and Safety Monitoring Plan has been developed and will be submitted to the 
central IRB and NIH for approval prior to the accrual of human subjects (see details below).  
 
Medical or professional intervention in the event of adverse effects to the subjects.  
All research performed under this study will conform to laws, regulations policies and procedures 
pertaining to protections for human subjects.  Collaborating centers and the Coordinating Center shall 
immediately notify each other, and the investigator shall promptly notify the IRB, upon identifying any 
aspect of the Protocol, including unanticipated problems involving risk and information discovered during 
site monitoring visits/remote site monitoring visits or in the study results that may adversely affect the 
safety, well-being, or medical care of subjects, or that may affect the willingness of subjects to continue 
participation in the research, may influence the conduct of the study, or may alter the IRB’s approval to 
continue the study.  When subject safety could be directly affected by study results, the Coordinating 
Center will notify participating sites who will provide written communication to affected subjects.  
 
The Investigator and/or research coordinator at each participating center will be responsible for 
collecting data in regard to adverse events. The investigator must decide whether each incident meets the 
definition of a SAE. Once the local Principal Investigator (PI) determines that a serious adverse event 
meets reporting requirements, he/she must report the SAE, and related safety information, to the 
Coordinating Center on the required Significant Adverse Event Report Form (See form attached) provided 
for this purpose.  Additionally, local SAEs should be reported to the Coordinating Center and IRB of record 
per policy. If the adverse event results in the need to revise the informed consent, or other study 
documents, the PI will submit a request for a modification through the Coordinating Center to the IRB of 
record. An extensive Data Safety Monitoring Plan (DSMP) is provided. 
 
Potential Benefits of the Proposed Research to Human Subjects and Others  
The prevalence of frequent/high PVC burden and cardiomyopathy is key as it is likely that subjects 
are under recognized. Furthermore, understanding the potential benefits of RFA of PVCs versus AAD 
therapy in subjects with CM and frequent PVCs are particularly important to subjects as we will try to 
understand the best treatment strategy to eliminate PVCs and if indeed both improve LV function, change 
quality of life, improve or even eliminate HF symptoms, morbidity and mortality, as well as avoid the need 
for implantable cardiac devices with all associated medical expenses. In addition, understanding the PVC 
features associated with CM is paramount to properly target subjects that are likely to respond to RFA of 
PVCs, and avoid this invasive procedure in subjects that are less likely or do not have clinical benefit. 
 
Risks versus anticipated benefits to research participants and others.  
 The risks of the subjects participating in this research proposal are reasonable, since it is not clear 
if the benefits outweigh the risks of RFA. Even though risks of RFA are considered small, these can be 
serious (cardiac tamponade, bleeding, stroke, AV block, myocardial infarction) and even result in death. 
Current clinical practice offers RFA to subjects with frequent PVCs associated with cardiomyopathy 
supported only on retrospective and non-randomized observational studies with a relatively short 3-6 
month follow up period. It is unclear if PVCs would decrease with time and without intervention with 
subsequent improvement of LV function without the need for invasive procedures. Thus, we believe that 
we need to further study the benefits of this invasive procedure to assure that it justifies the risks associated 
with it. 
 
Importance of the Knowledge to be gained  
Discuss the importance of the knowledge gained or to be gained as a result of the proposed research.  
The PAPS pilot study will help us understand the prevalence of PVC-CM and gather key information 
to better design and power a large randomized trial – the PAPS study. This large randomized study would 
aim to improve evidence-based treatment options in subjects with frequent PVCs and LV dysfunction with 
or without heart failure, as we plan to compare RFA of PVCs vs. antiarrhythmic drug (AAD) therapy.  
Subject’s health could be improved in those subjects with PVC-CM if subsequent normalization of 
LV function occurs after RFA of PVCs, avoiding heart failure and device implantation. Otherwise, these 

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subjects can be incorrectly considered or diagnosed with a persistent irreversible form of CM with 
subsequent HF morbidity and mortality. Thus, subjects with PVC-CM could have a significant improvement 
and/or normalization of quality of life, heart failure symptoms and NYHA class, while decreasing morbidity 
and mortality associated with HF and CM after elimination of PVCs with RFA. Moreover, these subjects 
would not require implantable cardiac devices.  
Change in current clinical practice would occur if our study’s hypotheses are proven correct, since 
Holter monitors would be routinely requested as standard of care to rule out PVC-CM in all the following 
subjects: 1) newly diagnosed CM with or without heart failure and 2) chronic LV dysfunction that 
demonstrate PVCs with or without heart failure and/or implantable cardiac devices. Furthermore, this study 
would attempt to understand predisposing factors and PVC features associated with PVC-cardiomyopathy. 
This would lead to a change in current practice as it will guide us to closely follow up those subjects at risk 
to develop PVC-CM. 
The proposed study will impact several aspects of subject care, such as: 1) evaluate clinical 
benefits of RFA of PVC in subjects with suspected PVC-CM, by assessing changes in quality of life, HF 
symptoms and morbidity, 2) assess improvement in LV function after RFA of PVCs and/or AADs, which 
will in turn reduce the need for expensive implantable cardiac defibrillators (ICDs); 3) identify the PVC 
burden threshold required to induce CM, helping us to properly diagnose PVC-CM and target specific 
therapy, such as RFA of PVCs, to only those subjects likely to respond to RFA; and 4) decrease the 
financial burden associated with poor quality of life, heart failure symptoms and hospital admissions, and 
ICDs in subjects with frequent PVCs and CM. 
 
Risks to subjects in relation to the importance of the knowledge that may be expected to result.  
Risks associated with research subjects in this proposed study are considered small and acceptable 
since most of these subjects would have been scheduled for RFA of PVCs without a clear understanding 
of the benefits associated with RFA. In contrast, the risks related to those subjects undergoing RFA of 
PVCs are small but can be potentially severe (as described above).  
Current gaps in knowledge include: 1) possible placebo effect of RFA as spontaneous resolution of 
PVCs could have occurred even without RFA of PVCs, 2) best treatment strategies, either RFA or AADs, 
to achieve successful PVC suppression, 3) unclear clinical benefits (quality of life, NYHA class, HF 
symptoms, HF morbidity and mortality, implantable cardiac devices) of RFA of PVCs or AADs in the setting 
of PVC-CM, and 4) PVC features required to induce CM, in which subjects should be referred to RFA of 
PVCs or initiate AADs. Until now, there have been no randomized-controlled studies of subjects with PVC-
CM to clarify and answer these questions.  
 
In summary, without clear evidence of the benefit of RFA in subjects with cardiomyopathy 
associated with frequent PVCs, we believe that the risk of withholding RFA is similar to the risk of those 
subjects undergoing an invasive procedure such as RFA of PVCs. 
 
Data and Safety Monitoring Plan (DSMP) 
A detailed Data and Safety Monitoring Plan (DSMP) will be submitted to the IRB and NIH (funding 
institution) for approval prior to the accrual of human subjects. The Data Safety Monitoring Plan is written 
to ensure the safety of the participants and verifying the validity and integrity of the data (see details in 
document: Protection of Human Subjects).  Details are expanded on document: Data Safety Monitoring 
Plan. 
A Data and Safety Monitor Board (DSMB) will consist of 2 heart failure specialists (Drs. James Fang 
and Ryan Tedford) and a cardiac electrophysiologist (Dr. Thomas Dewland) (see letters of support) that 
have no direct investment in the study to prevent jeopardizing subject safety. In addition to the Coordinating 
Center and central IRB, the DSMB will review the research protocol and plans for data safety and 
monitoring, evaluate the progress of the trial with periodic assessments of data quality and timeliness, 
participant recruitment, accrual and retention, participant risk versus benefit, and reports from related 
studies.  
The DSMB will meet every 4 months to review data and adverse event reports. Additionally, they will 
meet to review interim analysis when available. This will be performed in a closed session with open access 
to the PI if requested by the Board. Data monitoring will focus on several areas: 1) Performance, which will 
allow us to assess site performance with respect to subject recruitment, retention and follow-up, flow of 
data forms, protocol adherence and quality of data; 2) Safety, which will allow us to assess the magnitude 

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of adverse events; and 3) Treatment, in order to monitor and assess treatment effects (described under 
Section: Potential Risks). 
 
 
 
ClinicalTrials.gov Requirements  
As required, the PAPS pilot study has been registered at www.clinicaltrials.gov (NCT03228823).  
https://clinicaltrials.gov/ct2/show/NCT03228823?term=NCT03228823 
 
 
Inclusion of Women, minorities and children 
As per instructions, these aspects are detailed in separate documents:  
1) Inclusion of Women and Minorities. 
2) Inclusion of Children. 
 

PAPS Pilot Study: Clinical Investigation Plan                                  Page 41 of 50, Version 8.0 (22-Apr-2019)  
 
DATA SAFETY MONITORING PLAN 
 
The PAPS Pilot study is a national multicenter randomized control study to enroll between 36-39 
subjects with cardiomyopathy associated with frequent PVCs. This is a phase IV trial with moderate risk 
as participating subjects will be randomized to two different strategies (RFA versus AAD) commonly used 
in clinical practice to treat subjects with frequent PVCs. We consider this study to be moderate risk since 
most subjects with a suspected PVC-CM would undergo RFA as a common clinical practice (as discussed 
above).  All research performed under this study will conform to laws, regulations and VA policies and 
procedures pertaining to protections for human subjects.   
In addition to Coordinating Center and central IRB oversight, a Data Safety Monitoring Board 
(DSMB) will be organized according to the FDA recommendations to review all serious adverse events as 
well as study progress (including all adverse events) every 4 months after study initiation. The DSMB will 
be integrated by faculty members from institutions without active enrollment in the study and without a 
vested interest in the proposed research that have different expertise (see DSMB section in Protection of 
Human Subjects document). The members of the DSMB will have full access to all study records and will 
have the authority to discontinue the study at any time. Please consult the Protocol in Appendix for 
additional details. 
 
A detailed Data and Safety Monitoring Plan (DSMP) will be submitted to the IRB and NIH (funding 
institution) for approval prior to the accrual of human subjects. The Data Safety Monitoring Plan is written 
to ensure the safety of the participants and verifying the validity and integrity of the data.  
During each scheduled visit and in between visits, subjects will be asked and instructed to call in 
regard to any event out of the ordinary. Those subjects randomized to the RFA group will be evaluated 
immediately, throughout the first 24 hours and 1-2 weeks after the procedure by the research team as 
standard follow up on any of these procedures. It will be the responsibility of the investigator/coordinator 
to assess the subject personally and request laboratory or any appropriate tests if needed. All adverse 
events including serious adverse events (SAE) will be monitored for all subjects during their participation 
in this study. 
 
a. 
Adverse event (AE) grading and attribution scale. The investigator will try to determine the 
relationship of adverse event to RFA and/or AAD therapy as not related, possibly related, or definitely 
related using standard criteria for clinical trials.  All grades of toxicity will be noted.  
 
The following grading and attribution scale will be employed: 
0 
= No adverse event or within normal limits 
1 
= Mild AE, not requiring treatment 
2 
= Moderate AE, resolved with treatment 
3 
= Severe adverse event (SAE) is any untoward medical occurrence that at any point during the study: 
• 
Results in death 
• 
Life-threatening – refers to an event in which the subject was at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization – Hospital admission is 
usually interpreted as requirement of at least one overnight stay in subjects in the medical therapy arm 
or PVC suppression; whereas in subjects in the PVC suppression arm, a prolonged hospital stay will 
be defined if more than two days of hospital stay is required after RFA ablation. Treatment and release 
from an emergency department generally does not qualify as a hospitalization, unless the event 
qualified as an SAE based on other criteria.  
• 
Results in persistent or significant disability/incapacity 
• 
Considered medically significant by the investigator or requires intervention to prevent any of the 
outcomes above. Medically significant are those events considered important in the investigator’s 
opinion and which may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the outcomes listed in the definition 
above. 
 

PAPS Pilot Study: Clinical Investigation Plan                                  Page 42 of 50, Version 8.0 (22-Apr-2019)  
 
 
 
 
 
 
b. Reporting of Adverse Events (AE) 
The Investigator and/or research coordinator at each participating center will be responsible for 
collecting data in regard to adverse events. The investigator must decide whether each incident meets the 
definition of a SAE. 
Reporting Requirement: Once the local Principal Investigator (PI) determines that an adverse event meets 
the IRBs’ reporting requirements, he/she must report the SAE and related safety information to the 
Coordinating Center on the required Significant Adverse Event Report Form (See form attached) provided 
for this purpose. Supporting documents, including a copy of the Informed Consent, should also be emailed/ 
submitted through REDCap. For reasons of confidentiality, subject’s names must not be included in the 
report. Additionally, local SAEs must be reported to the IRB of record per policy. If the adverse event results 
in the need to revise the informed consent, or other study documents, the PI will submit a request for a 
modification through the Coordinating Center to the IRB of record. 
 
c. Annual Data and Adverse Events Report 
This report will be prepared annually by the PI and research coordinator at the Coordinating Center. 
This report will include the number of subjects actively enrolled, those that abandon and complete the 
research protocol, as well as, all side effects and adverse events in both groups.  
In addition, an interim analysis or treatment monitoring will be performed by VCU Research 
Incubator. Due to a small risk related to RFA (estimated 2-3%), this interim analysis will be performed once 
the first 15 subjects (half of sample size) have completed a 15-month protocol. Data reports and interim 
analysis will be reviewed by the IRB at the Coordinating Center and DSMB during its convened meetings. 
 
d. Data management and safety review  
Collaborating centers and the Coordinating Center shall immediately notify each other, and the 
Coordinating Center shall promptly notify the IRB, upon identifying any aspect of the Protocol, including 
unanticipated problems involving risk and information discovered during site monitoring visits/remote 
monitoring visits or in the study results that may adversely affect the safety, well-being, or medical care of 
subjects, or that may affect the willingness of subjects to continue participation in the research, may 
influence the conduct of the study, or may alter the IRB’s approval to continue the study.  When subject 
safety could be directly affected by study results, the Coordinating Center will notify participating sites who 
will provide written communication to affected subjects.  
A Data and Safety Monitoring Board (DSMB) will consist of 2 heart failure specialists (Drs. James 
Fang and Ryan Tedford) and a cardiac electrophysiologist (Dr. Thomas Dewland) (see letters of support) 
that have no direct investment in the study to prevent jeopardizing subject safety. In addition to the IRB, 
the DSMB will review the research protocol and plans for data safety and monitoring, evaluate the progress 
of the trial with periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, and reports from related studies.  
The DSMB will meet every 4 months to review data and adverse event reports. Additionally, they 
will meet to review interim analysis when available. This will be performed in a closed session with open 
access to the PI if requested by the Board. Data monitoring will focus on several areas: 1) Performance, 
which will allow us to assess site performance with respect to subject recruitment, retention and follow-up, 
flow of data forms, protocol adherence and quality of data; 2) Safety, which allows us to assess the 
magnitude of adverse events; and 3) Treatment, in order to monitor and assess treatment effects.  
 
The DSMB has the responsibility to make written reports of their findings and recommendations to 
the Coordinating Center, IRB, NIH/NHLBI (funding institution) and investigators concerning continuation 
or conclusion of the trial if it considers that RFA has a significantly higher benefit or increased risk as 
compared to the control arm. Annual data safety, adverse event reports and interim analyses may result 
in the need to revise the informed consent, or other study documents, for which the PI must submit a study 
amendment to the IRB. This could result in early study termination only if continuation will not produce 
benefit to subjects or if the treatment outcome is known to have benefit. 
 
 
 
 

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In accordance with the terms of the Federal Wide Assurance, the Office for Human Research 
Protections (OHRP) and the Federal Drug Administration (FDA) will be notified in a timely manner of 1) 
serious or continuing noncompliance; 2) significant adverse events involving risk to participants or others; 
or 3) suspension or termination of IRB approval for a study. 
 
Governance plan, administrative, technical and scientific responsibilities of PIs and research 
coordinators are detailed in the document: Leadership plan. If an unexpected scenario was to occur, all 
PIs will have to be in agreement in order to change or deviate from the protocol with appropriate notification 
to collaborating centers. Similarly, if during a review or recommendation of the Data Safety Monitor Board 
(DSMB) is made, all PIs will discuss and agree to modify or make appropriate changes to address concerns 
of the DSMB. 
 
 

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Prospective Assessment of PVC Suppression in Cardiomyopathy (PAPS): A Pilot Study 
 
REPORT OF SIGNIFICANT ADVERSE EVENT 
Serious and unexpected events that are related to research under the supervision of the local IRB must be reported 
to the Human Protection Administrator (HPA) in your institution. This form, should be submitted as soon as 
possible to your IRB and coordinating Center (McGuire VA Medical Center), but NO LATER THAN 24-48 
WORKING HOURS after first awareness of the problem. Refer to the IRB Guidelines for Reporting Significant 
Adverse Events for more information. 
 
PRINCIPAL INVESTIGATOR: ________________________ DEPARTMENT: _____________________ 
INSTITUTION: _______________________________________________________________________ 
SUBJECT'S INITIALS: ________          AGE:_____________        DATE OF INCIDENT: ______________ 
RESEARCH PROCEDURE INVOLVED:________________________________________________________ 
 
  
 
 
DESCRIBE IN DETAIL THE NATURE AND TIMING OF EVENT(S) (A Letter Explaining Any Other 
Details Should be Attached if Needed.):___________________________________________________________ 
 
 
 
 
The Likelihood The Injury Was Caused By The Study Is:   
Definitely Unrelated_______ Unlikely______ Possible______   Probable________  
Event Appears To Be:  
Directly______ Indirectly______ Not Related To Research Treatment______ 
Check All That Apply: 
Resulted in Hospitalization______ Resulted in Disability______ Required Supportive Treatment______ Subject 
Remains on the Study______ Subject Died _________ 
 
DESCRIBE TREATMENT OF THE INJURY: 
By Whom: ____________________________ Where: _______________________________________ 
 
DID PI REPORT THIS INCIDENT TO: Coordinating Center______ Co-Investigator(s)______ Other_____  
 
Signature of PI:____________________________________________ Date:____________________ 
Printed Name of PI:_________________________________________Phone:___________________ 
Signature of Person Reporting:___________________________________ Date:_____________________ 
Printed Name of Person Reporting:________________________________ Phone:____________________ 
 
DOES THIS EVENT REQUIRE REVISION TO THE PROTOCOL? Yes______ No______ 
DOES THIS EVENT REQUIRE REVISION TO THE CONSENT? Yes______ No _____  
If YES to Either, Please Submit Appropriate Paperwork.  
 
REMINDER: If there is any new information contained in this report that might have an impact on issues of risk 
connected with this study a revision must be made to the protocol and/or consent. 
 

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Prospective Assessment of PVC Suppression in Cardiomyopathy (PAPS): A Pilot Study 
 
Serious Adverse Events 
 
Date: ____________ 
 
Subject 
Age 
Treatment 
date 
Event 
Onset 
Date 
Outcomes (e.g. hospitalization, concomitant 
meds, study, status, etc.) 
 
 
 
 
 
 
 
Relationship 
□ Definitely Unrelated   
□ Unlikely 
 
□ Possibly related 
□ Probably related 
 
□ Definitely related 
Description 
1. Event or problem 
□ Resolved 
 
□ Ongoing  
 
 
□ Copy of SAE reported attached 
 
□ Anticipated    
□ Unanticipated 
2. Was the subject withdrawn from the project 
□ Yes on  
(date)  
□ No  
 
 
□ Not applicable 
 
Actions taken: 
1. Do you recommend modifications in the project (e.g. protocol changes, informed consent 
changes)? 
□ Yes  
If yes, submit a Modification of Approved Research IRB submission Form 
□ No 
 
2. Has the sponsor been notified of the event or problem? 
□ Yes  
□ No  
 
□ Not applicable 
 
3. Describe actions taken or will take to minimize risks: 
_______________________________________________________________________________
______________________________________________________________________________ 
 
 
 
 
___________________________ 
 
 
 
___________________ 
Investigator Signature  
 
 
 
 
Date 
(Sub investigator may sign if the investigator is unavailable) 
 
 
 
 
 
 

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Prospective Assessment of PVC Suppression in Cardiomyopathy (PAPS): A Pilot Study 
 
Adverse Events 
 
Date: ________________________ 
 
Subject 
Adverse 
Event 
Onset 
Date 
Ending 
Date 
Severity Studyrelated 
Yes or No? 
Action 
Outcome 
 
 
 
 
 
 
 
 
 
Codes: 
Severity 
Drug Related 
1 – Mild 
0 = Definitely Unrelated 
2 = Moderate 
1 = Unlikely 
3 = Severe 
2 = Possibly Related 
4 = Life threatening 
3 = Probably Related 
 
4 = Definitely Related 
 
Action (taken) 
Outcome 
0 = None 
1 = Resolved 
1 = Dose Modification 
2 = Recovered with minor sequelae 
2 = Counteractive Medication 
3 = Recovered with major sequelae 
3 = Medical / Surgical intervention (specify under 
comments)  
4 = Condition still present and under treatment 
4 = Hospitalization 
5 = Condition continues to worsen 
5 = Treatment/drug permanently discontinued 
6 = Subject died 
6 = Other (specify under comments) 
 
 
Comments: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_______________ 
 
 
 
 
___________________________ 
 
 
 
___________________ 
Investigator Signature  
 
 
 
 
Date 
(Sub investigator may sign if the investigator is unavailable) 
 
 
 

PAPS Pilot Study: Clinical Investigation Plan                                  Page 47 of 50, Version 8.0 (22-Apr-2019)  
 
 
INCLUSION OF WOMEN AND MINORITIES 
 
Based on observational non-randomized studies, PVC-CM does not appear to have a gender or 
age predisposition. Furthermore, no definite data has been published in regard to the prevalence of PVC-
CM and/or degree of response to radiofrequency ablation (RFA) or antiarrhythmic drugs (AADs) by gender, 
race or ethnic groups. 
As outlined in the Research Strategy Section, all subjects that meet inclusion/exclusion criteria will 
be offered participation in this study regardless of gender, age, race, ethnicity, geographic, or clinical 
status. We will attempt to have diversity in age, gender, race and ethnicity in our study by involving the 
general population treated in high-volume referral University Hospitals across the country. We expect to 
have a wide range of age groups and an even proportion of gender in this proposed study. However, we 
cannot describe or predict the goals of race and ethnic groups.  
We will request each collaborating/participating center to identify local referrals with a high 
percentage of women and minorities. In addition, we will request collaborators to directly approach primary 
care providers in several forms on a regular basis (every quarter) to make them aware of the relevance 
and importance of completing the proposed clinical trial including women and minorities.   
 
We intend to compare response to RFA and AADs between these different populations; however, 
the PAPS study is not powered to compare between different populations since this would require several 
hundred subjects. Findings of the PAPS study could potentially provide the basis for designing future 
studies properly powered to assess differences in response between gender and minorities. 
 
 
 
 
 
 
INCLUSION OF CHILDREN 
 
The prevalence of premature ventricular contractions (PVCs) is generally age-dependent, ranging 
from <1% in children < 11 years to 69% in subjects >75 years. Furthermore, frequent PVCs in children 
appear to have minor impact on LV function with few cases of PVC-induced cardiomyopathy.   
Children (defined as individuals under 18 years of age) will be excluded from the proposed research 
since PVC-induced CM is extremely rare in children. Furthermore, the risk of complications with invasive 
procedures in this population may be unwarranted given the unknown benefits. An attempt to enroll 
children would result in a significant delay to complete the proposed study with a need to expand this study 
for several years. 
 
 

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RESOURCE SHARING PLAN 
 
Data Sharing Plan 
Note: The requirement for a data-sharing plan applies only to studies that are requesting funding at a level greater than $500,000 in direct costs 
in any project year.  
 
Our proposed study does not require funding greater than $500,000 in direct costs in a year, for 
which this section does not apply to our proposal.  This grant application is solely to initiate a pilot study 
of frequent PVCs and cardiomyopathy. Results of this preliminary data will not provide final definitive 
data, yet we will make it available. However, we will make clear that this pilot data is not intended to 
answer benefits of different PVC suppression strategies to avoid misinterpretation or inaccurate 
conclusions based solely on our preliminary data. 
 
Replication of Research Findings 
 
The PAPS pilot study is a multidisciplinary prospective multicenter collaborative randomized-
controlled trial to be performed in a broad population of subjects with cardiomyopathy associated with 
frequent PVCs. If funding is granted, this pilot data will provide a better estimate of the prevalence of 
frequent PVCs and cardiomyopathy, as well as pave the way for the PAPS trial, a large-scale multicenter 
randomized clinical trial.  
Thus far, only retrospective and observational non-randomized studies have been performed. If 
the PAPS study were to be launched in the future, it could be the first prospective randomized trial to 
study the effects of catheter radiofrequency ablation in subjects with PVC-induced cardiomyopathy. 
Particularly it could help us better identify subjects that will benefit from PVC suppression with 
subsequent improvement in subject’s health, subject outcomes and narrow a gap in knowledge in regard 
to those subjects with frequent PVCs and cardiomyopathy.  
 
We understand the relevance of making available information that would allow any other 
researchers/colleagues to further develop or expand other relevant knowledge in this important area. 
Thus, upon receiving funding, we plan to pursue the following steps: 
1) Register the trial at www.clinicaltrials.gov 
2) Register our study at the International Prospective Register of Systematic Reviews 
(http://www.crd.york.ac.uk./prospero/) 
3) Describe study datasets, including code books, meta-data related to datasets, and documented 
programming code used for creating the final study population, for creating variables, and for 
conducting all outcomes analysis. This information will be provided within 3 months of the end of the 
final funding year. 
4) Submit a manuscript to a major peer-review journal such as Circulation, Heart Rhythm Journal or The 
Journal of American College of Cardiology that describes study population and detailed methodology 
including study population, data definitions, main objectives, hypothesis, preliminary findings of pilot 
study, future directions of the study including primary and secondary outcomes, studied variables and 
analysis plan. This would be submitted for publication within 12 months of receiving funding. 
 
 
 
 

PAPS Pilot Study: Clinical Investigation Plan                                  Page 49 of 50, Version 8.0 (22-Apr-2019)  
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