Pediatric REPlAcement of the PulmonaRy ValvE in Tetralogy of Fallot - The PREPARE-TOF Study
Phase: NA
Conditions: Tetralogy of Fallot
Sponsor: Children's Hospital of Philadelphia

 
Template version: May 28, 2014 
 
Mark A Fogel, MD, FACC, FAHA, FSCMR, FNASCI, FAAP 
Professor of Pediatrics (Cardiology) and Radiology 
Perelman School of Medicine at the University of 
Pennsylvania 
Director of Cardiac Magnetic Resonance 
The Children's Hospital of Philadelphia 
Division of Cardiology 
 
8th Floor, NW tower, Room 8NW46 
34th Street and Civic Center Blvd 
Philadelphia, PA 19004 
(P): 215-590-7566 (F): 215-590-5825 
email: fogel@email.chop.edu 
 
 
Clinical Trials.gov Update  
July 14, 2022  
Re: Record (NCT) Number NCT03634072 
Study Title: Pediatric REPlAcement of the PulmonaRy ValvE in Tetralogy of Fallot – The PREPARE-
TOF study 
PI Name: Mark Fogel MD 
Date of Document:  
 
To Whom It May Concern:  
Please see the attached IRB approved protocol version date November 8, 2019 for your review.   
If you have any questions or require any further information, please contact me via email@ 
FOGEL@chop.edu 
 
 
Thank you for your time, 
Principal Investigator  
Mark Fogel, MD 
  
 
 
 
 
 
 
  
 
  

 
 
ii
Title: 
Pediatric REPlAcement of the PulmonaRy ValvE in Tetraology of 
Fallot – The PREPARE-TOF study 
Short Title 
TOF and PVR 
Drug or Device 
Names(s) 
N/A 
FDA IND 
N/A 
Regulatory Sponsor: 
NIH/NHLBI 
eIRB Number 
18-015046 
Protocol Date: 
11/08/2019  
Amendment 1 Date: 9/7/2018 
Amendment 4 Date: 9/30/2019 
Amendment 2 Date: 1/10/2019 
Amendment 5 Date:11.08.2019 
Amendment 3 Date: 3/21/2019 
Amendment 6 Date: 
Sponsor  
NIH/NHLBI 
 
Study Principal Investigator: Mark A Fogel MD 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd 
Philadelphia PA 19104 
Phone 215-590-7566 
email: fogel@email.chop.edu 
Site Principal Investigator: Mark A Fogel MD 
The Children’s Hospital of Philadelphia 
Office Address 
Philadelphia, PA, 19104 
Phone 215-590-7566 
email: fogel@chop.edu 
 
 

 
 
 
 
 
iii
TABLE OF CONTENTS 
Table of Contents .................................................................................................................. iii 
Abbreviations and Definitions of Terms............................................................................. vi 
Abstract ................................................................................................................................ vii 
Protocol Synopsis .................................................................................................................. xi 
Table 1: Schedule of Study Procedures .......................................................................... xviii 
Study Diagram .................................................................................................................... xix 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 2 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ..................................................................... 2 
1.3.1 
Non-Clinical Studies ....................................................................................................................... 2 
1.3.2 
Clinical Studies ............................................................................................................................... 2 
1.4 
SELECTION OF DRUGS AND DOSAGES................................................................................................... 2 
1.5 
RELEVANT LITERATURE AND DATA ..................................................................................................... 2 
1.6 
COMPLIANCE STATEMENT .................................................................................................................... 7 
2 
STUDY OBJECTIVES .............................................................................................................................. 7 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 8 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 8 
3.1.1 
Screening Phase .............................................................................................................................. 9 
3.1.2 
Study Treatment Phase (start of the study intervention) ................................................................. 9 
3.1.3 
Phase 2 .......................................................................................................................................... 10 
3.1.4 
Follow-up Phase ........................................................................................................................... 10 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ...................................................................... 10 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................. 10 
3.3.1 
Duration of Study Participation .................................................................................................... 11 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ................................................ 11 
3.4 
STUDY POPULATION ........................................................................................................................... 12 
3.4.1 
Inclusion Criteria .......................................................................................................................... 12 
3.4.2 
Exclusion Criteria ......................................................................................................................... 12 
4 
STUDY PROCEDURES .......................................................................................................................... 13 
4.1 
SCREENING VISIT ............................................................................................................................... 14 
4.2 
STUDY TREATMENT PHASE ................................................................................................................ 15 
4.2.1 
Visit 1 ............................................................................................................................................ 15 
4.3 
PHASE 2 OF THE STUDY – FOLLOWUP ................................................................................................. 21 
4.4 
FOLLOW-UP PHASE ............................................................................................................................. 21 
4.5 
UNSCHEDULED VISITS ........................................................................................................................ 21 
4.6 
CONCOMITANT MEDICATION ............................................................................................................. 22 
4.7 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 22 
4.8 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 22 
4.8.1 
Early Termination Study Visit ....................................................................................................... 22 
5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 23 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 23 
5.1.1 
Medical Record Review ................................................................................................................. 23 
5.1.2 
Physical Examination .................................................................................................................... 27 
5.1.3 
Vital Signs ..................................................................................................................................... 27 
5.1.4 
Exercise CMR (figure 6) ............................................................................................................... 27 
5.1.5 
Biventricular strain (figure 7): ...................................................................................................... 27 
5.1.6 
Metabolic Exercise Testing (if not clinically indicated and therefore, research related): ............ 27 

 
  
 
 
 
iv
5.1.7 
Assessment of QOL ....................................................................................................................... 28 
5.1.8 
Patient Questionnaries:................................................................................................................. 28 
5.1.9 
Physician Questionnaires: ............................................................................................................ 28 
5.1.10 
Interventions (Surgical and Transcatheter PVR) ...................................................................... 30 
5.2 
EFFICACY EVALUATIONS ................................................................................................................... 30 
5.3 
PHARMACOKINETIC EVALUATION ...................................................................................................... 31 
5.4 
SAFETY EVALUATION ......................................................................................................................... 31 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 33 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 33 
6.2 
SECONDARY ENDPOINTS .................................................................................................................... 33 
6.3 
STATISTICAL METHODS...................................................................................................................... 34 
6.3.1 
Baseline Data and Efficacy Analysis ............................................................................................. 34 
6.3.2 
Pharmacokinetic Analysis ............................................................................................................. 35 
6.3.3 
Safety Analysis .............................................................................................................................. 35 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 36 
6.4.1 
Endpoints and Statistics in Context ............................................................................................... 36 
6.5 
INTERIM ANALYSIS ............................................................................................................................ 37 
7 
STUDY INTERVENTION: PVR OR NO-PVR .................................................................................... 38 
7.1 
DESCRIPTION ...................................................................................................................................... 38 
7.1.1 
Packaging ...................................................................................................................................... 38 
7.1.2 
Labeling ........................................................................................................................................ 38 
7.1.3 
Dosing ........................................................................................................................................... 38 
7.1.4 
Treatment Compliance and Adherence ......................................................................................... 38 
7.1.5 
Drug Accountability ...................................................................................................................... 38 
8 
SAFETY MANAGEMENT ..................................................................................................................... 39 
8.1 
CLINICAL ADVERSE EVENTS .............................................................................................................. 39 
8.2 
ADVERSE EVENT REPORTING ............................................................................................................. 39 
8.3 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 39 
8.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 39 
8.4.1 
Relationship of SAE to study drug or other intervention ............................................................... 40 
8.5 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 40 
8.5.1 
Follow-up report ........................................................................................................................... 40 
8.6 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .......................................... 40 
8.7 
MEDICAL EMERGENCIES (IF APPLICABLE) .......................................................................................... 41 
9 
STUDY ADMINISTRATION ................................................................................................................. 42 
9.1 
TREATMENT ASSIGNMENT METHODS................................................................................................. 42 
9.1.1 
Randomization............................................................................................................................... 42 
9.1.2 
Blinding ......................................................................................................................................... 42 
9.1.3 
Unblinding .................................................................................................................................... 42 
9.2 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 42 
9.3 
CONFIDENTIALITY .............................................................................................................................. 43 
9.4 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 43 
9.4.1 
Data and Safety Monitoring Plan ................................................................................................. 43 
9.4.2 
Risk Assessment ............................................................................................................................. 43 
9.4.3 
Potential Benefits of Study Participation ...................................................................................... 43 
9.4.4 
Potential Risks of Study Participation ........................................................................................... 44 
9.4.5 
Risk-Benefit Assessment ................................................................................................................ 46 
9.5 
RECRUITMENT STRATEGY .................................................................................................................. 47 
9.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 48 
9.6.1 
Waiver of Consent ......................................................................................................................... 49 
9.6.2 
Waiver of Assent ............................................................................................................................ 49 
9.6.3 
Waiver of HIPAA Authorization .................................................................................................... 49 

 
  
 
 
 
v
9.7 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 49 
9.7.1 
Reimbursement for travel, parking and meals .............................................................................. 49 
9.7.2 
Payments to parent for time and inconvenience (i.e. compensation) ............................................ 49 
9.7.3 
Payments to subject for time, effort and inconvenience (i.e. compensation) ................................. 49 
9.7.4 
Gifts ............................................................................................................................................... 49 
10 
PUBLICATION ........................................................................................................................................ 49 
11 
REFERENCES ......................................................................................................................................... 49 
 
 

 
  
 
 
 
vi
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
TOF 
 
Tetralogy of Fallot 
PVR 
 
Pulmonary Valve Replacement 
CMR 
 
Cardiac Magnetic Resonance 
MRI 
 
Magnetic Resonance Imaging 
VSD 
 
Ventricular Septal Defect 
RV 
 
Right Ventricular 
LV 
 
Left Ventricular 
RVVO 
 
Right Ventricular Volume Overload 
PR 
 
Pulmonary Regurgitation  
QOL 
 
Quality of Life 
DF 
 
Diffuse Fibrosis 
PCMR 
 
Phase Contrast Magnetic Resonance 
CI 
 
Cardiac Index 
EST 
 
Exercise Stress Test 
RVEDVi 
 
Right Ventricular End-Diastolic Volume Index 
NIH 
 
National Institutes of Health  
FDA 
 
Food and Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
vii
ABSTRACT 
Context: 
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect and the vast 
majority of survivors of corrective surgery will be left with some degree of right ventricular 
(RV) volume overload due to pulmonary regurgitation (PR). TOF patients with significant 
PR are known to develop RV enlargement with right heart failure, diminished biventricular 
function, ventricular arrhythmia, sudden death and decreased exercise performance over 
time. Nearly all studies in this regard are retrospective with much less data in pediatric TOF 
than adults. 
Multiple studies in adult TOF survivors have suggested that pulmonary valve replacement 
(PVR) may alleviate many clinical symptoms and allow RV remodeling; furthermore, 
numerous studies have suggested that PVR in the asymptomatic patients may prevent 
clinical decline. The timing of PVR is crucial as prosthetic valve integrity is limited. If 
performed too early, the valve will require replacement earlier than it might have otherwise 
in the future and if performed too late, the patient may experience an adverse clinical 
outcome and incomplete RV remodeling. 
Despite the lack of robust prospective evidence, PVR is nevertheless occurring in adolescent 
TOF patients. With the advent of transcatheter PVR, an increasing number of patients will 
undergo this procedure, making knowledge of the benefits and timing of the procedure, 
which have generally been based on cardiac magnetic resonance (CMR) derived RV 
volumes mostly in adults, even more critical. Retrospective studies have varied regarding 
the optimal threshold values for PVR; the practice of when and even if PVR should be 
performed varies widely between institutions and even within practice groups.  
To guide clinicians, a randomized, prospective trial is needed to determine if PVR in 
adolescents is beneficial both in the short and long terms. We propose to perform a 
feasibility protocol to obtain preliminary data and to create a structured framework upon 
which a future, large scale trial can be built. Our long-term goal is to perform a rigorous 
prospective trial in adolescent TOF patients to determine specific hemodynamic and 
physiologic criteria in asymptomatic TOF survivors to identify the optimal timing of PVR 
and to demonstrate its benefit, creating a new paradigm through a targeted approach that 
identifies subgroups at highest risk for long-term deficits. To design such a trial, the 
feasibility protocol we propose will obtain pilot data including parameters such as the 
number of patients to screen, acceptance of a randomized PVR trial, comparisons after 1-1.5 
years between those who do and do not undergo PVR in quality of life (QOL) (research 
procedure), exercise testing and Holter monitoring (clinical procedures) which will inform 
the endpoints for the larger, longer term trial. This feasibility protocol will use innovative 
CMR techniques to determine the mechanism of clinical outcome in this patient population. 
Objectives:  
Specific Aim 1: To determine the operational feasibility of a randomized, multicenter trial of 
PVR in adolescent TOF survivors to assess its impact on outcome – a main goal of an R34 
planning grant. Study teams from Children’s Hospital of Philadelphia, Cincinnati Children’s 

 
 
 
 
 
 
viii
Hospital, Children’s Healthcare of Atlanta, Lurie Children’s and Children’s National 
Medical Center will recruit asymptomatic TOF patients to be randomized to PVR or “no-
PVR” groups based on mostly on CMR RV volumes to prove operational feasibility. There 
is precedence for interventional trials in congenital heart disease (eg Single Ventricle 
Reconstruction Trial from the Pediatric Heart Network). Hypothesis: A randomized, 
multicenter, clinical trial of PVR in TOF survivors is operationally feasible. 
Specific Aim 2: To measure clinical parameters needed to design a large scale clinical trial by 
performing a short term pilot protocol. At entry, in addition to CMR (clinical procedure), all 
subjects will undergo exercise testing (clinical procedure), Holter monitoring (clinical 
procedure) and complete QOL questionnaires (research procedure) which will be repeated 
12-18 months later. EST will be performed for research purposes if not performed for 
clinical purposes. Patients will be randomized to PVR and no-PVR groups. Comparison 
between PVR and no-PVR groups will be made for parameters including mortality, exercise 
testing, physical functioning QOL score, prevalence of arrhythmia and medical care 
utilization. Preliminary data for these parameters would be collected will inform outcome 
measures in the larger trial. A comparison of biventricular function between groups will also 
be made. Hypothesis: There are clinical metrics that can be utilized to inform the 
endpoints of a robust longer term, large scale trial of PVR in asymptomatic TOF survivors 
to discern who would benefit and optimize timing of the procedure. 
Specific Aim 3: To determine mechanisms of the effects of PVR in the definitive trial by 
obtaining preliminary data on diffuse fibrosis (DF), performing exercise CMR (research 
procedure) and measuring biventricular strain (post processing of clinical images as a 
research procedure). Subjects will undergo repeat CMR 12-18 months after enrollment 
including measurement of DF, exercise CMR and strain measures to determine biventricular 
function and PR at rest and exercise, comparing PVR and no-PVR groups and correlating 
with short term outcomes. Hypothesis: PVR in asymptomatic TOF survivors who fall 
within specified guidelines results in improved ventricular function at exercise, improved 
strain and have less DF when compared to no-PVR and correlates with clinical outcomes. 
Study Design:  
This is a prospective, multi-center pilot protocol to assess the operational feasibility of a 
randomized, multicenter trial of PVR in adolescent TOF survivors. 
Setting/Participants: 
This is a multi-center study.   
We will enroll 100 patients with TOF from 5 centers: The Children’s Hospital of 
Philadelphia (CHOP), Cincinnati Children’s Hospital (Cinn), Emory University School of 
Medicine/Children’s Healthcare of Atlanta (Emory), Lurie Children’s (Lurie) and Children’s 
National Medical Center (DC)  
 
Study Interventions and Measures:  

 
  
 
 
 
ix
The study team from The Children’s Hospital of Philadelphia (CHOP), Cincinnati 
Children’s Hospital (Cinn), Emory University School of Medicine/Children’s Healthcare of 
Atlanta (Emory), Lurie Children’s (Lurie) and Children’s National Medical Center (DC) 
will participate in this R34. CHOP, Cinn and Emory have worked successfully together in 
the past on other projects including a recent RO1 (HL098252-01). CHOP and DC recently 
began a collaboration using 3D rapid prototyping models, holding their first symposium in 
February 2014. This group of 5 centers brings together well published experts in CMR (Drs 
Fogel, Lang, Slesnick, Rigsby and Cross), exercise (Dr. Paridon), QOL (Dr. Marino), 
catheterization (Dr. Kim) and surgery (Drs Gaynor and Fuller). Experienced “trialists” 
such as Drs Paridon and Marino will be complemented by the experience of Dr. Fogel in 
industry where he ran large scale clinical drug trials for 3 years at Wyeth-Ayerst as well as 
Dr. Scholtens, biostatistics faculty at Lurie Childrens, who has >10 years of experience in 
collaborative biostatistics and currently serves as the primary statistician for a large-scale 
international multicenter epidemiologic study. All are involved in clinical care and have 
been involved in clinical studies. 
 
Although five participating centers may seem a large number for a feasibility pilot 
protocol, there are 2 major justifications for its use. First, because this is a 3 year award, 
there is limited time for follow-up mandating rapid enrollment, which is more feasible from 
multiple centers. Second, we intend to demonstrate and fine-tune the multicenter aspects of 
the trial in preparation for a full study. This includes solidifying functions of a data 
collection center, imaging core and safety monitoring. 
 
CHOP will be the principle site as well as the CMR Core Laboratory and 
Northwestern University (NU) will provide the data management and biostatistical support. 
Dr. Fogel (CHOP) and Dr. Marino (NU) have been the CMR Core Laboratory and data 
management and biostatistical support respectively for numerous other studies. A strict 
firewall will be in place at both CHOP and NU to ensure that Drs. Fogel and Marino do not 
participate in and will be blinded to any site data. Teleconferences monthly will be held 
between centers to discuss issues and make decisions regarding the conduct of the feasibility 
protocol. Analysis of 
CMR data will be 
performed at each site 
and in the department 
of Radiology at 
CHOP. EST, QOL, 
echocardiograms and 
Holter monitoring will 
be performed at each 
site. Figures to the 
right depict the 
workflow and 
communications link 
for CMR data 
(leftward) and data 
other than CMR 
(rightward). 
Work flow for CMR data 
Work flow for data other than CMR 

 
  
 
 
 
x
Overall Approach of this R34: The overall approach of this proposal is to test feasibility of 
a multicenter, randomized, controlled interventional trial at each of these centers (Aim 1), 
obtain preliminary data to inform the large scale definitive trial by performing a small pilot 
protocol of such a trial (Aim 2) and to determine possible mechanistic effects of the results 
with novel CMR techniques (Aim 3). The small pilot protocol will randomize asymptomatic 
TOF patients to PVR or “no-PVR” groups based primarily on clinical CMR RV volumes 
(see entry criteria in Aim 2). PVR groups will be further divided into transcather PVR 
(where clinically indicated) and surgical PVR (for all others). Recruitment rates will be 
assessed (Aim 1) and coordination of centers tested (e.g. communication via Skype, etc.; 
Aim 1). CMR Core lab and data management and biostatistical support performance will be 
evaluated (e.g. time to process a CMR study; Aims1 and 2). A data safety monitoring board 
will be established. There is precedence for interventional trials in congenital heart disease 
(eg Single Ventricle Reconstruction Trial from the Pediatric Heart Network). 
The study intervention is randomization between PVR and no-PVR groups; PVR groups 
will get catheter-based or surgical based PVR, whichever is clinically indicated. Study 
measures will include review of medical records including those from CMR (eg ventricular 
volumes, ejection fraction, PR), exercise testing (eg VO2 at VAT, Work at VAT) and Holter 
monitoring (eg amount of ectopy). Other research related procedures include patient/family 
questionnaires, physician questionnaires and Quality of Life testing (QOL), exercise CMR 
and post-processing of clinical cine images to obtain biventricular strain. EST will be 
performed for research purposes if not performed for clinical purposes. These will all be 
performed at the beginning of participation and then 1-1.5 years afterwards. See body of the 
protocol for more details on specific measures. 
 
 
 
 
 
 
 
 
 
 
 
 
                        

 
  
 
 
 
xi
PROTOCOL SYNOPSIS 
 
Study Title 
 
Tetralogy of Fallot and Pulmonary Valve Replacement 
Funder 
NIH/ NHLBI 
Clinical Phase 
Not applicable 
Study Rationale 
Tetralogy of Fallot (TOF) is the most common cyanotic congenital 
heart defect and the vast majority of survivors of corrective surgery 
will be left with some degree of RV volume overload PR). TOF 
patients with significant PR are known to develop right ventricular 
(RV) enlargement with right heart failure, diminished biventricular 
function, ventricular arrhythmia, sudden death and decreased 
exercise performance over time. Nearly all studies in this regard are 
retrospective with much less data in pediatric TOF than adults. 
Multiple studies in adult TOF survivors have suggested that 
pulmonary valve replacement (PVR) may alleviate many clinical 
symptoms and allow RV remodeling; furthermore, numerous 
studies have suggested that PVR in the asymptomatic patients may 
prevent clinical decline. The timing of PVR is crucial as prosthetic 
valve integrity is limited. If performed too early, the valve will 
require replacement earlier than it might have otherwise in the 
future and if performed too late, the patient may experience an 
adverse clinical outcome and incomplete RV remodeling. 
Despite the lack of robust prospective evidence, PVR is 
nevertheless occurring in adolescent TOF patients. With the advent 
of transcatheter PVR, an increasing number of patients will undergo 
this procedure, making knowledge of the benefits and timing of the 
procedure, which have generally been based on cardiac magnetic 
resonance (CMR) derived RV volumes mostly in adults, even more 
critical. Retrospective studies have varied regarding the optimal 
threshold values for PVR; the practice of when and even if PVR 
should be performed varies widely between institutions and even 
within practice groups.  
To guide clinicians, a randomized, prospective trial is needed to 
determine if PVR in adolescents is beneficial both in the short and 
long terms. We propose to perform a feasibility protocol to obtain 
preliminary data and to create a structured framework upon which a 
future, large scale trial can be built. Our long-term goal is to 
perform a rigorous prospective trial in adolescent TOF patients to 
determine specific hemodynamic and physiologic criteria in 
asymptomatic TOF survivors to identify the optimal timing of  PVR 
and to demonstrate its benefit, creating a new paradigm through a 
targeted approach that identifies subgroups at highest risk for long-

 
 
 
 
 
 
xii
term deficits. To design such a trial, the feasibility protocol we 
propose will obtain pilot data including parameters such as the 
number of patients to screen, acceptance of a randomized PVR trial, 
comparisons after 1-1.5 years between those who do and do not 
undergo PVR in quality of life (QOL), exercise testing and Holter 
monitoring which will inform the endpoints for the larger, longer 
term trial. EST will be performed for research purposes if not 
performed for clinical purposes. This feasibility protocol will use 
innovative CMR techniques to determine the mechanism of clinical 
outcome in this patient population. There is precedence for 
interventional trials in congenital heart disease (eg Single Ventricle 
Reconstruction Trial from the Pediatric Heart Network). 
Study Objective(s) 
Specific Aim 1: To determine the operational feasibility of a 
randomized, multicenter trial of PVR in adolescent TOF survivors 
to assess its impact on outcome – a main goal of an R34 planning 
grant. Study teams from Children’s Hospital of Philadelphia, 
Cincinnati Children’s Hospital, Children’s Healthcare of Atlanta, 
Lurie Children’s and Children’s National Medical Center will 
recruit asymptomatic TOF patients to be randomized to PVR or 
“no-PVR” groups based on mostly on CMR RV volumes to prove 
operational feasibility. There is precedence for interventional trials 
in congenital heart disease (eg Single Ventricle Reconstruction Trial 
from the Pediatric Heart Network). Hypothesis: A randomized, 
multicenter, clinical trial of PVR in TOF survivors is 
operationally feasible. 
Specific Aim 2: To measure clinical parameters needed to design a 
large scale clinical trial by performing a short term pilot protocol. 
At entry, in addition to CMR (clinical procedure), all subjects will 
undergo exercise testing (clinical procedure), Holter monitoring 
(clinical procedure), complete patient/family questionnaire and 
complete QOL questionnaires (both research procedures) which will 
be repeated 12-18 months later. EST will be performed for research 
purposes if not performed for clinical purposes. Comparison 
between PVR and no-PVR groups will be made for clinical 
parameters including mortality, exercise testing, physical 
functioning QOL score, prevalence of arrhythmia and medical care 
utilization. Preliminary data for these parameters would be collected 
will inform outcome measures in the larger trial. A comparison of 
biventricular function between groups will also be made. 
Hypothesis: There are clinical metrics that can be utilized to 
inform the endpoints of a robust longer term, large scale trial of 
PVR in asymptomatic TOF survivors to discern who would benefit 
and optimize timing of the procedure. 
Specific Aim 3: To determine mechanisms of the effects of PVR in 
the definitive trial by obtaining preliminary data on diffuse fibrosis 

 
 
 
 
 
 
xiii
(DF), performing exercise CMR and measuring biventricular strain. 
Subjects will undergo repeat CMR 12-18 months after enrollment 
including measurement of DF, exercise CMR (research procedure) 
and strain measures (research procedure) to determine biventricular 
function and PR at rest and exercise, comparing PVR and no-PVR 
groups and correlating with short term outcomes.  
Hypothesis: PVR in asymptomatic TOF survivors who fall within 
specified guidelines results in improved ventricular function at 
exercise, improved strain and have less DF when compared to no-
PVR and correlates with clinical outcomes. 
 
Test Article(s) 
PVR or no-PVR in a randomized fashion 
Study Design 
 
This is a prospective, multicenter, randomized pilot protocol to 
assess the operational feasibility and to obtain preliminary data to 
inform a future large scale randomized, multicenter trial of PVR in 
adolescent TOF survivors.  
Subject Population 
key criteria for 
Inclusion and Exclusion: 
Inclusion Criteria 
For patients with TOF 
1. Males or females with repaired TOF, currently between 13 
and 21 years of age. 
2. On clinical CMR: RVEDVi between 140 and 180 cc/m2 
inclusive with RVEF > 40% and LVEF > 50%. If data 
available and adequate RV outflow tract peak velocity < 3 
meters/second (if not available this can be skipped); there will 
be no indexed RVESVi criteria; by defining RVEDVi and 
RVEF, we will be inherently defining RVESVi, at least 10% 
pulmonary regurgitation fraction.  
3. On clinical echocardiogram: If data available and adequate, 
RV outflow tract peak velocity < 3 meters/second (if not 
available this can be skipped), at least mild pulmonary 
insufficiency and tricuspid regurgitation with an RV pressure 
estimate < 1/2 systemic pressure. 
4. On EST, aerobic capacity > 60% of predicted. 
5. No QRS duration criteria on ECG. 
For physicians: Any cardiologist who practices at any of the 5 
participating sites. 
The Exclusion Criteria 
For patients with TOF 
1. Any condition judged by the patient’s physician that 
would cause this trial to be detrimental to the patient. 
2. Specific forms of TOF excluded are those with 
endocardial cushion defects, TOF with absent pulmonary 

 
 
 
 
 
 
xiv
valve and TOF with multiple aorto-pulmonary collaterals 
requiring unifocalization. 
3. Unilateral branch pulmonary artery stenosis (one lung 
receives < 25% of total flow) 
4. Contraindication to non-sedated exercise CMR (e.g. 
pacemaker/implanted cardioverter defibrillator); need for 
sedation 
5. If data available, moderate or greater tricuspid 
regurgitation on echocardiogram or CMR or Qp/Qs > 1.5 
(if not available this can be skipped) 
6. Significant strokes/hemiplegia or inability to exercise 
7. Genetic syndrome/developmental delay which would 
make QOL and EST date uninterpretable 
8. Pregnancy.  
9. Previous pulmonary valve replacement (PVR). 
For physicians: none. 
 
Number Of Subjects  
 
We will enroll 100 patients with TOF from the 5 centers including 
CHOP. For physicians agreeing to answer questionnaires, we 
estimate this will be ~200 subjects will be enrolled. 
Study Duration 
1. Each subject’s participation will last ~ 1-1.5 years from 
enrollment to followup  
2. Exercise CMR component to the CMR scans will last~ 15 
minutes. Metabolic exercise test (if not clinically indicated 
and therefore, research related) will last ~ 60 minutes 
3. Assessment of QOL will last ~ 20 minutes 
4. Fill out patient questionnaire about this trial will last ~10-15 
minutes 
5. For physicians answering physician questionnaire, this will 
last ~20 minutes 
 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
1. Screening and subsequent recruitment begins ~3 months 
after grant approved 
2. Patients will be recruited simultaneously 
3. Study treatment will be in 2 phases – at recruitment where 
randomization occurs and then at followup 1-1.5 years later 
4. Data entry will be on-going 
5. 1.5-2 year enrollment period 
6. End recruitment. Data cleaning, analysis and manuscript 
writing in last few months 
Efficacy Evaluations 
Aim 1: Results of questionnaires, ability to recruit the required 
number of patients in the time given, Protocol logs demonstrating 
how many patients were screened, eligible and approached, how 
many dropped out and for what reason among other metrics. Factors 

 
 
 
 
 
 
xv
which will affect follow-up in a larger trial are also key such as 
patients moving out of the area, pregnancy and need for pacemaker 
will be recorded and will be used as preliminary data for dropout 
rates and sample size for the larger trial. 
Aim 2: Exercise parameters on EST such as maximum oxygen 
consumption and work at ventilatory anaerobic threshold; Quality of 
life indexes, CMR parameters such as ventricular volumes, ejection 
fraction and mass; Holter parameters such as the amount of ectopy. 
Aim 3: Measures of diffuse and discrete fibrosis, myocardial strain 
and performance parameters on exercise CMR. 
Pharmacokinetic 
Evaluations 
Not applicable 
Safety Evaluations 
Clinical evaluations such as death, transplantation, need for 
hospitalization and medication, failure of PVR with need to replace 
or need, in the non-PVR goup for PVR, requirement in general for 
additional interventions.  
A data safety monitoring board will be established through the NIH.  
Statistical And Analytic 
Plan 
Please see body of this application for a detailed analysis. 
A data coordinating center will be established at Northwestern 
University (NU). A REDCAP database will used.  
For randomization, we will use a 2:1 PVR:no-PVR randomization 
scheme. The statistician will generate a randomization scheme using 
blocked randomization with varying block sizes of 3 and 6 within 
study site. To assess success of randomization in balancing patient 
characteristics across treatment arms, we will calculate means and 
standard deviations for relevant continuous variables and tables of 
counts and frequencies for categorical variables, comparing across 
PVR and no PVR groups using t- and chi-square tests, respectively. 
If imbalance is observed, analyses of the outcomes will be 
conducted with and without adjustment for these covariates. 
DSMB interim analysis: The DSMB will formally review adverse 
event frequency for the PVR and no-PVR groups after 45 trial 
participants have completed follow-up data collection; they will be 
blinded to treatment group status and only frequencies, not sample 
sizes, will be presented to mask the 2:1 randomization. A 
statistically significant difference (p<0.05) in adverse event 
frequency will merit further investigation into continuing the trial. 
This interim analysis is planned for formal evaluation of safety; an 
interim analysis of treatment effect is not planned due to the pilot 
and feasibility nature of the study. 
Aim 1: Descriptive statistics appropriate for measures of feasibility 
and performance will be calculated (eg overall percent and monthly 
pace of patient recruitment at each site, means and standard 

 
 
 
 
 
 
xvi
deviations of patient/physician survey answers). These data 
summaries will be used to determine whether a large-scale clinical 
trial is feasible; specific criteria for proceeding with a larger trial are 
outlined at the end of this proposal. 
Aims 2 and 3: Descriptive statistics for all variables will be 
computed, including parametric and non-parametric measures of 
central tendency and variability. Continuous outcome variables for 
Aims 2 and 3 will be checked for normality using histograms and 
qplots, both for baseline and follow-up measures at 1-1.5 years after 
randomization, and for the difference between these two 
observations. If normality is suspect, we will explore 
transformations to improve normality or apply non-parametric 
counterparts for the analyses described in what follows. Data will be 
analyzed using SAS. 
 
The change from enrollment to 1-1.5 years after randomization 
in each candidate parameter for the intended primary endpoint in the 
definitive trial will be treated as outcomes which will be 
summarized for the PVR and no-PVR groups using means and 
standard deviations; they will be formally compared between groups 
using linear regression models with a dummy variable for treatment 
assignment (PVR vs. no-PVR) as the primary variable of interest 
with adjustment for study site and possibly other covariates that 
were not balanced across treatment group and might be associated 
with the outcomes. Treatment differences with p<0.05 in regression 
models will be considered statistically significant. Intent-to-treat 
analyses will be conducted such that treatment assignment will be 
assigned as randomized regardless of adherence. Complete data 
analyses will be conducted initially, but the frequency of missing 
data within each treatment group will be calculated. Since baseline 
data determines study eligibility, most missing data will occur at the 
anticipated follow-up time. We will compare demographic and 
clinical characteristics of patients with complete data to those 
without using t- and chi-square tests as appropriate to determine 
whether “missingness” may be informative. Depending on what we 
observe, we will perform sensitivity analyses using multiple 
imputation approaches and compare results to complete data 
analyses. Importantly, describing “missingness” frequency and 
potential bias in its occurrence will assist in planning a larger trial 
by emphasizing areas crucial for follow-up. It will help plan for 
imputation strategies that may be necessary in the larger trial and 
could suggest additional variables for in the larger trial to strengthen 
imputation models in the larger setting if required.  
 
Several of the other candidate parameters which will be tested 
for the definitive trial for both Aims 2 and 3 are continuous 
variables measured at 2 time points; differences will be analyzed 

 
 
 
 
 
 
xvii 
using the approach described for the primary endpoints. Comparison 
of frequency of additional discrete secondary outcome variables for 
Aim 2 (eg death, hospitalization) will utilize chi-square tests given 
the sample size followed by logistic regression controlling for site 
and any other relevant variables. Cox modeling of time-to-event 
data will be considered if frequencies are higher and event times 
more varied than expected although this is unlikely given the 
number of events anticipated. Within the PVR group, we will 
tabulate frequency of valve failure and re-intervention and in the no 
PVR group, we will tabulate the frequency of need for PVR or other 
interventions. These are not comparative analyses but will inform 
event rates for future trial design. Analyses for comparing the 
surgical and transcather PVR groups for all candidate parameters for 
the definitive trial will be adjusted for time since repair will be 
conducted by performing all analyses as just described. While 
patients will not be randomized to mode of PVR and this may 
introduce some bias, we will control for confounding to the extent 
possible and incorporate the similarities and differences of surgical 
or transcather PVR group in planning of the larger trial. Pairwise 
Spearman’s correlation coefficients including 95% confidence 
intervals will be calculated for the variables listed in Aim 3 and the 
clinical outcomes in Aim 2. All statistical tests will be conducted at 
nominal 2-sided, 5% significance level. While we recognize the 
multiplicity of variables and statistical tests, the purpose of this pilot 
trial is not to provide conclusive evidence of clinical effect, but 
rather to indicate possible effect size and use it to plan for a larger 
trial if the preliminary effect size is clinically relevant. Because of 
the preliminary nature of this pilot study, no correction for multiple 
comparisons will be made. 
 
DATA AND SAFETY 
MONITORING PLAN 
The PI at each site will have overall responsibility for monitoring 
the overall safety during the study In addition, the study coordinator 
will be involved in all studies and will also monitor for safety. Each 
site will be responsible for reporting all adverse events to their 
respective IRB and to the lead site in a timely fashion in compliance 
with all applicable regulations. The study investigators will be 
responsible for data management and accuracy of records.  They 
may assign designated qualified individuals to collect the 
information. All data will be entered into Redcap. 
A DSMB will be constituted from the NIH. 

 
 
 
 
 
 
xviii 
 TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Study 
Visit 
1 
Study Visit 2 
Study Visit 3 
Study Days 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
Review 
Inclusion/Exclusion 
Criteria 
X 
X* 
 
 
Demographics/Review 
of 
Medical History 
X 
X 
X 
 
Randomization to receive 
PVR or no-PVR 
 
X 
 
 
Review medical records 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Exercise Stress Test if not 
clinically indicated 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
QOL questionnaires  
 
X 
X 
 
Patient/family 
questionnaire 
 
X 
X 
 
Prior/Concomitant 
Medications 
 
X 
            X 
 
Adverse Event Assessment 
 
X 
            X 
 
Exercise CMR ## 
 
X 
              X 
 
Physician questionnaire 
 
X 
               X 
           X 
*if not done at screening. 
## this will occur as a pure study procedure and will be added on to at the end to an 
existing standard of care CMR at the end of the case; this will be done in 10 patients 
as a subanalysis. 
***Screening visit and Study visit can occur on the same day. 
 

 
 
 
 
 
 
xix
 STUDY DIAGRAM 
 
 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring 
are clinical care procedures. 
 
* screening activities are limited to review of medical/investigator records and do not 
include soliciting information directly from potential subjects 
 
* 

 
  
 
  
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect and the vast 
majority of survivors of corrective surgery will be left with some degree of right ventricular 
(RV) volume overload due to pulmonary regurgitation (PR). TOF patients with significant 
PR are known to develop RV enlargement with right heart failure, diminished biventricular 
function, ventricular arrhythmia, sudden death and decreased exercise performance over 
time. Nearly all studies in this regard are retrospective with much less data in pediatric TOF 
than adults. 
Multiple studies in adult TOF survivors have suggested that pulmonary valve replacement 
(PVR) may alleviate many clinical symptoms and allow RV remodeling; furthermore, 
numerous studies have suggested that PVR in the asymptomatic patients may prevent 
clinical decline. The timing of PVR is crucial as prosthetic valve integrity is limited. If 
performed too early, the valve will require replacement earlier than it might have otherwise 
in the future and if performed too late, the patient may experience an adverse clinical 
outcome and incomplete RV remodeling. 
Despite the lack of robust prospective evidence, PVR is nevertheless occurring in adolescent 
TOF patients. With the advent of transcatheter PVR, an increasing number of patients will 
undergo this procedure, making knowledge of the benefits and timing of the procedure, 
which have generally been based on cardiac magnetic resonance (CMR) derived RV 
volumes mostly in adults, even more critical. Retrospective studies have varied regarding 
the optimal threshold values for PVR; the practice of when and even if PVR should be 
performed varies widely between institutions and even within practice groups.  
To guide clinicians, a randomized, prospective trial is needed to determine if PVR in 
adolescents is beneficial both in the short and long terms. We propose to perform a 
feasibility protocol to obtain preliminary data and to create a structured framework upon 
which a future, large scale trial can be built. Our long-term goal is to perform a rigorous 
prospective trial in adolescent TOF patients to determine specific hemodynamic and 
physiologic criteria in asymptomatic TOF survivors to identify the optimal timing of  PVR 
and to demonstrate its benefit, creating a new paradigm through a targeted approach that 
identifies subgroups at highest risk for long-term deficits. To design such a trial, the 
feasibility protocol we propose will obtain pilot data including parameters such as the 
number of patients to screen, acceptance of a randomized PVR trial, comparisons after 1-1.5 
years between those who do and do not undergo PVR in quality of life (QOL), exercise 
testing and Holter monitoring which will inform the endpoints for the larger, longer term 
trial. This feasibility protocol will use innovative CMR techniques to determine the 
mechanism of clinical outcome in this patient population. There is precedence for 
interventional trials in congenital heart disease (eg Single Ventricle Reconstruction Trial 
from the Pediatric Heart Network; 
http://www.pediatricheartnetwork.org/Studies/CompletedStudies/SingleVentricleStudySurgi
cal.aspx ). 

 
  
 
  
 
2
1.2 Name and Description of Investigational Product or Intervention 
This study does not utilize an investigational product; it is utilizing an intervention. As 
mentioned in the Introduction above and the Literature and Data sections below, when the 
RV of a patient with TOF dilates, physicians and patients face a choice of PVR or of not 
performing PVR with the attendant risks and benefits to each. The intervention this study 
investigates is PVR vs no-PVR in a randomized fashion. 
1.3 Findings from Non-Clinical and Clinical Studies 
1.3.1 Non-Clinical Studies 
Not applicable 
1.3.2 Clinical Studies 
Please see Relevant Literature and Data section 
1.4 Selection of Drugs and Dosages 
Not applicable 
1.5 
Relevant Literature and Data 
Tetralogy is the most common cyanotic congenital heart defect 
and after surgical palliation, often have hemodynamically 
significant PR. Tetralogy of Fallot (TOF)1 has an incidence of ~ 6% 
of all congenital heart defects2 with ~1660 babies born each year in 
the US.3 The main pathologic mechanism is malalignment of the 
infundibular septum which results in a ventricular septal defect 
(VSD) and causes pulmonary stenosis. Right ventricular (RV) 
hypertrophy and an “overriding aorta” are the other 2 components 
to the “tetralogy” (Figure 1). Repair typically consists of VSD closure 
and relief of RV outflow tract obstruction typically by placement of a 
transannular patch, which in most instances, results in severe pulmonary 
regurgitation (PR) from disruption of pulmonary valve integrity; RV 
volume overload (RVVO) typically ensues (Figure 2).4,5 Another 
commonly used approach is placement of an RV to pulmonary artery 
conduit instead of a transannular patch which also results in PR and 
RVVO as most conduits do not have a valve. 
 
Due to PR, TOF survivors have RVVO, reduced RV and left 
ventricular (LV) performance and are at risk for poor clinical outcomes. Multiple studies 
that have investigated resting RV and LV function after TOF repair 6,7,8,9,10,11 consistently 
found diminished RV and LV performance with decreased RV and LV ejection fraction 
(EF), mostly in patients with PR. There is an increase in indexed RV end-diastolic volume 
(RVEDVi) which has been the focus of studies with regard to pulmonary valve replacement 
(PVR). Patients with RVVO are at risk for sudden death, ventricular arrhythmias, increased 
New York Heart Association (NYHA) class and decreased exercise performance (see 
below). A recent study suggests that TOF survivors have a higher degree of RV and LV 
Figure 1: Anatomy of TOF 
Figure 2: Repair of TOF 

 
  
 
  
 
3
diffuse fibrosis (DF) compared to normal, raising the possibility of an etiology;12,13 the 
degree and time course of this fibrosis has yet to be defined. 
 
Cardiac Magnetic Resonance (CMR) is the gold standard for reliably and accurately 
measuring ventricular volumes, ventricular performance and PR. Given the above, 
accurate measurement of ventricular volumes, performance and PR are crucial; toward that 
end, CMR has been utilized as the non-invasive imaging modality of choice as it can not 
only visualize 3 dimensional (3D) anatomy but can also determine 3D 
physiology and function. CMR is tomographic and unencumbered by 
acoustic windows or overlapping structures; cine CMR measures of 
ventricular volumes, mass (Figure 3) and cardiac index (CI) are 
considered the non-invasive “gold standard” for these parameters.14,15,16 
CMR has high reproducibility and decreased variability17,18 and 
therefore, less patients are needed to power studies. It has been applied 
in children for many years by all the imaging laboratories participating 
in this proposal.19,20 
 
To determine PR, the CMR technique of phase contrast velocity 
mapping (PCMR)21  is employed which has also been applied by our 
laboratories for many years;22,23 CI can be directly measured from the 
cross-sectional area of blood vessels. Internal checks are used (e.g. 
flow in the main pulmonary artery must equal flow in the branches) 
making this technique highly accurate in assessing cardiovascular 
performance. 
 
T1 mapping is a relatively new CMR technique which can 
determine DF and has been applied in multiple pathologic conditions. 
In scarred regions, T1 relaxation times (an intrinsic CMR tissue property) is longer without 
gadolinium and shorter with gadolinium. The LV and RV tissue characteristics in TOF may 
be different than normals as suggested in recent articles12,13 and may be a possible reason for 
decreased biventricular performance in this population. T1 mapping values are have low 
variability between repeat scans.24 
 
Myocardial strain by CMR has been assessed for over 25 years using myocardial 
tagging,25 however, the recent development of feature tracking and tissue tracking allows for 
strain measurements with standard cine.26 CMR strain has recently demonstrated to be 
prognostic in adult TOF survivors.26 
 
Finally, exercise CMR is also a relatively new technique where individuals undergo 
lower limb exercise using an MRI compatible ergometer so that ventricular performance and 
blood flow can be measured under stress conditions.27 Exercise capacity in TOF patients is 
impaired and the ability of CMR to determine ventricular function and flows at exercise is 
an important component to the overall cardiovascular assessment of the TOF survivor. 
 
Exercise capacity is significantly decreased in TOF survivors with PR and RVVO when 
compared to normal individuals.28,29,30 This exercise incompetence may result from either 
primary LV dysfunction or by “ventricular-ventricular” interaction, where the dilated RV 
impinges on LV geometry causing poor performance. When TOF patients were studied at 
rest and during exercise testing (EST), the incremental exercise response of LV EF in TOF 
patients was depressed relative to controls and LV EF during exercise correlated with both 
RVEDVi and the severity of PR.30 When comparing exercise performance in TOF patients 
RV
R
L
RV
Figure 3: CMR 4-chamber 
(top) & short axis views 
(bottom) of TOF patient with 
RVVO. Note large RV. 

 
  
 
  
 
4
and controls, significant differences exist in peak workload, maximal heart rate and systolic 
blood pressure.29  
 
The decreased LV performance at rest and at exercise may also be due to “ventricular-
ventricular interaction.”31,32,33,34,35,36,37,38 The LV and RV effect the other’s biomechanics by 
mechanical coupling, mostly through the septum;35 with RVVO, this interaction may be 
deleterious and at the root of decreased LV performance and exercise tolerance.39,40,41,42 For 
example, correlations of PR and LVEF have been found at rest39 and at exercise.30 
additionally, significant correlations exist between exercise and the degree of PR.39,40 A 
review of 22 exercise studies43 found that 14 showed a significant relationship between PR 
with abnormal RV function and decreased exercise capacity. Further implicating RVVO are 
studies that demonstrate once the RVVO is abolished by PVR, exercise tolerance 
improved.41,42 
 
Diminished ventricular performance in TOF is associated with worse clinical outcomes 
and is related to important clinical variables. In a study of 100 consecutive TOF 
survivors,44 by multivariate analysis, ventricular performance with lower LV EF was one of 
the strongest predictors of poor clinical outcome (odds ratio [OR]=3.88 for a 10% decrease, 
P=0.002). Among RV variables, lower RV EF was one of the strongest risk factors (OR= 
2.41 for a 10% decrease, P=0.01). A follow-up study performed in 88 of these patients > 4 
years later with endpoints of increase NYHA class, sustained ventricular tachycardia and 
sudden death demonstrated that higher RVEDVi and a lower RV EF correlated with 
increasing probability of adverse events.45 Increasing NYHA class has been found to be 
associated with lower LV EF and RV EF (OR 3.88 and 2.41 for a 10% decrease, P<0.01).46 
Decreased biventricular strain by CMR has been demonstrated only recently to be 
prognostic of adverse outocmes.26 Numerous studies in the last decade have demonstrated 
that once the RV becomes too dilated, there is lack of functional recovery - the threshold of 
what is “too dilated” remains controversial and varied throughout the studies.47,48,49,76 
Health-related quality of life (QOL) in TOF is an important clinical outcome and 
endpoint for a future clinical trial: QOL is defined as the influence of a specific illness or 
injury, medical therapy, or health services policy on the ability of the patient to both 
function in and derive personal satisfaction from physical, psychological, and social life 
contexts.50 It has emerged as a high priority not only for patients and their families, but also 
for the NIH, FDA and insurance providers.51,52,53 
Given the relative decreasing mortality and prolonged survival in TOF survivors, issues 
of QOL are increasingly important.54,55 Morbidity related to underlying physiology and 
ventricular dysfunction have physical and psychological effects that may have an adverse 
effect on QOL. Late effects from TOF repair include neurodevelopmental abnormalities,56,57 
diminished physical functioning,58,59 and psychosocial issues.60 QOL scores in the pediatric 
TOF survivor are significantly lower than healthy controls and patients with mild CHD.61 
Several generic measures of pediatric QOL exist.62 The Pediatric Quality of Life 
Inventory (PedsQL) V. 4.063,64 is a commonly used, self-administered generic pediatric 
cardiac QOL measure for children and adolescents with CHD or acquired heart disease (8-
18 years) which has been validated65,66 with published norms available.67 Generic measures, 
however, may not be responsive to small changes in a child's condition or function and may 
overlook clinically relevant aspects of a child's life related to a specific disease condition.68 
Disease-specific measures assess symptoms that are specific to an illness, population, 
and/or treatment; the main drawback is that it does not allow comparison of QOL among 

 
  
 
  
 
5
children and adolescents with different illnesses. Dr. Marino, one of the co-investigators on 
this proposal, developed and validated the Pediatric Cardiac Quality of Life Inventory 
(PCQLI),69,70,71,72 which is a self-administered, disease-specific pediatric cardiac QOL 
measure for children (8-12 years) and adolescents (13-18 years) with CHD or acquired heart 
disease. Utilizing both instruments allows for a comprehensive QOL assessment. 
 
PVR eliminates PR, decreases RVVO and improves symptoms but the threshold volume 
above which a PVR should be performed is unknown: The above strongly suggests that PVR 
may be advantageous to these patients by eliminating PR; RV volumes have been used as the 
key parameter to determine timing of PVR. Besides decreasing RVEDVi and eliminating 
PR,73 PVR generally decreases tricuspid insufficiency, decreases symptoms and increases 
NYHA class.74,75 For example, Therrien et al.76 studied adult TOF patients before and after 
PVR and found RVEDVi and indexed RV end-systolic volume (RVESVi) decreased 34% and 
37% respectively. Importantly, no patient achieved a normal RVEDVi and RVESVi after PVR 
if their RVEDVi prior to surgery was >170 cc/m2 and their RVESVi was >85 cc/m2. In a 
prospective, non-randomized CMR study77 in pediatric TOF patients who underwent PVR at 
an RVEDVi >150 cc/m2, a significant decrease in RV volumes and mass after PVR (6 months 
after surgery) was found; no clinical outcomes were reported. Frigiola et al78 reported an 
aggressive PVR strategy by operating on patients with an average RVEDVi of 142+43 cc/m2, 
very close to the value of 139 cc/m2 in the power loss study from our lab on TOF (see 
preliminary data) and the 135 cc/m2 our lab found which increased the likelihood of an 
LVEDP of > 12 mm Hg (see preliminary data). They found that early PVR led to RVEDVi 
normalization, improvement in biventricular function and much improved submaximal 
exercise capacity. Warner et al found the ability to achieve an increased peak workload after 
PVR.79 
 
Although PVR had clinical benefits in these retrospective studies, the effect on objective 
exercise performance and arrhythmia is less clear. There are conflicting reports on various 
exercise stress test parameters with some studies showing improvement41,47,78 in parameters 
such as submaximal exercise testing and others not.80,81 Similarly, some studies have shown 
a decrease in the amount of ventricular tachycardia and QRS duration increase (e.g. the report 
by Therrien et al82) whereas other reports show no change.83,84 
 
The benefit of PVR must be weighed against the interventional risk and the natural history 
of repaired TOF without PVR. Numerous studies have demonstrated that PVR is very low 
risk surgically as well as via a transcatheter approach. Available bioprosthetic valves, 
however, have a limited life span; in one recent study of 227 TOF survivors, freedom from 
reintervention or structural valve disease after PVR was 94% and 74% at 5 years 
respectively;85 younger age increased time to structural valve disease. Undertaking PVR 
“starts the clock” which will eventually lead to repeat PVR and further interventions. This is 
balanced by the natural history of TOF survivors without PVR; although mortality rate is only 
10% in the first 2 decades of life, it significantly increases afterwards and many patients suffer 
exercise intolerance, arrhythmia, heart failure, and sudden death. A pulmonary valve can be 
replaced; a failed RV is much more problematic. In a study of long term outcomes after TOF 
repair, the rate of sudden cardiac death was 0.3%/year; sudden cardiac death was the most 
common cause of late death. A similar study showed that the late mortality risk increased 
significantly to 0.94%/year.86,87  
 
The studies presented above are small, nearly all retrospective and nearly all in adults 
with little focus on clinical outcome. These limitations are especially true of PVR data; this 

 
  
 
  
 
6
has led to varying practices of when and even if PVR is performed between institutions and 
even within practice groups. There are strong beliefs on both sides regarding PVR without 
robust, randomized, prospective data to support either approach. A recent study of 799 over 
35 centers found significant between-center heterogeneity in age at PVR.88 For example, an 
asymptomatic TOF patient with an RVEDVi of 161 cc/m2 may come to clinic on one day 
and have a cardiologist schedule surgery whereas if the patient serendipitously came on 
another day to the same clinic but saw a different cardiologist, they would be told adamantly 
that surgery was not needed. Rationales are based on some data but are mostly anecdotal, 
experience, or a “gut feeling.” Small retrospective studies are variable with regard to what 
the lower limit should be to undergo PVR to maximize the benefit. 
 
Overall Significance – making a leap forward in TOF survivorship and follow-up care: 
The planned large scale trial will be the first prospective, randomized, multicenter trial of 
PVR in TOF in any age group. The R34 application, which is a clinical trials pilot protocol, 
is key to obtaining preliminary data to inform that trial. The feasibility protocol which we 
propose has the potential to not only add to the literature on adolescents with TOF but also 
holds the potential to begin to definitively answer the question of if and when to perform 
PVR. This question takes on increasing importance as PVR is increasing across the US88 
without robust, randomized, prospective evidence that it ultimately benefits patients. As an 
R34, this feasibility protocol will not only be a “proof of concept,” it will obtain the 
necessary information needed to create endpoints for the prospective, randomized, 
multicenter clinical trial which we envision. It will also obtain much needed data on these 
children which has not previously been available. One of the important objectives of this 
R34 will be to determine the operational feasibility of performing a randomized, controlled, 
multicenter PVR trial while there is still equipoise on both sides of the randomization 
scheme. This application is the first step towards heeding the call for a multicenter dataset 
which “is clearly needed to assist in management in patients with TOF.”89 
 
The obvious clinical significance to the proposed trial is that PVR has the potential 
to change QOL of teenagers and young adults in their daily routine as well as their 
exercise tolerance, especially in this age group where playing sports, for example, is 
socially important. The ability to “keep up with their peers,” enjoy freedom from 
arrhythmia, stay in school and out of the hospital on no or minimal medication all play a role 
in elevating how well a patient after TOF repair feels about himself and appreciates the day. 
The current proposal, an R34, will yield needed information in the short term but is the first 
step in a much longer one. As noted above, mortality and other morbidities of TOF repair 
increase dramatically after the first 2 decades of life. We hypothesize that intervention as an 
adolescent may mitigate these complications by decreasing the chronic RVVO, “unloading 
the RV” at an earlier age and preventing irreversible remodeling and dysfunction. 
 
There are disadvantages of PVR as mentioned above and risks always need to be weighed 
against the potential benefit. The patient would need to undergo surgery or transcatheter 
PVR involving a short hospital stay. Valves can malfunction in the short term and will 
definitely need to be replaced long term. However, the potential for RV dysfunction and 
right sided heart failure in the long term looms large; replacing a pulmonary valve is much 
easier than replacing or managing a failing or failed RV with its attendant risk of 
ventricular tachycardia, need for transplantation, poor exercise tolerance and sudden death. 
 
The proposed trial also has the potential to decrease cost by preventing long-term 
sequelae. The cost of PVR can be offset by the prevention of heart transplantation, long-

 
  
 
  
 
7
term hospital stays, frequent clinic visits and potentially avoidable pharmacologic therapy. 
All these may involve the use of expensive tests and diagnostic procedures that may be 
decreased in frequency by the careful utilization of PVR at the optimal time. 
 
Although this application’s primary purpose is to obtain preliminary data for a 
large scale clinical trial to answer the question of the necessity and optimal timing of 
PVR, it will also involve a small pilot feasibility protocol which will obtain short term 
TOF PVR data in a prospective, rigorous fashion. With PVR becoming more prevalent88 
and easier to perform via catheter, there is a temptation to perform PVR more often; a well-
controlled prospective study, supported by this R34 planning proposal, is needed exigently 
to set boundaries for this temptation. 
 
Our hypothesis is that PVR benefits outweigh the surgical/transcatheter risks in a 
select group of TOF survivors and that an optimal timing for this procedure exists. As 
mentioned above, random events can lead to a patient undergoing PVR or not; instead of 
serendipity dictating the patient’s fate, this proposal will channel these patients into a 
structured framework to prospectively collect data to determine the benefits of PVR as well 
as optimal timing. Importantly, this R34 doesn’t pose additional clinical risk; it merely 
restructures routine clinical practice to obtain badly needed information on PVR to plan for 
a large multicenter trial. There is precedence for interventional trials in congenital heart 
disease (eg Single Ventricle Reconstruction Trial from the Pediatric Heart Network; 
http://www.pediatricheartnetwork.org/Studies/CompletedStudies/SingleVentricleStudySurgi
cal.aspx ). 
 
1.6 
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46 and the HIPAA Privacy Rule and the Good Clinical 
Practice: Consolidated Guideline approved by the International Conference on 
Harmonisation (ICH). Note: Only include the sections of Title 21 if the study is regulated by 
the FDA. Only include ICH compliance if the study will actually comply with these 
requirements.  All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements. Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study. 
 
2 
STUDY OBJECTIVES 
Specific Aim 1: To determine the operational feasibility of a randomized, multicenter trial 
of PVR in adolescent TOF survivors to assess its impact on outcome – a main goal of an 
R34 planning grant. Study teams from Children’s Hospital of Philadelphia, Cincinnati 
Children’s Hospital, Children’s Healthcare of Atlanta, Lurie Children’s and Children’s 

 
  
 
  
 
8
National Medical Center will recruit asymptomatic TOF patients to be randomized to PVR 
or “no-PVR” groups based on mostly on CMR RV volumes to prove operational feasibility. 
Hypothesis: A randomized, multicenter, clinical trial of PVR in TOF survivors is 
operationally feasible. 
Specific Aim 2: To measure clinical parameters needed to design a large scale clinical trial 
by performing a short term pilot protocol. At entry, in addition to CMR, all subjects will 
undergo exercise testing, Holter monitoring and complete QOL questionnaires which will be 
repeated 12-18 months later. Comparison between PVR and no-PVR groups will be made 
for clinical parameters including mortality, exercise testing, physical functioning QOL 
score, prevalence of arrhythmia and medical care utilization. Preliminary data for these 
parameters would be collected will inform outcome measures in the larger trial. A 
comparison of biventricular function between groups will also be made. Hypothesis: There 
are clinical metrics that can be utilized to inform the endpoints of a robust longer term, 
large scale trial of PVR in asymptomatic TOF survivors to discern who would benefit and 
optimize timing of the procedure. 
Specific Aim 3: To determine mechanisms of the effects of PVR in the definitive trial by 
obtaining preliminary data on diffuse fibrosis (DF), performing exercise CMR and 
measuring biventricular strain. Subjects will undergo repeat CMR 12-18 months after 
enrollment including measurement of DF, exercise CMR and strain measures to determine 
biventricular function and PR at rest and exercise, comparing PVR and no-PVR groups and 
correlating with short term outcomes. Hypothesis: PVR in asymptomatic TOF survivors 
who fall within specified guidelines results in improved ventricular function at exercise, 
improved strain and have less DF when compared to no-PVR and correlates with clinical 
outcomes. 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This is a prospective, multi-center, randomized pilot protocol to assess the operational 
feasibility and to obtain preliminary data to inform a future large scale randomized, 
multicenter trial of PVR in adolescent TOF survivors. The general schema breaks down this 
project into 3 parts as delineate in the Aims: 
• Operational feasibility 
• Pilot protocol to obtain preliminary data 
• Mechanistic effects of the findings 
Operational feasibility will involve assessing results of questionnaires, and surveys, ability 
to recruit the required number of patients in the time given, Protocol logs demonstrating how 
many patients were screened, eligible and approached, how many dropped out and for what 

 
  
 
  
 
9
reason among other metrics. Factors which will affect follow-up in a larger trial are also key 
such as patients moving out of the area, pregnancy and need for pacemaker will be recorded 
and will be used as preliminary data for dropout rates and sample size for the larger trial. 
The pilot protocol to obtain preliminary data will include exercise parameters on EST such 
as maximum oxygen consumption and work at ventilatory anaerobic threshold; Quality of 
life indexes, CMR parameters such as ventricular volumes, ejection fraction and mass; 
Holter parameters such as the amount of ectopy. Patients will be randomized to PVR via 
catheter or surgery, whichever is clinically appropriate, or no-PVR. 
Mechanistic effects will include measures of diffuse and discrete fibrosis, myocardial strain 
and performance parameters on exercise CMR. 
There will be on-going safety evaluations throughout. Clinical evaluations such as death, 
transplantation, need for hospitalization and medication, failure of PVR with need to replace 
or need, in the non-PVR group for PVR, requirement in general for additional interventions 
will be obtained. IRB review will be obtained every year. A data safety monitoring board 
will be established through the NIH. 
 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring. 
 
3.1.1 Screening Phase 
Subjects will be identified from patients who undergo CMR for their TOF and screened to 
determine if they meet eligibility criteria listed in the protocol inclusion and exclusion 
criteria. If so, they will be approached for informed consent and subject assent. 
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study related procedures being performed, including discontinuation 
of current therapy. 
All cardiologists who treat patients with TOF will be eligible to participate; there is no 
screening process. They will be approached for informed consent- this will be obtained prior 
to any study related procedures being performed – questionnaires.  
3.1.2 Study Treatment Phase (start of the study intervention) 
After patients meet eligibility criteria and agree to participate, after informed consent, the 
patients will be randomized to PVR and no-PVR groups. Both patient groups will undergo 
research related procedures (eg quality of life questionnaires, review of medical records) at 
that time. The patients in the PVR group will then undergo PVR. Both patients groups will 
be followed per standard of care clinical protocols. 
Physicians will be given questionnaires to fill out regarding their views of the study. 

 
  
 
  
 
10
3.1.3 Phase 2 
After 1-1.5 years, both patient groups will undergo research related procedures (eg quality of 
life questionnaires, review of medical records). This will generally occur when they are seen 
for their clinical visits per standard of care protocols. 
After one year and every year after until study termination, physicians will be given 
questionnaires to fill out regarding their views of the study and to determine if it has 
changed at all. 
3.1.4 Follow-up Phase 
Not applicable 
 
3.2 Allocation to Treatment Groups and Blinding 
Patients will be randomized by computer by the statistician and her team at the Data 
Coordinating Center at Northwestern Univeristy who will maintain the schedule; this will be 
a 2:1 randomization of PVR to no-PVR. There will be no blinding and the assignment will 
not be concealed from the investigators. There will be no stratifications within each group. 
3.3 
Study Duration, Enrollment and Number of Sites 
This is a multicenter 3 year project with recruitment to commence when the study team is 
assembled and the IRB approved. We will enroll 100 patients with TOF (over the 1.5-2 year 
enrollment period to achieve 1-1.5 year follow-up) from the 5 centers. See statistics section 
for calculations. 
The Study Team and Structure: The study team from The Children’s Hospital of 
Philadelphia (CHOP), Cincinnati Children’s Hospital (Cinn), Emory University School of 
Medicine/Children’s Healthcare of Atlanta (Emory), Lurie Childrens (Lurie) and Children’s 
National Medical Center (DC) and Northwestern University will participate in this R34. 
CHOP, Cinn and Emory have worked successfully together in the past on other projects 
including a recent RO1 (HL098252-01). CHOP and DC recently began a collaboration using 
3D rapid prototyping models, holding their first symposium in February 2014. This group of 
5 centers brings together well published experts in CMR (Drs Fogel, Lang, Slesnick, Rigsby 
and Cross), exercise (Dr. Paridon), QOL (Dr. Marino), catheterization (Dr. Kim) and 
surgery (Drs Gaynor and Fuller). Experienced “trialists” such as Drs Paridon and Marino 
will be complemented by the experience of Dr. Fogel in industry where he ran large scale 
clinical drug trials for 3 years at Wyeth-Ayerst as well as Dr. Scholtens, biostatistics faculty 
at Northwestern University, who has >10 years of experience in collaborative biostatistics 
and currently serves as the primary statistician for a large-scale international multicenter 
epidemiologic study. All are involved in clinical care and have been involved in clinical 
studies. 
 
Although five participating centers may seem a large number for a feasibility pilot, 
there are 2 major justifications for its use. First, because this is a 3 year award, there is 
limited time for follow-up mandating rapid enrollment, which is more feasible from multiple 
centers. Second, we intend to demonstrate and fine-tune the multicenter aspects of the trial 

 
  
 
  
 
11
in preparation for a full study. This includes solidifying functions of a data collection center, 
imaging core and safety monitoring. 
 
CHOP will be the principle site as well as the CMR Core Laboratory and 
Northwestern University (NU) will provide the data management and biostatistical support . 
Dr. Fogel (CHOP) and Dr. Marino (NU) have been the CMR Core Laboratory and data 
management and biostatistical support respectively for numerous other studies. A strict 
firewall will be in place at both CHOP and NU to ensure that Drs. Fogel and Marino do not 
participate in and will be blinded to any site data. Teleconferences monthly will be held 
between centers to discuss issues and make decisions regarding the conduct of the feasibility 
protocol. Analysis of CMR data will be performed at each site and in the department of 
Radiology at CHOP. EST, QOL, echocardiograms and Holter monitoring will be performed 
at each site. Figures 4A (CMR data) and 4B (data other than CMR) depict the workflow and 
communications link. 
 
 
3.3.1 Duration of Study Participation 
• Each subject’s participation will last ~ 1-1.5 years from enrollment to follow-up 
• Exercise CMR component to the CMR scans will last~ 15 minutes EST will be 
performed for research purposes if not performed for clinical purposes. Metabolic 
exercise test (if not clinically indicated and therefore, research related) will last ~ 60 
minutes. 
• Assessment of QOL will last ~ 20 minutes 
• Fill out patient questionnaire about this trial will last ~10-15 minutes 
• For physicians answering physician questionnaire, this will last ~20 minutes 
 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at approximately 5 investigative sites in the United States. The 
study team from The Children’s Hospital of Philadelphia (CHOP), Cincinnati Children’s 
Figure 4A: Work flow for CMR data 
Figure 4B: Work flow for data other than 
CMR 

 
  
 
  
 
12
Hospital (Cinn), Emory University School of Medicine/Children’s Healthcare of Atlanta 
(Emory), Lurie Children’s (Lurie) and Children’s National Medical Center (DC) will 
participate in this R34. Recruitment will stop when approximately 100 subjects are enrolled. 
It is expected that approximately 100 subjects will be enrolled to produce 90 evaluable 
subjects. See statistical section for addition information. For physicians agreeing to answer 
questionnaires, we estimate this will be ~200 subjects will be enrolled. 
3.4 
Study Population 
3.4.1 Inclusion Criteria 
For patients with TOF 
1. Males or females with repaired TOF, currently between 13 and 21 years of age. 
2. On clinical CMR: RVEDVi between 140 and 180 cc/m2 inclusive with RVEF > 40% and 
LVEF > 50%. If data available and adequate RV outflow tract peak velocity < 3 
meters/second (if not available this can be skipped); there will be no indexed RVESVi 
criteria; by defining RVEDVi and RVEF, we will be inherently defining RVESVi, at least 
10% pulmonary regurgitation fraction.  
3. On clinical echocardiogram: If data available and adequate, RV outflow tract peak velocity 
< 3 meters/second (if not available this can be skipped), at least mild pulmonary 
insufficiency and tricuspid regurgitation with an RV pressure estimate < 1/2 systemic 
pressure. 
4. On EST, aerobic capacity > 60% of predicted. 
5. No QRS duration criteria on ECG. 
For physicians: Any cardiologist who practices at any of the 5 participating sites. 
3.4.2 Exclusion Criteria 
For patients with TOF 
1. Any condition judged by the patient’s physician that would cause this trial to be detrimental 
to the patient. 
2. Specific forms of TOF excluded are those with endocardial cushion defects, TOF with 
absent pulmonary valve and TOF with multiple aorto-pulmonary collaterals requiring 
unifocalization. 
3. Unilateral branch pulmonary artery stenosis (one lung receives < 25% of total flow) 
4. Contraindication to non-sedated exercise CMR (e.g. pacemaker/implanted cardioverter 
defibrillator); need for sedation 
5. If data available, moderate or greater tricuspid regurgitation on echocardiogram or CMR 
or Qp/Qs > 1.5 (if not available this can be skipped) 
6. Significant strokes/hemiplegia or inability to exercise 
7. Genetic syndrome/developmental delay which would make QOL and EST date 
uninterpretable 
8. Pregnancy.  
9. Previous pulmonary valve replacement (PVR). 
For physicians: none. 
 

 
  
 
  
 
13
4 
STUDY PROCEDURES 
As a primary purpose of an R34 is to be able to plan for a future study, assessing the 
operational feasibility of a randomized, multicenter trial of PVR in pediatric TOF to assess 
its impact on outcome falls under study procedures. The investigators at each center have 
recruited physicians who are willing to enroll their patients with TOF after repair into this 
proposal.  
Acceptance of a randomized PVR trial, screening and eligibility: Physicians within each 
institutions, whether they are participating or not in this pilot study, will be asked to complete 
a brief survey each year to assess satisfaction with the pilot protocol along with physician 
assessment of patient reaction to the study. This data will be analyzed to determine if and how 
the approach to recruitment should change. These surveys will include, on a scale of 1-10, 
questions such as how comfortable both the physician and the patient are to undergoing 
randomization to PVR, was the need for such a trial adequately explained and free text as to 
why the patient or physician did or did not want to participate. Pilot protocol logs will 
demonstrate how many patients were screened, eligible and approached, how many dropped 
out and for what reason among other metrics; all this data is critical to designing a future 
definitive study.  
 
Any patient approached for the pilot study will be surveyed to determine their reaction to 
it within the limitations of HIPAA and whether or not they sign an informed consent; there is 
precedent for this process in other studies.90 Crucially, patients’ rationale for enrolling or not 
enrolling will be recorded as part of standard practice for study coordinators. This data will 
be analyzed on an annual basis to determine if and how the approach to recruitment should 
change. Finally, factors which will affect follow-up in a larger trial such as patients moving 
out of the area, pregnancy and need for pacemaker will be recorded and will be used as 
preliminary data for dropout rates and sample size for the larger trial. Again, all critical 
information to designing a definitive study. 
Figure 5 depicts the overall 
schema of study procedures for the 
pilot protocol. Patients will be screened 
as they are referred for CMR, EST and 
Holter monitoring from their 
cardiologists or other healthcare 
provider on a clinical basis. If they 
meet the inclusion criteria and do not 
meet exclusion criteria, after informed 
written consent, patients will be 
randomized to either PVR or no-PVR 
groups; these patients are ones being 
followed by physicians who have 
agreed to the protocol and have 
equipoise in the PVR vs no-PVR 
decision. Indeed, multimodality 
imaging guidelines recently published 
have recommended yearly CMRs in those 
patients with moderate RV volume overload.91 The risks of surgery as well as transcather 
Figure 5: Overall Approach to the pilot protocol. 

 
  
 
  
 
14
PVR and the natural history of TOF will be discussed with the patients prior to enrollment. 
The PVR group will be subdivided into those undergoing transcatheter PVR and those 
undergoing surgery. If randomized to an intervention, the intervention will occur within 6 
months. One to 1.5 years after intervention, clinical history, echocardiogram (if clinically 
indicated only), CMR, EST and Holter monitor will be repeated as standard of care and 
QOL questionnaires administered. This data will form the basis for comparison of the 
effects of PVR clinically and subgroup analysis will be performed between surgical and 
transcatheter intervention groups to inform the future large scale trial. 
 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring 
are clinical care procedures. Note that the exercise CMR will include CMR sequences that 
are not FDA approved but have been developed by Siemens Medical Solutions and are 
“Works In Progress” packages. 
 
4.1 
Screening Visit 
TOF patients will be recruited from the cohort of patients followed at The Children's 
Hospital of Philadelphia (CHOP), Cincinnati Children’s Hospital (Cinn), Emory University 
School of Medicine/Children’s Healthcare of Atlanta (Emory), Lurie Children’s (Lurie) and 
Children’s National Medical Center (DC) Patients will be approached to participate in the 
study during clinic visits or visits to the hospital for other reasons. In addition, patients may 
be reached by phone, video (eg Skype) for recruitment. The principal investigator, any of the 
co-investigators and/or study coordinator will approach the family for consent either by 
phone, video or in-person. A full understanding of all study related procedures and processes 
will be explained to the patient, including exercise CMR scans, cardiopulmonary exercise 
testing (if not performed for clinical reasons) and how the proposed research will help 
medical practice, although all these tests will be clinically indicated and be performed only 
on a clinical basis. Child assent will be obtained in the presence of the parents if < 18 years 
of age. All will be documented by signing the informed consent form which may be done 
via mail or in-person. The child and his/her parents/guardians will be given a consent form 
to read and keep, outlining the important details of the study. The consent form will be 
signed by the parents/guardians (or patient if over 18 years old) prior to enrollment in the 
study. One of the study physicians will be available to answer all questions concerning the 
study.  The consent process for parents or legal guardians, adult subjects and children who 
require assent who do not speak English will be facilitated by an interpreter from Language 
Services at the Children’s Hospital of Philadelphia.  Each participating site is responsible for 
adhering to their local governing regulatory bodies, i.e. IRB with regard to administering 
consent to non-English speaking families.  
Please note that CMR parameters are utilized in the inclusion criteria. If the patient meets 
these criteria, they will then be approached to participate and enrolled and hence, the review 

 
  
 
  
 
15
of the medical records associated with those clinically indicated tests will be considered part 
of the Screening Visit. 
 
Also note that the screening activities themselves are limited to review of 
medical/investigator records and do not include soliciting information directly from 
potential subjects; only when subjects meet inclusion criteria and do not meet exclusion 
criteria will the patient be approached. 
 
4.2 
Study Treatment Phase  
4.2.1 Visit 1 
Patients will be randomized to PVR or no-PVR; PVR group will undergo valve replacement 
by catheter or surgery, whichever is clinically indicated. 
 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring 
are clinical care procedures. 
 
 
Extraction of the following parameters. This data includes: 
 
Name 
MR number 
Date of Birth 
 
Demographics/Medical History: 
Age at MRI 
Height 
Weight 
Gender 
Ethnicity, birth order, social class, etc 
Body surface area 

 
  
 
  
 
16
Type of tetralogy (tetralogy, tetralogy with pulmonary atresia, tetralogy with absent 
pulmonary valve leaflets, tetralogy with conoseptal hypoplasia), coronary anomaly 
Type of repair (transannular patch, no transannular patch, conduit) 
Number of other cardiovascular or cardiovascular related surgeries, date, type 
Pulmonary artery angioplasty (yes, no, and if yes – which PA) (stent: PA/conduit, RPA, 
LPA) 
Residual VSD (yes,no)  (small vs mod/large) 
Residual pulmonary stenosis (yes, no) 
Date and age of definitive repair 
Cardiopulmonary bypass time, circulatory arrest time, cross clamp times 
Complications, hospital length of stay, hospitalizations with causes and results, 
Date of MRI(s) 
Years between repair and MRI 
Years between MRI and followup (outcomes) 
Years between MRIs 
Other medical diagnoses (eg 22Q11 deletion status) 
 
Physical exam and Vital Signs 
Any abnormal physical exam finding other than routine findings for a patient with TOF 
Temperature 
Blood pressure 
Heart rate 
Respiratory Rate 
Oxygen saturation 
 
CMRs: 

 
  
 
  
 
17
BOTH right ventricle and left ventricle from cine imaging: 
End diastolic volume (indexed) 
End systolic volume (indexed) 
Stroke volume (indexed) 
Ejection fraction 
Cardiac index 
RV/LV ratio of End diastolic volume and end systolic volume 
RV mass/volume ratio 
LV mass/volume ratio 
 
Velocity maps: 
Cardiac index (aortic) 
Aortic regurgitation fraction 
Pulmonary regurgitation fraction 
Pulmonary regurgitant volume (indexed) 
Net flow to right pulmonary artery 
Net flow to left pulmonary artery 
LPA/RPA ratio (% flow to each PA) 
Regurgitant fraction of RPA  
Regurgitant fraction of LPA 
LPA/RPA ratio regurgitant fraction 
 
Right pulmonary artery stenosis if moderate or severe (yes, no) 
Left pulmonary artery stenosis if moderate or severe (yes, no) 
 

 
  
 
  
 
18
T1 Mapping: Native T1, post-gadolinium T1, the partition coefficient and, if a 
hematocrit is available, the extracellular volume (ECV) will be calculated. 
 
Exercise performance qualitative (intolerance, poor or good?) 
Exercise performance data 
aVO2 (indexed (ml/kg/min), unindexed (ml/min), and percent predicted at peak 
exercise and AT 
Oxygen pulse 
VE/VCO2 slope 
Pulmonary function parameters: forced expiratory volume in 1 second (FEV1), 
Functional vital capacity (FVC) 
Peak physical work capacity 
Hospitalizations 
Diagnostic/interventional caths 
Other procedures 
Medication (yes, no and if so, free text what meds) 
Arrhythmia on holter monitoring (yes, no and if so, what) 
 
Echocardiographic data 
Diagnoses 
Amount and degree of tricuspid insufficiency 
RV pressure estimate 
Pulmonary stenosis and/or regurgitation estimate 
Biventricular function parameters (eg left ventricular shortening fraction, qualitative 
estimate of RV shortening, myocardial velocities) 
 
Catheterization data 

 
  
 
  
 
19
Diagnoses and interventions (if any) 
Amount and degree of tricuspid insufficiency 
Saturations in various chambers and vessels (eg RV, LV, right atrium) 
Pressures in various chambers and vessels (eg RV, LV, right atrium) 
Flow measurements (eg cardiac index, Qp/Qs) 
 
Research CMR evaluations 
Exercise CMR Protocol: Supine exercise using an MRI 
compatible ergometer (Figure 6) will occur for 3-5 minutes 
immediately outside the bore to achieve 80% of the 
maximum heart rate on metabolic EST; CMR imaging will 
then take place within 10 seconds. The patient will do this 
multiple times  for a total time in the scanner of 
approximately 15 minutes to obtain: a) “Real-time” ECG 
gated cine SSFP across the short axis of the both 
ventricles from atrioventricular valve to apex to obtain 
ventricular volumes and cardiac index and b) “real time” 
and segmented PCMR in the MPA and branch pulmonary 
arteries and aorta.  
Biventricular strain: Cine short axis and 4-
chamber images, which were obtained 
clinically, will undergo tissue tracking (post-
processing on computer, after the study) to 
analyze biventricular circumferential, radial 
(cine short axis) and longitudinal strain (4-
chamber view). The global and regional 
strain (16 segment model) will be calculated 
and analyzed (figure 7). 
 
Cardiopulmonary EST Protocol (if not clinically indicated and therefore, research 
related) 
Cardiopulmonary EST Protocol: This will be performed using a standard ramp cycle 
ergometry protocol with collection of expired gases. Subjects will pedal in an unloaded state 
for 3 minutes and workload will then be increased continuously with a slope chosen to 
achieve each subject's predicted maximal work rate in watts after 10 to 12 minutes of 
cycling. Expired gases will be measured by a mass spectrometer which is FDA approved for 
clinical use for 3 minutes of quiet rest before unloaded pedaling and throughout the exercise 
protocol. VO2, carbon dioxide production (VCO2), and minute ventilation (VE) will be 
measured on a breath-by-breath basis. Maximal VO2 will be defined as the highest VO2 
achieved by the subject during the EST. VAT will be measured by V-slope method and 
confirmed by the dual criteria measurements of the ventilatory equivalents of CO2 and O2 
Figure 6: MRI compatible ergometer. Patient 
exercises outside the bore and then moved into 
scanner for measurements in < 10 seconds.
Figure 7: Longitudinal feature tracking strain of the RV at 
end-diastole (left heart) and end-systole (right heart). Color 
code for strain map is on the left. 

 
  
 
  
 
20
(VE/ VCO2 and VE/ VO2). Values for VO2 will be indexed to body weight and expressed 
as percentage of predicted values for healthy age- and gender-matched subjects as reported 
by Cooper and Weiler-Ravell using a similar protocol. The ventilatory equivalents of carbon 
dioxide (VE/VCO2) will be measured at VAT. The respiratory exchange ratio RER 
(VCO2/VO2) will be measured continuously. Achievement of a maximal aerobic capacity 
will be defined as a peak RER of ≥ 1.10. 
Please note that the device used to measure expired gas is approved for use at CHOP. This is 
the same device that is utilized for a standard of care exercise test. The device that is used is 
a metabolic cart which is a clinically validated and FDA approved piece of equipment that is 
used in clinical care every day. 
Patient/Family Questionnaires: These will be administered to all patients and families who 
agree to answer questions about this investigation (whether they are participating in 
randomization or not) at the beginning of their participation and if they decide to participate 
in trial and be randomized, at the end of their participation. It will take ~ 20 minutes. The 
questionnaires may be mailed to patients or completed in person at a study visit. 
Physician Questionnaires: These will be administered to all physicians who agree to 
answer questions about this investigation (whether they are participating in allowing their 
patients to undergo randomization or not) once per year. It will take < 20 minutes. This will 
be the initial questionnaire. 
Assessment of QOL: Utilization of the PCQLI will allow for patient and parent-proxy 
assessment of QOL using a disease specific tool, allowing for better discrimination between 
subgroups. The PedsQL Core 4.0 will allow for comparison with healthy and other chronic 
disease populations. The QOL questionnaires will take ~ 20 minutes for patients to finish. The 
questionnaires may be mailed to patients or completed in person at a study visit. Patients and 
parents will be instructed to ensure the inventories are completed independently to minimize 
contamination resulting from patient-parent discussion. Patients and guardians will be 
recruited consecutively. 
 
Randomization: See Statistics Section below. 
 
Interventions (Surgical and Transcatheter PVR): Both surgical and transcatheter PVR 
will be performed per each institutions clinical protocol as standard of care. Both surgeon 
and interventional cardiologist will use their best clinical judgment to optimize patient 
outcome; this approach will make the findings of this proposal widely applicable. PVR, 
whether surgery or catheter based, requires general anesthesia, insertion of catheters and 
insertion of a valve in the pulmonary position. Surgery requires a median sternotomy and 
sealing up the wound with sternal wires and stitches along with cardiopulmonary bypass and 
circulatory arrest. Catheter based intervention includes inserting a catheter in the groin 
region generally and then direct pressure on the insertion site after the procedure is 
completed. Please see Risks section below. 
 

 
  
 
  
 
21
4.3 Phase 2 of the Study – Followup – Visit 2 
Between 1 – 1.5 years after enrollment, a follow-up visit will occur with the exact same 
study procedures as in Study visit above in 4.2.1; this will occur around the time of their 
clinical visit for their followup CMR and exercise testing. Additional data to be abstracted 
include:  
For all groups: 
Death 
Transplant 
Pacemaker (unlikely) 
NY heart association class (if available) 
Additional procedures 
Additional diagnosis 
Need for medication 
Hospitalizations with cause and followup 
Any additional complications to being in the individual group such as, in the no-PVR 
group, need for pulmonary valve replacement (surgery vs catheter) or in the PVR 
group, need for replacement or malfunctioning of the inserted pulmonary valve. 
Physician Questionnaires: These will be administered to all physicians who agree to 
answer questions about this investigation (whether they are participating in allowing their 
patients to undergo randomization or not) once per year. It will take < 20 minutes. This will 
be the 2nd questionnaire to be filled out. 
4.4 Visit 3 (only applicable to Physician component of this study) 
Physician Questionnaires: These will be administered to all physicians who agree to 
answer questions about this investigation (whether they are participating in allowing their 
patients to undergo randomization or not) once per year. It will take < 20 minutes. This will 
be the 3rd questionnaire to be filled out. 
4.5 Follow-up Phase 
Not applicable 
4.6 Unscheduled Visits 
All unscheduled visits will be handled as per clinical standard of care as each group is 
clinically indicated, given the equipoise in the decision.  

 
  
 
  
 
22
4.7 Concomitant Medication 
All prior and concomitant medications used within 60 days prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and 
reason for use will be included. 
4.8 Rescue Medication Administration 
Not applicable 
4.9 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, or AEs.  The Investigator or the Sponsor 
may also withdraw subjects who violate the study plan, or to protect the subject for reasons 
of safety or for administrative reasons.  It will be documented whether each subject 
completes the clinical study. If the Investigator becomes aware of any serious, related 
adverse events after the subject completes or withdraws from the study, they will be 
recorded in the source documents and on the CRF. 
4.9.1 Early Termination Study Visit 
SUBJECTS WHO WITHDRAW FROM THE STUDY WILL HAVE MEDICAL 
RECORD REVIEW AS A PROCEDURE AS THE EARLY TERMINATION 
VISIT. 

 
  
 
  
 
23
STUDY EVALUATIONS AND MEASUREMENTS 
Randomization to PVR and no-PVR groups will be performed as a research procedure. 
4.10 Screening and Monitoring Evaluations and Measurements 
4.10.1 Medical Record Review 
See 4.2.1 as well. We will extract the following for review: 
Demographics/Medical History: 
Age at MRI 
Height 
Weight 
Gender 
Ethnicity, birth order, social class, etc 
Body surface area 
Type of tetralogy (tetralogy, tetralogy with pulmonary atresia, tetralogy with absent 
pulmonary valve leaflets, tetralogy with conoseptal hypoplasia), coronary anomaly 
Type of repair (transannular patch, no transannular patch, conduit) 
Number of other cardiovascular or cardiovascular related surgeries, date, type 
Pulmonary artery angioplasty (yes, no, and if yes – which PA) (stent: PA/conduit, RPA, 
LPA) 
Residual VSD (yes,no)  (small vs mod/large) 
Residual pulmonary stenosis (yes, no) 
Date and age of definitive repair 
Cardiopulmonary bypass time, circulatory arrest time, cross clamp times 
Complications, hospital length of stay, hospitalizations with causes and results, 
Date of MRI(s) 
Years between repair and MRI 
Years between MRI and followup (outcomes) 
Years between MRIs 

 
  
 
  
 
24
Other medical diagnoses (eg 22Q11 deletion status) 
 
Physical exam and Vital Signs 
Any abnormal physical exam finding other than routine findings for a patient with TOF 
Temperature 
Blood pressure 
Heart rate 
Respiratory Rate 
Oxygen saturation 
 
CMRs: 
BOTH right ventricle and left ventricle from cine imaging: 
End diastolic volume (indexed) 
End systolic volume (indexed) 
Stroke volume (indexed) 
Ejection fraction 
Cardiac index 
RV/LV ratio of End diastolic volume and end systolic volume 
RV mass/volume ratio 
LV mass/volume ratio 
 
Velocity maps: 
Cardiac index (aortic) 
Aortic regurgitation fraction 
Pulmonary regurgitation fraction 

 
  
 
  
 
25
Pulmonary regurgitant volume (indexed) 
Net flow to right pulmonary artery 
Net flow to left pulmonary artery 
LPA/RPA ratio (% flow to each PA) 
Regurgitant fraction of RPA  
Regurgitant fraction of LPA 
LPA/RPA ratio regurgitant fraction 
 
Right pulmonary artery stenosis if moderate or severe (yes, no) 
Left pulmonary artery stenosis if moderate or severe (yes, no) 
 
T1 Mapping: Native T1, post-gadolinium T1, the partition coefficient and, if a 
hematocrit is available, the extracellular volume (ECV) will be calculated. 
 
Exercise performance qualitative (intolerance, poor or good?) 
Exercise performance data 
aVO2 (indexed (ml/kg/min), unindexed (ml/min), and percent predicted at peak 
exercise and AT 
Oxygen pulse 
VE/VCO2 slope 
Pulmonary function parameters: forced expiratory volume in 1 second (FEV1), 
Functional vital capacity (FVC) 
Peak physical work capacity 
Hospitalizations 
Diagnostic/interventional caths 
Other procedures 

 
  
 
  
 
26
Medication (yes, no and if so, free text what meds) 
Arrhythmia on holter monitoring (yes, no and if so, what) 
 
Echocardiographic data 
Diagnoses 
Amount and degree of tricuspid insufficiency 
RV pressure estimate 
Pulmonary stenosis and/or regurgitation estimate 
Biventricular function parameters (eg left ventricular shortening fraction, qualitative 
estimate of RV shortening, myocardial velocities) 
 
Catheterization data 
Diagnoses and interventions (if any) 
Amount and degree of tricuspid insufficiency 
Saturations in various chambers and vessels (eg RV, LV, right atrium) 
Pressures in various chambers and vessels (eg RV, LV, right atrium) 
• 
Flow measurements (eg cardiac index, Qp/Qs) 
• 
 
For all groups in Followup: 
Death 
Transplant 
Pacemaker (unlikely) 
NY heart association class (if available) 
Additional procedures 
Additional diagnosis 
Need for medication 

 
  
 
  
 
27
Hospitalizations with cause and followup 
Any additional complications to being in the individual group such as, in the no-PVR 
group, need for pulmonary valve replacement (surgery vs catheter) or in the PVR group, 
need for replacement or malfunctioning of the inserted pulmonary valve. 
 
4.10.2 Physical Examination 
Physical examination records associated with visit related to the CMR will be utilized in the 
review of medical records. See above 
4.10.3 Vital Signs 
Vital sign records associated with visit related to the CMR will be utilized in the review of 
medical records. Heart rate would have been captured by either automated device, by pulse 
or by stethoscope. Respiratory rate would have been measured by stethoscope or visual 
inspection. Temperature would have been measured by thermometer. Blood pressure would 
have been measured with an automated device or with an aneroid sphygmoma. See above 
4.10.4 Exercise CMR (figure 6) 
Data abstracted include: “Real-time” ECG gated cine SSFP across the short axis of the both 
ventricles from atrioventricular valve to apex to obtain ventricular volumes and cardiac index 
and b) “real time” and segmented PCMR in the MPA and branch pulmonary arteries and aorta.  
 
4.10.5 Biventricular strain (figure 7): 
Data abstracted include: biventricular circumferential, radial (cine short axis) and 
longitudinal strain (4-chamber view). Time to peak strain will also be included. The global 
and regional strain (16 segment model) will be calculated and analyzed (figure 7). 
4.10.6 Metabolic Exercise Testing (if not clinically indicated and therefore, research 
related): 
Exercise performance qualitative (intolerance, poor or good?) 
Exercise performance data 
aVO2 (indexed (ml/kg/min), unindexed (ml/min), and percent predicted at peak 
exercise and AT 
Oxygen pulse 
VE/VCO2 slope 
Pulmonary function parameters: forced expiratory volume in 1 second (FEV1), 
Functional vital capacity (FVC) 
Peak physical work capacity 

 
  
 
  
 
28
4.10.7 Assessment of QOL  
Assessment of QOL: Utilization of the PCQLI will allow for patient and parent-proxy 
assessment of QOL using a disease specific tool, allowing for better discrimination between 
subgroups. The PedsQL Core 4.0 will allow for comparison with healthy and other chronic 
disease populations. The QOL questionnaires will take ~20 minutes for patients to finish. 
The questionnaires may be mailed to patients or completed in person at a study visit. 
Patients and parents will be instructed to ensure the inventories are completed independently 
to minimize contamination resulting from patient-parent discussion. Patients and guardians 
will be recruited consecutively. 
4.10.8 Patient Questionnaries: 
Answers to questions in free text: 
How old are you (your child)? 
Did you (your child) have: no PVR? Surgery for PVR? Catheterization for PVR? 
Why did you (your child) decide to participate in this trial? 
Before participating in this trial, what had your physician told you or what have 
you read about PVR in TOF? 
What one aspect convinced you to participate in this trial? 
What are the positive aspects of this trial from your standpoint? 
What are the negative aspects of this trial from your standpoint? 
What would you change about this trial and how to improve it for a future trial? 
Is there anything else you’d like to tell us about this trial? 
 
4.10.9 Physician Questionnaires: 
Answers to questions as free text: 
A. For those not participating in the trial 
How many TOF patients do you see on a monthly basis? 
Approximately what are their age ranged? 0-13 years old 13-21 >22 

 
  
 
  
 
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Do you think TOF patients at some point should undergo PVR and if so, what 
criteria do you use, if any, for PVR? 
If you do feel PVR is indicated, does age play a factor and if so, please elaborate 
on your criteria 
With the advent of transcather PVR, how much more likely are you to have your 
patients undergo PVR? 
Why did you decide not to participate and have your patients not participate in 
this trial? Is there anything that would change your mind to participate in trial 
such as this? 
B. For those participating in the trial: 
How many TOF patients do you see on a monthly basis? 
Approximately what are their age ranged? 0-13 years old 13-21 >22 
Why did you decide to participate in this trial? 
Before participating in this trial, what criteria do you use for PVR? 
While participating in this trial, has your criteria changed and if so, how? 
Does age play a factor in PVR and if so, please elaborate on your criteria? 
With the advent of transcather PVR, how much more likely are you to have your 
patients undergo PVR? 
What are the positive aspects of this trial from your standpoint? 
What are the negative aspects of this trial from your standpoint? 
What would you change about this trial and how to improve it for a future trial? 
What was the reaction of your patients when you first brought up this trial of PVR 
in TOF? 
Can you please list some of the positive things the patients said regarding this trial 
Can you please list some of the negative things the patients said regarding this 
trial? 

 
  
 
  
 
30
What did the patients say, if anything, they would change about this trial and 
improve it for a future trial? 
Is there anything else you’d like to tell us about this trial? 
To be delineate clearly, research procedures are limited to randomization to undergo or not 
undergo PVR, exercise stress testing if this procedure is not completed clinically, exercise 
CMR, post-processing of biventricular strain, administration of questionnaires, medical 
history interviews, and review of medical records; clinical care procedures are (non-
exercise) CMR, echocardiograms, physical exams, pregnancy tests, and Holter monitoring 
are clinical care procedures. 
 
4.10.10Interventions (Surgical and Transcatheter PVR)  
Both surgical and transcatheter PVR will be performed per each institutions clinical protocol 
as standard of care. Both surgeon and interventional cardiologist will use their best clinical 
judgment to optimize patient outcome; this approach will make the findings of this proposal 
widely applicable. PVR, whether surgery or catheter based, requires general anesthesia, 
insertion of catheters and insertion of a valve in the pulmonary position. Surgery requires a 
median sternotomy and sealing up the wound with sternal wires and stitches along with 
cardiopulmonary bypass and circulatory arrest. Catheter based intervention includes 
inserting a catheter in the groin region generally and then direct pressure on the insertion site 
after the procedure is completed. Please see Risks section below. 
4.11 Efficacy Evaluations 
Please see Statistics section for analysis 
Aim 1: Results of questionnaires, and surveys, ability to recruit the required number of 
patients in the time given, Protocol logs demonstrating how many patients were screened, 
eligible and approached, how many dropped out and for what reason among other metrics. 
Factors which will affect follow-up in a larger trial are also key such as patients moving out 
of the area, pregnancy and need for pacemaker will be recorded and will be used as 
preliminary data for dropout rates and sample size for the larger trial. 
Aim 2: Principle parameters to be tested for the intended primary endpoints: The 
difference between values at enrollment and 1-1.5 years after randomization between those 
TOF patients with and without PVR for a) Exercise performance parameters such as oxygen 
consumption (VO2) at ventilatory anaerobic threshold (VAT)41 normalized for age, weight, 
and sex as well as VAT, peak workload and % predicted peak workload47 as well an New 
York Heart Association Class and b) Disease Specific QOL - Pediatric Cardiac Quality of 
Life Inventory (PCQLI) Patient and Parent Scores. Although some retrospective studies in 
symptomatic adults have failed to demonstrate improvement and PVR in VO2, Eysken et al. 
found improvement in VO2 and VAT in children 8-18 years of age;41 Warner et al. found an 
increase in peak workload and % predicted peak workload.47 Length of follow-up for 
patients is limited by the duration and funding of this award but will provide critical 
information as pilot data for a future trial. 

 
  
 
  
 
31
 
Other parameters to be tested for the intended primary or secondary endpoints: 
The difference between PVR and non-PVR patients at enrollment and 12-18 months later 
with: a) Other measures of EST performance such as forced vital capacity, forced expiratory 
volume at 1 second (FEV1), maximum voluntary ventilation, maximal work rate, maximal 
respiratory exchange ratio, breathing reserve, and maximum heart rate, b) Disease Specific 
PCQLI: Disease Impact and Psychosocial Impact subscale scores as well as Generic QOL 
Measure - Pediatric Quality of Life Inventory (PedsQL) Version 4.0 Generic Core (total and 
both Physical and Psychosocial Health Summary scores) and c) change in QRS duration or 
arrhythmia on Holter monitor (eg ectopy burden). 
 
Other key parameters to be taken under consideration will be the difference between 
those with and without PVR for: a) Death, hospitalization, need for medication, b) 
additional surgical or catheter based procedures, c) in the PVR group, failure of the valve 
and need for re-intervention and d) in those patients without PVR, need for valve placement 
or other interventions. In addition, the difference between those patients with surgical and 
transcatheter PVR for the intended endpoints mentioned will be analyzed. 
 
Other metrics to be obtained will include biventricular performance parameters (eg 
ventricular volumes and mass, ejection fraction) and hemodynamics such as pulmonary 
regurgitant fraction and cardiac index. 
Aim 3: Primary parameters to be tested for the definitive clinical trial: The difference 
between PVR and no-PVR for a) exercise RVEDVi, RVESVi, RV EF and RV output, b) 
measures of global DF and c) measures of myocardial strain. 
Other parameters to be tested for the definitive clinical trial include the difference 
between those with and without PVR for: a) Global measures of LV performance such as 
CI, LV EF, indexed LV EDV and LV ESV at exercise, b) Measures of pulmonary blood 
flow (eg PR fraction and antegrade diastolic flow) at exercise, c) Regional DF using the 16 
segment AHA model and d) longitudinal and regional LV and RV strain. In addition, 
correlation of exercise ventricular function, strain, physiologic parameters and DF with 
clinical outcomes (Aim 2) will take place. 
 
4.12 Pharmacokinetic Evaluation 
Not applicable 
4.13 Safety Evaluation 
All study procedures will be monitored for safety. The principle investigator or his designee, 
study coordinators and other health care professionals will record any issues, problems or 
concerns along with adverse events that may be associated with this project. Subject safety 
will be monitored by adverse events, vital signs, physical examinations, and discussions 
with the patient during surveys and at clinical visits.  
Adverse events will be recorded and appropriately assigned to either the PVR or no-PVR 
group. Record of death, hospitalization, requirement for medication or increase in 
medication, need for additional interventions, patients in the no-PVR group requiring PVR, 
patients in the PVR group requiring revision or replacement of the valve will be noted and 
evaluated statistically.  

 
  
 
  
 
32
This project will undergo review by an NIH mandated data safety monitoring board who 
will oversee the project. All data will follow HIPAA mandated policies and procedures to 
minimize and eliminate any breach of confidentiality. 

 
  
 
  
 
33
5 
STATISTICAL CONSIDERATIONS 
5.1 
Primary Endpoint 
Aim 1: a) The ability to recruit the required number of patients in the time given (recruiting 
the full complement of 90 patients over 18 months across 5 centers (ie 1 patient per month per 
center) to achieve 500 patients across 8 centers over the course of 2-3 years in the larger 
definitive trial) b) Results of questionnaires and surveys to determine whether a large full 
scale trial is operationally feasibly 
 
Aim 2: Principle parameters to be tested for the intended primary endpoints of the full 
scale trial: The difference between values at enrollment and 1-1.5 years after randomization 
between those TOF patients with and without PVR for a) Exercise performance parameters 
such as oxygen consumption (VO2) at ventilatory anaerobic threshold (VAT)41 normalized for 
age, weight, and sex as well as VAT, peak workload and % predicted peak workload47 as well 
an New York Heart Association Class and b) Disease Specific QOL - Pediatric Cardiac 
Quality of Life Inventory (PCQLI) Patient and Parent Scores. Although some retrospective 
studies in symptomatic adults have failed to demonstrate improvement and PVR in VO2, 
Eysken et al. found improvement in VO2 and VAT in children 8-18 years of age;41 Warner et 
al. found an increase in peak workload and % predicted peak workload.47 Length of follow-
up for patients is limited by the duration and funding of this award but will provide critical 
information as pilot data for a future trial. 
 
Aim 3: Primary parameters to be tested for the definitive clinical trial: The difference 
between PVR and no-PVR for a) exercise RVEDVi, RVESVi, RV EF and RV output, b) 
measures of global DF and c) measures of myocardial strain. 
5.2 
Secondary Endpoints 
Aim 1: Protocol logs demonstrating how many patients were screened, eligible and 
approached, how many dropped out and for what reason among other metrics. Factors which 
will affect follow-up in a larger trial are also key such as patients moving out of the area, 
pregnancy and need for pacemaker will be recorded and will be used as preliminary data for 
dropout rates and sample size for the larger trial. 
 
Aim 2: Other parameters to be tested for the intended primary or secondary endpoints 
for the full scale trial: The difference between PVR and non-PVR patients at enrollment and 
12-18 months later with: a) Other measures of EST performance such as forced vital capacity, 
forced expiratory volume at 1 second (FEV1), maximum voluntary ventilation, maximal work 
rate, maximal respiratory exchange ratio, breathing reserve, and maximum heart rate, b) 
Disease Specific PCQLI: Disease Impact and Psychosocial Impact subscale scores as well as 
Generic QOL Measure - Pediatric Quality of Life Inventory (PedsQL) Version 4.0 Generic 
Core (total and both Physical and Psychosocial Health Summary scores) and c) change in 
QRS duration or arrhythmia on Holter monitor (e.g. ectopy burden). 
 
Other key parameters to be taken under consideration will be the difference between those 
with and without PVR for: a) Death, hospitalization, need for medication, b) additional 
surgical or catheter based procedures, c) in the PVR group, failure of the valve and need for 

 
  
 
  
 
34
re-intervention and d) in those patients without PVR, need for valve placement or other 
interventions. In addition, the difference between those patients with surgical and 
transcatheter PVR for the intended endpoints mentioned will be analyzed. 
 
Other metrics to be obtained will include biventricular performance parameters (eg 
ventricular volumes and mass, ejection fraction) and hemodynamics such as pulmonary 
regurgitant fraction and cardiac index. 
Aim 3: Other parameters to be tested for the definitive clinical trial include the difference 
between those with and without PVR for: a) Global measures of LV performance such as 
CI, LV EF, indexed LV EDV and LV ESV at exercise, b) Measures of pulmonary blood 
flow (eg PR fraction and antegrade diastolic flow) at exercise, c) Regional DF using the 16 
segment AHA model and d) longitudinal and regional LV and RV strain. In addition, 
correlation of exercise ventricular function, strain, physiologic parameters and DF with 
clinical outcomes (Aim 2) will take place. 
5.3 
Statistical Methods 
5.3.1 Baseline Data and Efficacy Analysis 
Aim 1: This aim is intended to determine feasibility of a multicenter randomized 
prospective trial. Descriptive statistics appropriate for measures of feasibility and 
performance will be calculated, for example, overall percent and monthly pace of patient 
recruitment at each site, means and standard deviations of patient/physician survey answers, 
percent of teleconference representation from each center, mean data turn-around times for 
CMR core lab and frequency and mean time-to-resolution of data queries initiated by the 
data management and biostatistical support. These data summaries will be used to determine 
whether a large-scale clinical trial is feasible; specific criteria for proceeding with a larger 
trial are outlined at the end of this proposal. 
Aims 2 and 3: Prior to formal statistical analyses, descriptive statistics for all variables will 
be computed, including parametric and non-parametric measures of central tendency and 
variability. Continuous outcome variables for Aims 2 and 3 will be checked for normality 
using histograms and qplots, both for baseline and follow-up measures at 1-1.5 years after 
randomization, and for the difference between these two observations. If normality is 
suspect, we will explore transformations to improve normality or apply non-parametric 
counterparts for the analyses described in what follows. Data will be analyzed using SAS. 
 
The change from enrollment to 1-1.5 years after randomization in each candidate 
parameter for the intended primary endpoint in the definitive trial will be treated as 
outcomes which will be summarized for the PVR and no-PVR groups using means and 
standard deviations; they will be formally compared between groups using linear regression 
models with a dummy variable for treatment assignment (PVR vs. no-PVR) as the primary 
variable of interest with adjustment for study site and possibly other covariates that were not 
balanced across treatment group and might be associated with the outcomes. Treatment 
differences with p<0.05 in regression models will be considered statistically significant. 
Intent-to-treat analyses will be conducted such that treatment assignment will be assigned as 
randomized regardless of adherence. Complete data analyses will be conducted initially, but 
the frequency of missing data within each treatment group will be calculated. Since baseline 

 
  
 
  
 
35
data determines study eligibility, most missing data will occur at the anticipated follow-up 
time. We will compare demographic and clinical characteristics of patients with complete 
data to those without using t- and chi-square tests as appropriate to determine whether 
“missingness” may be informative. Depending on what we observe, we will perform 
sensitivity analyses using multiple imputation approaches and compare results to complete 
data analyses. Importantly, describing “missingness” frequency and potential bias in its 
occurrence will assist in planning a larger trial by emphasizing areas crucial for follow-up. It 
will help plan for imputation strategies that may be necessary in the larger trial and could 
suggest additional variables for in the larger trial to strengthen imputation models in the 
larger setting if required.  
 
Several of the other candidate parameters which will be tested for the definitive trial 
for both Aims 2 and 3 are continuous variables measured at 2 time points; differences will 
be analyzed using the approach described for the primary endpoints. Comparison of 
frequency of additional discrete secondary outcome variables for Aim 2 (e.g. death, 
hospitalization) will utilize chi-square tests given the sample size followed by logistic 
regression controlling for site and any other relevant variables. Cox modeling of time-to-
event data will be considered if frequencies are higher and event times more varied than 
expected although this is unlikely given the number of events anticipated. Within the PVR 
group, we will tabulate frequency of valve failure and re-intervention and in the no PVR 
group, we will tabulate the frequency of need for PVR or other interventions. These are not 
comparative analyses but will inform event rates for future trial design. Analyses for 
comparing the surgical and transcather PVR groups for all candidate parameters for the 
definitive trial will be adjusted for time since repair will be conducted by performing all 
analyses as just described. While patients will not be randomized to mode of PVR and this 
may introduce some bias, we will control for confounding to the extent possible and 
incorporate the similarities and differences of surgical or transcather PVR group in planning 
of the larger trial. Pairwise Spearman’s correlation coefficients including 95% confidence 
intervals will be calculated for the variables listed in Aim 3 and the clinical outcomes in 
Aim 2. All statistical tests will be conducted at nominal 2-sided, 5% significance level. 
While we recognize the multiplicity of variables and statistical tests, the purpose of this pilot 
trial is not to provide conclusive evidence of clinical effect, but rather to indicate possible 
effect size and use it to plan for a larger trial if the preliminary effect size is clinically 
relevant. Because of the preliminary nature of this pilot study, no correction for multiple 
comparisons will be made. 
5.3.2 Pharmacokinetic Analysis 
Not applicable 
5.3.3 Safety Analysis 
All subjects entered into the study at Visit 1 will be included in the safety analysis. The 
frequencies of AEs by type, body system, severity and relationship to study intervention will 
be summarized. SAEs (if any) will be described in detail. 
AE incidence will be summarized along with the corresponding exact binomial 95% two-
sided confidence intervals. 

 
  
 
  
 
36
 
5.4 Sample Size and Power  
The sample size is powered on the the EST parameter in Eysken et al41 and QOL parameters 
from our preliminary data between PVR and no-PVR groups (table 1). For the EST values, 
we utilized for VAT (% predicted for age and gender) 86+11% before and 107+14% after 
PVR (estimated change of 21+21%). For the QOL measurements, we utilized the standard 
deviation of the patient and parent 
PCQLI scores of 14.5 and 16.2 
respectively. Sample size for Aim 
3 based on Oosterhof et al73 are 
also included. Enrolling 100 
patients with a dropout rate of 
10% leaves 90 evaluable patients (60 PVR, 30 
no-PVR based on 2:1 randomization). Analysis is on an intent-to-treat basis. We will use 2-
sided α=0.05 and 80% power. Table 2 provides the minimal detectable difference with 80% 
power using the assumed standard deviation and sample size. The width of the 2-sided 95% 
confidence interval for the difference between the 2 groups is provided, indicating the 
estimation of accuracy for the group differences. 
5.4.1 Endpoints and Statistics in Context 
This is an R34 proposal which is intended to obtain pilot and preliminary data to inform a 
large scale clinical trial. As such, all design components of this protocol are intended to 
support this overarching goal including the Endpoints and the Statistics. In the end, this 
project is necessary and needs to be sufficient to support a decision to proceed with a 
clinical trial of PVR in TOF and to have the necessary preliminary data to design and 
support the endpoints. 
5.4.1.1 Minimum Criteria need to proceed to a large scale trial 
The following are minimum criteria needed to move forward with the definitive clinical 
trial: a) recruiting the full complement of 90 patients over 18 months across 5 centers (ie 1 
patient per month per center) to achieve 500 patients across 8 centers over the course of 2-3 
years in the larger definitive trial, b) an increase in VAT (or any exercise parameter) of > 
15% or QOL measures of > 10% consistent with lower 95% confidence interval bounds of 
detectable differences based on preliminary data to account for potential sampling error, c) 
no clinically relevant (as decided by the DSMB) difference in death, hospitalization, need 
for medication or NYHA class between PVR and no-PVR groups and d) in the PVR group, 
<10% of patients with PVR failure. Not meeting these criteria would indicate a failed 
feasibility trial. 
5.4.1.2 Expected Health Impact 
The definitive study which this feasibility protocol will support has the potential to impact 
literally thousands of individuals in the United States considering ~1,660 children are born 
each year with TOF.3 Avoidance of catastrophic RV failure, multiple hospitalizations, 
arrhythmia (all of which can have an adverse impact on productivity as well as lost wages) 
and death along with improved exercise performance and QOL in these individuals would 
Table 1: Sample Size Statistics 

 
  
 
  
 
37
have tremendous value. As mentioned above, although PVR will need future valve 
replacements, replacing a valve is much easier than replacing or managing a failing or failed 
RV with its attendant risk of ventricular tachycardia and sudden death. Besides avoiding 
morbidity and mortality, the investigators believe that PVR will 
5.4.1.3 Proposed Environment for the Full Clinical Trial: 
The full study will involve a much larger consortium. Dr. Fogel will administer the larger 
trial from CHOP and Dr. Marino will manage the data management and biostatistical 
support. Besides the current institutions, others that have expressed interest include Texas 
Children’s Hospital, University of Michigan CS Mott Children’s Hospital, Children’s 
Hospital of Wisconsin, New York-Prebyterian Children’s Hospital and Children’s Hospital 
Colorado. These are large, experienced pediatric cardiology / cardiac surgery centers 
capable of ensuring a successful outcome of the full clinical trial. Baseline and 
demographic characteristics will be summarized by standard descriptive summaries (e.g. 
means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). 
5.5 
Interim Analysis 
DSMB interim analysis: The DSMB will formally review adverse event frequency for the 
PVR and no-PVR groups after 45 trial participants have completed follow-up data 
collection; they will be blinded to treatment group status and only frequencies, not sample 
sizes, will be presented to mask the 2:1 randomization. A statistically significant difference 
(p<0.05) in adverse event frequency will merit further investigation into continuing the trial. 
This interim analysis is planned for formal evaluation of safety; an interim analysis of 
treatment effect is not planned due to the pilot and feasibility nature of the study. 
 
 

 
  
 
  
 
38
 
6 
STUDY INTERVENTION: PVR OR NO-PVR 
6.1 Description 
Patients will undergo PVR or no-PVR in a randomized fashion. 
6.1.1 Packaging 
Not applicable 
6.1.2 Labeling 
Not applicable 
6.1.3 Dosing 
Not applicable 
6.1.4 Treatment Compliance and Adherence 
Not applicable. If a patient in the no-PVR group requires PVR, this will be noted in the 
efficacy as well as safety evaluations mentioned above. 
6.1.5 Drug Accountability 
Not applicable 
 

 
  
 
  
 
39
7 
SAFETY MANAGEMENT 
7.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 
Adverse Event Reporting 
The Investigators are responsible for recording and reporting unanticipated problems related 
to the research and AE reporting will only occur for events linked to the study and not 
clinical procedures, the surgery or sequelae of the surgery, and will follow the CHOP IRB 
Guidelines. All SAEs will be reported to the IRB in accordance with CHOP IRB policies. 
Adverse Events that are not serious will be summarized in narrative or other format and 
submitted to the IRB at the time of continuing review. 
7.3 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
7.4 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• death, 
• a life-threatening event (at risk of death at the time of the event),  
• requires inpatient hospitalization or prolongation of existing hospitalization, 
• a persistent or significant disability/incapacity, or 
• a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 

 
  
 
  
 
40
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
7.4.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention will  be characterized using one of 
the following terms in accordance with CHOP IRB Guidelines: definitely, probably, 
possibly, unlikely or unrelated.  
7.5 
IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse 
Events that are related to the research activity. Other unanticipated problems related to the 
research involving risk to subjects or others will also be reported promptly. Written reports 
will be filed using the eIRB system and in accordance with the timeline below. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life 
Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of 
important AEs may be 
reported at time of 
continuing review 
7.5.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
7.6 
Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting will be consistent with regulatory, sponsor or GCRC requirements  

 
  
 
  
 
41
7.7 
Medical Emergencies (if applicable) 
For any medical emergencies, the primary co-investigator at each site or his designee will be 
responsible for investigating the emergency and resolving issues surrounding the 
emergency. Study teams and medical personnel associated with the patient will be in contact 
with each other to determine the correct way to proceed. For nights and weekends, all sites 
have cardiology fellows on call who know how to get in contact with the investigator at each 
site; they will be assigned to be called during those hours. The following is a list of who to 
notify during regular business hours: 
In an emergency at: 
 
 
Person to notify 
CHOP  
 
 
 
Mark Fogel 
Emory  
 
 
 
Tim Slesnick 
DC 
 
 
 
 
Russell Cross 
Cinn 
 
 
 
 
Sean Lang 
Lurie Childrens 
 
 
Josh Robinson 
NU  
 
 
 
 
Brad Marino 

 
  
 
  
 
42
8 
STUDY ADMINISTRATION 
8.1 Treatment Assignment Methods 
8.1.1 Randomization 
Patients will be randomized by computer by the statistician and her team at the Data 
Coordinating Center at NU who will maintain the schedule; this will be a 2:1 randomization 
of PVR to no-PVR. There will be no blinding and the assignment will not be concealed from 
the investigators. There will be no stratifications within each group. 
8.1.2 Blinding 
This study will not be blinded 
8.1.3 Unblinding 
Not applicable 
8.2 
Data Collection and Management 
This plan will be consistent with and follow CHOP Policy A-3-6: Acceptable Use of 
Technology Resources that defines the requirements for encryption and security of computer 
systems. 
Northwestern University will perform high quality data management and analysis functions. 
CRFs will be developed in conjunction with the study PI, site PIs and statistician. A Manual 
of Operations, including instructions for CRF completion and data capture will also be 
developed to support standardized study operations and data collection. All data will be 
coded at the sites by assignment of a unique study ID number for all participants and 
reported on all CRFs and source documents; the key which links this number to identifying 
information will be stored in a separate, secure location at each site. Data will be entered by 
the site study coordinators into a web-based REDCap database that will be created and 
extensively tested by the Northwestern University. Staff responsible for data entry will be 
granted access only to data from their site through the use of site-specific REDCap User 
Groups. Access to REDCap is conducted only on NU networks or over SSL VPN and all 
data are stored on a server encrypted using standard 2048-bit SSL certificate using https 
protocol. In addition to web-based entry, each site will scan in and upload all CRFs to the 
NU via a secure FTP site. A set of predetermined critical variables will be checked between 
the CRFs and the database. For 10% of cases, all data will be cross-checked. A series of 
range and logic checking scripts will be developed and run routinely for all data. Only study 
personnel will have access to data for their respective site. Data will be backed up on a 
separate server at Northwestern University. 
The identifiers will be destroyed as delineated in the CHOP data retention policy A-3-9 
(available for download at 
https://at.chop.edu/communities/policyprocedure/administrative/Active/a-3-9.pdf).  This 
laboratory (NU and CHOP) will maintains a file drawer specifically for such archives, each 
folder labeled “Destroy by….,” with the earliest dates at the front.” Data retention policy 
will meet NIH/NHLBI guidelines. 

 
  
 
  
 
43
8.3 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  
Northwestern University will coordinate data transfer between institutions in a HIPAA 
compliant manner to ensure privacy. Data sent across institutions will be on secure servers 
with only individual study team members having the ID and passwords. All data will be 
coded when crossing to the Northwestern University or to CHOP. Spreadsheets with 
identifying codes will be password protected and locked in secure files at each institution 
behind their firewalls. 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between provider (the PI) and any recipient 
researchers (including others at CHOP) before sharing a limited dataset (dates and zip 
codes).  
8.4 
Regulatory and Ethical Considerations 
8.4.1 Data and Safety Monitoring Plan 
The PI (or a designee if he is away) will have overall responsibility for monitoring the 
overall safety of the entire project during the study. At each site, each co-investigator will be 
responsible for safety. A physician will personally be at all CMR and EST studies. The IRB 
at CHOP will monitor this project and all adverse events will be reported to the IRB in a 
timely fashion in compliance with all applicable regulations.  
 
A Data Safety Monitoring Board (DSMB) will be organized by the NIH as per the request of 
Dr Egerson of NHLBI and contain at least 5 individuals, at least one of whom will be a 
pediatric cardiologist, a CMR physician and a catheterization doctor who will meet once 
yearly to assess the risk, benefit and safety of the study. The DSMB will review all the 
scientific data gathered to date as well as all the safety information such as adverse events 
that have occurred during the study period and will put its recommendations to the principle 
investigator and the rest of the research team in writing. The study team will be responsible 
for gathering all the information for the DSMB to review.  
 
8.4.2 Risk Assessment 
8.4.3 Potential Benefits of Study Participation 
There may be direct benefits to the subjects from this study if PVR is determined to have a 
salutary effect on QOL and exercise performance as well as decreasing complications of no-
PVR. Similarly, there may be direct benefits to the subjects from this study if no-PVR is 
determined to have a salutary effect on QOL and exercise performance as well as decreasing 
complications of PVR and avoiding surgery or catheterization. The patient will be 
contributing the overall scientific knowledge in the field of treating TOF. 
 

 
  
 
  
 
44
8.4.4 Potential Risks of Study Participation 
As stated, there is equipoise in the decision making process of PVR placement in TOF. It is 
so serendipitous that depending on who the patient sees as a physician, with the same 
clinical and imaging data, 2 very different decisions would be made, even within a given 
institution. This project simply organizes this disorganized approach to obtain data that will 
be useful in finally coming to a recommendation based on data. As such, the risk to the 
patient is no different that the risk of the patient having TOF and being apart of the medical 
system and not being part of this trial. That is to say, whether the patient enrolls in the study 
or not, the subject will wind up in one of the groups outlined in the study – PVR or no-PVR. 
Because of this, the risks to the patient are the same whether the patient and their physician, 
for example, choose to not have PVR or whether they get randomized to the no-PVR group 
in the study. Nevertheless, if a subject undergoes PVR who would not have outside of the 
research, then that subject is exposed to the risks of general anesthesia and the PVR 
procedure – thrombosis, infection, pain, stroke, and death. The same is true for an individual 
who would have had PVR but is randomized to medical management as a trial participant. 
These individuals might experience increase in symptoms, poorer QoL, etc.  
The risks presented by the two treatment groups are different.  
• Those randomized to PVR are risk of immediate complications from the 
procedure, general anesthesia and post-procedure care.  
• Those who are randomized to medical management (No-PVR) continue to 
be at risk from the medications and from disease progression. 
8.4.5 Risks for Subjects assigned to have PVR 
8.4.5.1 Risks associated with PVR procedure  
Subjects having PVR will need to be hospitalized. The valve could fail and need to be 
replaced. Potential complications from inserting the valve include: 
• Blood clots  
• Bleeding  
• Infection  
• Pain 
• Stroke 
• Need for blood transfusion 
• A scar on the chest (if PVR by surgery) 
• Abnormal heart beats (skipped, missed beats, fast or slow beats) 
• Death 
8.4.5.2 Risks associated with general anesthesia (GA) 
GA generally is required in order to have the PVR. There are very rare but serious side 
effects associated with general anesthesia including: irregular heartbeat, increases or 

 
  
 
  
 
45
decreases in blood pressure, rare reactions to medications used in the anesthesia, and 
blockage of breathing passages.  Other rare complications include nerve injury, lung injury, 
heart attack and brain damage. An extremely rare but serious complication is rapid increase 
in body temperature. All of these complications are treatable but might lead to coma or even 
death. 
8.4.6 Risks for medical management (No-PVR Group) 
• A start or increase in your symptoms  
• Decrease in ability to exercise 
• Poorer quality of life 
• Abnormal heart beats (skipped, missed beats, fast or slow beats) 
• A dilation of your right ventricle (the pumping chamber to the lungs) beyond 
the ability of the pumping chamber to come back to its normal shape 
• Right ventricle heart failure - the pumping chamber to the lungs  
• Hospitalization for heart failure, abnormal heart beats or increasing 
symptoms for example  
• Need to undergo PVR  
• Need for medication or additional medication 
• Death 
8.4.7 Risks for all Subjects 
8.4.7.1 Risks associated with exercise stress test (if this not ordered by your doctor):  
The risk of falling or injury is low. The doctor may stop the test if he/she feels it is not safe 
for the patient to continue. There may be some discomfort using the snorkel-like tube. 
During the study, the subject’s 
• Heart rate will be monitored by an electrocardiogram and a pulse oximetry 
monitor 
• Blood pressure will be monitored by a blood pressure cuff 
• Oxygen level will be monitored by a pulse oximetry monitor 
8.4.7.2 Risks associated with exercise CMR: 
For a select group who agree, we may ask the subject to exercise in the MRI scanner with a 
bicycle lying down which would be in addition to the standard MRI scan. There are no 
known risks of physical harm associated with the additional MRI scanning time. However, 
MRI machines produce loud banging noises, which cause some people to become stressed 
or upset which the subject will hear as they would during your routine MRI scan. The 
subject may also feel uncomfortable inside the magnet if they do not like to be inside small 
places or have difficulty lying still, similar to the standard scan. The subject may feel tired 
after you exercise. During exercise, the subject’s heart rate will be monitored by an 
electrocardiogram and pulse oximetry monitor and oxygen level will be measured by a pulse 
oximetry monitor as well. 

 
  
 
  
 
46
The MRI magnet is always on and attracts certain metal objects. Any metal objects on or 
inside of the subject’s body may heat up, move, and/or not function properly within the 
scanning room. Metal objects in the room can fly through the air toward the magnet and hit 
those nearby. There are many safety measures in place to reduce these risks. The staff will 
screen all persons and materials entering the scanning room for metal. When the study 
begins, the door to the room will be closed to minimize the risk of someone accidentally 
bringing a metal object into the scanner room. 
8.4.7.3 Risks associated with Questionnaires:  
Answering the questionnaires may bring up certain emotional feelings and concerns about 
the subject’s condition. The subject does not have to answer any questions that make him or 
her feel too uncomfortable. If the subject becomes too upset or need to talk to someone, the 
study will refer the subject to the Department of Psychosocial Services. 
8.4.7.4 Risks associated with breach of confidentiality:  
As with any study involving collection of data, there is the possibility of breach of 
confidentiality of data.  Every precaution will be taken to secure the subject’s personal 
information to ensure confidentiality.  At the time of participation, each participant will be 
assigned a study identification number.  This number will be used on study questionnaires, 
data collection forms, and in the database instead of names and other private information.  A 
separate list will be maintained that will link each participant’s name to the study 
identification number for future reference. 
8.4.8 Risk-Benefit Assessment 
Potential risk to the patient is extremely small (the same as being a TOF in the medical 
system), however the knowledge to be has the potential to not only add to the literature on 
adolescents with TOF but also holds the potential to begin to definitively answer the 
question of if and when to perform PVR. The procedures of this study – randomization with 
interventions (with attendant risks in each group as when the patient is not enrolled and in 
standard of care – the choice however being taken away from patient and physician), with 
medical record review, QOL, metabolic exercise testing (if not part of clinical care), 
physician surveys, exercise CMR and post-processing clinically obtained cine imaging for 
ventricular strain present a small risk relative to knowledge to be gained. 
The table below summarizes the major differences in possible benefits and risks with the 
two treatments. It is important to remember that it is not known whether PVR works or 
which group will do better. Since it is unknown whether or not PVR prevents disease 
progression, the subject’s symptoms may get worse regardless of which arm they are 
assigned to. 
 
Treatment 
Arm 
Possible Benefits 
Possible Risks 
PVR 
• 
Improved exercise capacity 
• 
Complications from PVR procedure 
including:  

 
  
 
  
 
47
• 
Improved quality of life 
pain, bleeding, clots, that could 
lead to death 
• 
Need to undergo valve replacement 
No-PVR 
• 
Avoidance of the 
complications of PVR  
• 
Progression of symptoms due to 
right heart failure that could lead 
to death 
• Decreased ability to exercise 
• 
Decrease in quality of life 
• 
Need for additional medications 
 
8.5 
Recruitment Strategy 
The Principal Investigator or designee at each clinical center and the study coordinator will 
be responsible for case ascertainment and subject recruitment. Subjects will be recruited 
from each of the participating sites. Potential subjects will be identified from patients who 
are referred to or who are already patients in cardiology clinics at the study sites. Most 
importantly, patients will be identified from CMR logs and the CMR schedule. Prior to 
study launch, study staff will conduct informational sessions with all physicians, nurses, and 
other colleagues at their sites who care for the target population to describe the trial and 
solicit support for recruitment.  
Study staff will review site databases/medical records and the CMR and EST schedule for 
potentially eligible patients based study specified inclusion criteria. A screening log 
specifying reasons for exclusion will be kept. Screening will continue throughout the study 
at participating sites to identify any additional subjects that are new or were missed in the 
initial screening process. 
Please note that the screening activities themselves are limited to review of 
medical/investigator records and do not include soliciting information directly from potential 
subjects; only when subjects meet inclusion criteria and do not meet exclusion criteria will the 
patient be approached. 
 
The study team may potentially be utilizing the Recruitment Enhancement Core for 
recruitment purposes (through the mailing of opt-out cards). The recruitment opt-out cards 
will include the required REC language. 
Identified potentially eligible patients will be approached during a clinic visit or CMR scan, 
or, if eligibility is determined outside of a clinical visit, parents and potentially eligible 
patients will be contacted by study staff, as permitted by local IRB regulations, including 
mailing with opt-out card, a telephone call, video (eg Skype) email and/or other methods of 
approved initial contact. If a patient is interested in the study, the site personnel will be 
responsible for enrolling and consenting subjects either in person or via mail for signing the 
consent form. If the patient declines study participation or does not attend the screening 
visit, this will be recorded in the screening log. After consent has been obtained, each 

 
  
 
  
 
48
subject will be assigned a study identification (ID) number in order to keep study 
information confidential. The link between subject name and ID number will be stored only 
at the study site. Screening measures will be performed. Subjects who do not meet study 
eligibility criteria after screening assessment will be discontinued from study participation, 
and will not be scheduled for further study visits or measures. The screening data will be 
recorded and kept. Subjects who meet eligibility criteria at the screening visit and provide 
informed consent will be scheduled for study visits which can occur on that same day. 
Recruitment of physicians to fill out questionnaires will occur during or after meetings or in 
clinics. The Investigator will comply with IRB SOP 501 
(https://irb.research.chop.edu/sites/default/files/documents/irbsop501_2014-9-8.pdf) by not 
enrolling physicians who report to the investigators, that physicians' participation will not 
affect their performance evaluations or employment, and that only investigators who are not 
the physicians' direct supervisors will obtain consent. 
8.6 
Informed Consent/Assent and HIPAA Authorization 
Subject consent or parental/guardian permission (informed consent) and, if applicable, child 
assent, will be obtained prior to any study related procedures being performed with a 
member of the study team. The principal investigator or a designee will be able to discuss 
and answer any questions related to the study with both the parent (if applicable) and the 
subject (to obtain consent if they are an adult or assent if they are a child); if a designee is 
obtaining consent, the PI will be available in case more questions arise and the subject or 
family would like to discuss the questions with the PI. Adult subjects will provide consent 
for themselves. The principal investigator or qualified designee will obtain written consent 
either in person at the time of the CMR, at a routine clinic visit or other appropriate venue or 
via mail. In person consent will be obtained in a private area and families and subjects will 
be encouraged to ask questions.  If consent is obtained via mail, the study team will 
document that the principal investigator or qualified designee has spoken with the family 
and subject via telephone call or videoconference to answer any questions related to the 
study prior to having the family or subject, if they are 18 and older, to sign and return the 
consent forms. If the subject is under the age of 18 and is not available at the time of the 
initial phone call, then study team will provide flexibility for follow up phone calls in order 
to obtain assent. The consent forms will be signed by the PI or qualified designee after the 
family or adult subject has signed. The study team will provide shipping materials (i.e. 
stamps, labels, etc.) to return the signed consent forms to the study team. The study team 
will make sure to mail a copy of the fully executed consent form to the family to keep for 
their own records. Willingness to participate in the study will be confirmed when the subject 
is seen in person. The subject and family will not be coerced nor will they need to decide at 
that time to participate.  They can bring the consent form home with them and we will offer 
the family a contact phone number and email address.   A member of the study staff will 
contact the family approximately one week later to answer any further questions prior to 
obtaining consent.   
Subjects who decline to participate in the main study will be asked for the reason and this 
will be recorded per standard of practice of the study coordinator group. This data will be 
used for further research and analysis. Physicians who decline to participate in the study but 
who are gracious enough to fill out a questionnaire every year will be consented on a 

 
  
 
  
 
49
separate consent form by the study team at their convenience and in private; they will not be 
coerced in any way. 
Written informed consent will be obtained from physicians who agree to participate in the 
questionnaires in a private location. 
8.6.1 Waiver of Consent 
Not applicable 
8.6.2 Waiver of Assent 
Not applicable 
8.6.3 Waiver of HIPAA Authorization 
Not applicable 
8.7 
Payment to Subjects/Families 
8.7.1 Reimbursement for travel, parking and meals 
Although nearly all study related procedures are clinically indicated, the investigators 
recognize that patients and their families still take time out of their day to listen to the study 
plan and participate. This study is funded on a very limited budget. As such, a token amount 
of $25 will be given to recognize that fact. 
8.7.2 Payments to parent for time and inconvenience (i.e. compensation) 
See 8.6.1 
8.7.3 Payments to subject for time, effort and inconvenience (i.e. compensation) 
See 8.6.1 
8.7.4 Gifts 
See 8.6.1 
9 
PUBLICATION 
We anticipate the results of this study will be presented at national meetings and/or 
published in academic journals. We will not disclose PHI in any presentation or publication 
about the study. 
 
 
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