Long-term Outcomes of Children With HLHS (Hypoplastic Left Heart Syndrome) and the Impact of Norwood Shunt Type (A Study Conducted by the Pediatric Heart Network)
Conditions: Heart Defects
Sponsor: Carelon Research

Study Name: Long-term Outcomes of Children 
with HLHS and the Impact of Norwood Shunt 
Type (SVR III)- Protocol 
 
NCT Number: NCT02455531 
 
Document Date: May 28, 2024 
 
 
 
 
 
 

 
 
 
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Long-term Outcomes of Children with HLHS 
and the Impact of Norwood Shunt Type  
 
 
 
PROTOCOL 
 
 
 
 
 
 
 
VERSION DATE: May 28, 2024 
 
 
 
Funded by 
Pediatric Heart Network  
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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1. GENERAL INFORMATION 
 
1.1 Protocol Signature Page 
 
I have read the foregoing protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study in accordance with the design and specific provisions outlined 
herein; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they are 
fully informed regarding the [insert the word “device”, “drug”, or “biologic”, as applicable] and the 
conduct of the study.  
 
I will use the informed consent form approved by the National Heart lung and Blood Institute 
(NHLBI) and will fulfill all responsibilities for submitting pertinent information to the Institutional 
Review Board or Ethics Committee responsible for this study. 
 
I also agree to report all information or data in accordance with the protocol and, in particular, I 
agree to report any serious adverse experiences as defined in Section 7.2 of this protocol. 
 
I further agree that the NHLBI and/or its designee has access to any source documents from 
which case report form information may have been generated. 
 
I also agree to handle all clinical supplies (including drugs, biologics, and/or devices) provided 
and collect and handle all clinical specimens in accordance with the protocol. 
 
The below signed confirm herewith to have read and understood this study protocol and/or 
amendment and appendices; furthermore, to accomplish this study in accordance to the protocol 
and Good Clinical Practice guidelines, as well as local regulations and regulatory authorities. 
 
PRINTED OR TYPED NAME(S) 
 SIGNATURE 
 DATE 
 
  
  
Investigator  
  
  
Investigator 
  
  
Investigator  
  
  
Investigator 
  
  

 
 
 
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1.2 Protocol Synopsis 
 
Title 
Long-term Outcomes of Children with Hypoplastic Left Heart 
Syndrome  and the Impact of Norwood Shunt Type (SVR III)  
Study Objectives 
1. To determine if shunt type at the time of Norwood operation is 
associated with long-term differences in cardiac function, survival or 
contributors to quality of life. 
2. To characterize long-term outcomes and determine risk factors other   
than shunt type for adverse long term outcomes in children with 
hypoplastic left heart syndrome (HLHS) and other related single 
ventricle anomalies. 
Significance 
The proposed long-term follow-up of the Single Ventricle Reconstruction 
(SVR) trial cohort is required to determine the optimal shunt approach 
for children with HLHS. 
Study Design 
Prospective follow-up study of the SVR cohort 
Primary Aim 
To compare direct and indirect measures of right ventricular (RV) systolic 
and diastolic function between 11 year old subjects who had been 
randomly assigned to receive a right ventricle to pulmonary artery shunt 
(RVPAS) vs. a modified Blalock-Taussig shunt (MBTS) at the time of the 
Norwood operation. 
Secondary Aim(s) 
1. To compare the incidence of death or cardiac transplantation 
between those randomized to receive a RVPAS vs. a MBTS at the 
time of the Norwood operation. 
2. To compare exercise tolerance between those randomized to a 
RVPAS vs. a MBTS. 
3. To compare the incidence of arrhythmias between those 
randomized to a RVPAS vs. a MBTS. 
4. To compare neurodevelopmental outcomes at 11 years of age in 
those randomized to a RVPAS vs. a MBTS 
5. To develop risk stratification models for 1) cardiac outcomes, 2) 
transplant-free survival, and 3) neurodevelopmental outcomes. 
6. To collect specimens from subjects and their parents to further 
develop the biologic specimen repository. 
Accrual Objective 
Fixed cohort, ideally with a 2 year window for participation (11 + 1 year 
of age), but subjects can be enrolled at any time there is interest in 
participation up until September 30, 2020. 
Study Duration 
10.5 years (June 2015 - November 2025) 
Inclusion Criteria 
Transplant-free survivors of the SVR cohort (All SVR survivors are 
eligible to be followed for vital status.) 
Exclusion Criteria 
Participants who received cardiac transplantation or biventricular 
conversion will be excluded from all outcomes other than vital status.  
 

 
 
 
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1.3 Table of Contents 
 
1. 
GENERAL INFORMATION ................................................................................................. 2 
1.1 
Protocol Signature Page .............................................................................................. 2 
1.2 
Protocol Synopsis ........................................................................................................ 3 
1.3 
Table of Contents ........................................................................................................ 4 
1.5 
List of Abbreviations ..................................................................................................... 5 
2. 
STUDY AIMS AND HYPOTHESES .................................................................................... 7 
2.1 
Primary Aim: ................................................................................................................ 7 
2.2 Secondary Aims ............................................................................................................... 7 
3. 
BACKGROUND INFORMATION ........................................................................................ 9 
3.1 
Overview .....................................................................................................................99 
3.2 
Prior Studies ................................................................................................................ 9 
3.3 
Rationale for the Study ................................................................................................ 9 
3.4 
Rationale for the Study Outcomes ............................................................................ 100 
4. 
STUDY / TRIAL DESIGN ...................................................................................................12 
4.1 
Overview of Study Design ......................................................................................... 122 
4.2 
Procedures to Minimize Bias ..................................................................................... 122 
4.3 
Study Measures ..........................................................................................................12 
4.4 
Study Visits .................................................................................................................20 
4.5 
Repeat Study Evaluations ...........................................................................................21 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................................21 
5.1 
Subject Inclusion: ........................................................................................................21 
5.2 
Subject Exclusion:.......................................................................................................21 
5.3 
Subject Withdrawal Criteria .........................................................................................21 
5.4 
Subject Availability .................................................................................................... 211 
5.5 
Recruitment/Enrollment Procedures ......................................................................... 211 
6. 
SAFETY ASSESSMENTS AND MONITORING ............................................................... 223 
6.1 
Specification of Safety Parameters ........................................................................... 223 
6.2 
Recording and Reporting Adverse Events ................................................................ 223 
6.3 
Safety Monitoring ........................................................................................................26 
7. 
STATISTICS ......................................................................................................................26 
7.1 
Analysis Plan ..............................................................................................................26 
7.2 
Number of Subjects to be Enrolled ............................................................................ 277 
7.3 
Level of Significance ................................................................................................. 288 
7.4 
Interim Analyses and Stopping Rules for Termination of the Study .............................28 
7.5 
Spurious Data Procedures ..........................................................................................29 
7.6 
Deviation Reporting Procedures .................................................................................29 
7.7 
Subjects to be Included in Analyses ............................................................................29 
8. 
DATA MANAGEMENT .......................................................................................................29 
8.1 
Data Entry ...................................................................................................................29 
8.2 
Data Validation and Monitoring ...................................................................................30 
8.3 
Data Security and Integrity ..........................................................................................30 
9. 
QUALITY CONTROL AND QUALITY ASSURANCE (QC/QA) ...........................................30 
10. 
ETHICS AND HUMAN SUBJECTS CONSIDERATIONS................................................31 
10.1 
Potential Risks and Protection Against Risks ..............................................................31 
10.2 
Confidentiality .............................................................................................................31 
10.3 
Potential Benefits ........................................................................................................33 
10.4 
Risk/Benefit Ratio and Importance of Information to be Obtained ...............................33 
11. 
STUDY LIMITATIONS ....................................................................................................34 
12. 
REFERENCES ...............................................................................................................35 

 
 
 
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1.4 List of Abbreviations   
 
ABAS 
Adaptive Behavior Assessment System 
AE 
Adverse Event 
AUC 
Area under the Curve 
BRIEF 
Behavior Rating Inventory of Executive Function 
CEC 
Clinical Events Committee 
CI 
Confidence Interval 
CMR 
Cardiac Magnetic Resonance Imaging 
Connors 3 AI 
Connors 3rd Edition Attention Deficit and Hyperactivity Index 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCC 
Data Coordinating Center 
DMP 
Data Management Plan 
DMS 
Data Management System 
DSMB 
Data and Safety Monitoring Board 
DTI 
Doppler Tissue Imaging 
EC 
Executive Committee 
Echo 
Echocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HRQOL 
Health-Related Quality of Life 
HLHS 
Hypoplastic Left Heart Syndrome 
IART 
Intra-Atrial Reentrant Tachycardia 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
IDE 
Investigational Device Exemption 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVC 
Inferior Vena Cava 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web-based Response System 
LPA  
Left Pulmonary Artery 
MBTS 
Modified Blalock-Taussig Shunt 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MM 
Medical Monitor 
MOO 
Manual of Operations 
MRI 
Magnetic Resonance Imaging 
ND 
Neurodevelopmental 
NEPSY-II 
A Developmental NEuroPSYchological Assessment – Second Edition 
NCBI 
National Center for Biotechnology Information 
NIH 
National Institute of Health 
NHLBI 
National Heart, Lung and Blood Institute 

 
 
 
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OHRP 
Office for Human Research Protection 
Peds-QL 
Pediatric Quality of Life Inventory 
PC 
Phase Contrast 
PHN 
Pediatric Heart Network 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
RPA 
Right Pulmonary Artery 
RV 
Right Ventricle 
RVED 
Right Ventricular End Diastolic  
RVEDV 
Right Ventricular End Diastolic Volume 
RVEF 
Right Ventricular Ejection Fraction 
RVES 
Right Ventricular End Systolic 
RVESV 
Right Ventricular End Systolic Volume 
RVPAS 
Right Ventricular to Pulmonary Artery Shunt 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SMF 
Site Master File 
SMP 
Site Monitoring Plan 
SSFP 
Steady State Free Precession 
SSL 
Secure Socket Layer 
SVR 
Single Ventricle Reconstruction  
SVR II 
Single Ventricle Reconstruction Extension Study 
SVT  
Supraventricular Tachycardia 
SVC 
Superior Vena Cava 
TR 
Tricuspid Regurgitation  
TV 
Tricuspid Valve 
VO2 
Oxygen Consumption 
VO2 max 
Maximum Oxygen Consumption 
WIAT 
Wechsler Individual Achievement Tests 
WISC 
Wechsler Intelligence Scale for Children 
 
 
 
 
 

 
 
 
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2. STUDY AIMS AND HYPOTHESES 
 
2.1 Primary Aim:  
 
To compare direct and indirect measures of right ventricular (RV) systolic and diastolic function 
between 11 year old subjects who had been randomly assigned to receive a right ventricular-to-
pulmonary artery shunt (RVPAS) vs. a modified Blalock-Taussig shunt (MBTS) at the time of the 
Norwood operation.  
 
Hypothesis: Assignment to the RVPAS compared to the MBTS will be associated with worse RV 
performance in subjects at age 11 years. 
 
Primary Outcome: RV ejection fraction (RVEF) at 11 years, as measured by cardiac magnetic 
resonance (CMR).  
 
Secondary Outcomes: Secondary outcomes will include additional measures of ventricular 
systolic, diastolic, and global function by CMR and echocardiogram (echo); anatomic measures 
related to RV function; and physiologic measures affecting RV function. Secondary outcomes of 
the greatest importance include: 
• 
RVEF (measured by echo) 
• 
RV fractional area change (measured by echo and CMR) 
• 
Cardiac output (measured by CMR) 
 
 
 
2.2 Secondary Aims 
 
Secondary Aim 1: To compare the long-term effect of the RVPAS to that of the MBTS on 
the incidence of death or cardiac transplantation in children with hypoplastic left heart 
syndrome (HLHS) and other single RV anomalies undergoing the Norwood procedure.  
 
Hypothesis: The incidence of death or cardiac transplant will be higher in the RVPAS group 
compared to the MBTS group.  
 
Outcomes:  
• 
The composite of the earliest occurrence of mortality and cardiac transplantation using 
all available follow-up (ranging from 10 to 15 years). 
• 
Conditional freedom from death or cardiac transplantation by 11 years among subjects 
who survived >1 year post-randomization. 
• 
Survival at 11 years post-randomization and when the last enrolled subject is 11 years 
old. 
• 
Transplant at 11 years post-randomization and when the last enrolled subject is 11 years 
old. 
• 
The composite of the earliest occurrence of mortality, cardiac transplantation and 
pacemaker placement, using all available follow-up (ranging from 10 to 15 years). 
 
 

 
 
 
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Secondary Aim 2: To compare exercise tolerance between those randomized to receive a 
RVPAS vs. a MBTS at the time of the Norwood operation.  
 
Hypothesis: Subjects assigned to the RVPAS group will have lower exercise performance at 
age 11 years compared to those assigned to the MBTS group. 
 
Outcomes:  
• 
Exercise capacity: Maximal Oxygen Consumption (VO2max), maximal work rate, and 
anaerobic threshold   
 
Secondary Aim 3: To compare the incidence of arrhythmias between those randomized 
to receive a RVPAS vs. a MBTS at the time of the Norwood operation.  
 
Hypothesis: The RVPAS will be associated with a greater prevalence of ventricular 
arrhythmias, but will not differ from the MBTS in the prevalence of atrial arrhythmias.  
 
Outcomes: 
• 
History of ventricular arrhythmias by age 11 years by parent report and with medical 
record confirmation.  
• 
History of atrial arrhythmia by age 11 years, including intra-atrial reentrant tachycardia 
(IART) or supraventricular tachycardia (SVT), by parent report and with medical record 
confirmation 
 
Secondary Aim 4: To compare neurodevelopmental outcomes at 11 years of age in 
subjects randomized to a RVPAS vs. MBTS at the time of the Norwood operation.  
 
Hypothesis: Impaired neurodevelopment will not be associated with Norwood shunt type but 
mean scores will be lower in single ventricle patients compared to the normative population. 
 
Outcomes:  
• 
Achievement, as measured by the Wechsler Individual Achievement Tests (WIAT) (Math 
and Reading) 
• 
Intelligence, as measured by the Wechsler Intelligence Scale for Children (WISC)  
• 
Other domains of neurodevelopmental function including assessment of language, 
executive function, visual spatial skills, motor function, memory, social skills, behavior, 
health-related quality of life (HRQoL) and adaptive function.  
 
Secondary Aim 5: To develop risk stratification models for the following classes of long 
term outcomes: 1) cardiac outcomes, 2) transplant-free survival, and 3) 
neurodevelopmental outcomes. 
 
Hypothesis: Long-term outcomes at 11 years will be worse for participants with a higher 
frequency of medical events.  
Analyses for this aim will: 
• 
Provide information about the association of events and interventions other than the 
randomized surgical procedure with late outcomes.  
• 
Identify early cardiac and neurodevelopmental surrogate endpoints that might be useful 
in future studies of management strategies.  
• 
Determine if correlates of long-term outcomes vary according to patient subgroup 
factors.  

 
 
 
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Secondary Aim 6: To collect specimens from subjects with HLHS and other single RV 
anomalies and their parents in whom DNA samples either were not collected previously 
or are of insufficient quality or quantity,  to further develop the biologic specimen 
repository (biorepository). 
 
Purpose: To build on the collection of genetic material from the SVR cohort, to leverage the 
careful phenotyping of the SVR cohort to provide an opportunity for future phenotype-genotype 
studies and to make samples available for future hypothesis-driven  studies aimed at identifying 
genetic determinants of outcome in HLHS and related single RV  lesions.  
 
 
3. BACKGROUND INFORMATION 
 
3.1 Overview  
Hypoplastic left heart syndrome (HLHS) remains among the highest risk congenital cardiac 
malformations, with significant mortality and morbidity throughout childhood and early 
adulthood. Prior to 1980, when William Norwood described the palliative operation now 
commonly known as the Norwood procedure,1,2 children born with HLHS had virtually no chance 
of survival. By the late 1990s, early post-operative survival approached 80-85% in some 
centers.3,4  Despite this improvement, the ongoing risk of mortality in the early period, including 
10-20% interstage mortality,5,6,7 resulted in one-year survival rates of only 60%-70%.8-10 
Furthermore, among survivors, the morbidity associated with single ventricle physiology is 
substantial, with major negative consequences for quality of life and long-term survival.  
 
3.2 Prior Studies 
The Single Ventricle Reconstruction (SVR) trial was the first multicenter, randomized 
clinical trial to compare two operations in the field of congenital heart disease.8,11 Children with 
HLHS and other related single RV lesions were enrolled and randomized to receive either a 
MBTS or a RVPAS at the time of the initial Norwood procedure. This landmark study provided 
extraordinary insight not only into the consequences of both shunt types, but also into the 
course, treatment responses and short- and mid-term outcomes for these medically complex 
patients. Through the SVR Trial and SVR Extension Study (SVR II), outcomes, including but not 
limited to the primary outcome of transplant-free survival, have now been evaluated in this 
patient cohort when the last enrolled patient reached 12 months and again at 3 years of age. 
While early post-operative transplant-free survival during the interstage period7 and at one year8 
was better for those children randomized to a RVPAS, survival by the 3-year evaluation 
appeared equivalent between the two shunt types. Moreover, RVEF was somewhat diminished 
and the number of interventions was higher in the RVPAS group.12 These findings raised 
concern that the RV dysfunction in the RVPAS group may be progressive, leading to 
significantly worse long-term outcomes; if so, the benefits of the RVPAS for short-term survival 
may be outweighed by longer-term morbidity and mortality.  Thus, the optimal surgical approach 
for newborns with HLHS and related single RV lesions remains unclear. 
 
3.3  Rationale for the Study 
The Pediatric Heart Network (PHN) Investigators have a unique opportunity and 
responsibility to analyze the effect of the type of systemic-to-pulmonary artery shunt placed 
during the Norwood procedure on longer-term survival, as well as to define its effect on other 

 
 
 
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long-term outcomes in this multi-institutional cohort of exquisitely characterized subjects with 
single RV lesions. As subjects enrolled in the SVR cohort approach a decade of age, we aim: 1) 
to determine if shunt type at the time of Norwood operation is associated with any long-term 
differences in cardiac function, survival, or contributors to quality of life; and 2) to characterize 
long-term outcomes and determine risk factors other than shunt type for adverse long-term 
outcomes in children with HLHS and other related single ventricle anomalies. 
 
3.3.1. What is known to date about long-term outcomes of children with single ventricle 
heart defects?  
 
To enhance our understanding of outcomes among Fontan survivors, the PHN conducted 
the Fontan Cross Sectional Study, which characterized 546 patients with a spectrum of single 
ventricle malformations and ranging from 6 to 18 years of age at enrollment.13 This study and 
others have noted that after the Fontan procedure, patients experience significant deficits 
across multiple functional domains. Longitudinal follow-up of the Fontan Cross-Sectional Study 
cohort has yielded many insights into the medical challenges faced by this population. This work 
related to the Fontan cohort has been instrumental in informing the aims and design of the 
current proposal, but it does not include information on single ventricle patients with a RVPAS.  
Thus, long-term follow-up of the SVR cohort, in particular, is needed to determine the influence 
of shunt type on important long-term outcomes. Furthermore, unlike the Fontan cohort, the SVR 
cohort is an inception cohort that has been followed from birth, allowing us to analyze 
associations between critical early events and later outcomes.  
3.4 Rationale for the Study Outcomes 
 
3.4.1 Measurements of Cardiac Function and Assessment of Cardiac Anatomy:  
Ventricular dysfunction in patients with single ventricle physiology is common and can lead 
to symptoms of heart failure, dysfunction of other organ systems, and worse quality of life.  
Exercise intolerance, ventricular and atrial arrhythmias, protein-losing enteropathy, and hepatic 
cirrhosis may each be attributable, in part, to ventricular dysfunction. Because of the critical role 
of ventricular function on the development and progression of these outcomes, and due to the 
concern that initial shunt type may affect ventricular function, we have chosen RVEF, as 
measured by CMR, to be the primary outcome for this study.  
In the Fontan Cross Sectional Study, ejection fraction was decreased by 2D echo in 
approximately 27% of subjects.  The average RVEF for subjects with a single right ventricle was 
56% compared to a left ventricular ejection fraction of 60% in those with a single left ventricle.14   
By CMR, the RVEF was 55% for those with single RV lesions.  
Within the SVR cohort, the RVPAS group had a higher mean end-systolic volume  
compared to the MBTS group (55±17.8 vs. 49.1±6.6 ml/BSA1.3, p=0.004) and a lower RVEF 
(40.9±6.7% vs. 44.2±3.1%, p=0.004) at the pre-Fontan echo.15  Diastolic dysfunction was even 
more prevalent than systolic dysfunction, with 81% of all subjects with a single RV having 
abnormal diastolic filling properties.14 This is particularly problematic because diastolic 
ventricular dysfunction, accompanied by higher filling pressures and pulmonary vascular 
resistance, is a powerful risk factor for morbidity and functional limitation in patients with Fontan 
physiology. The planned SVR III assessment will include measurements of right ventricular 
systolic, diastolic, and global function indices.  
In addition to direct measures of RV function, other anatomic and physiologic variables will 
be assessed.  For example, atrioventricular valve regurgitation, aortic insufficiency and 
pulmonary artery size each can affect cardiac output and filling pressures in the single ventricle 
patient. One recent report described greater tricuspid regurgitation in patients with HLHS and 
the MBTS.16 Development of significant neo-aortic root dilatation and neo-aortic valve 

 
 
 
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regurgitation has been described later in childhood after Norwood palliation with a MBTS.17 
Within the SVR cohort, there was significant neo-aortic dilation by the pre-Fontan echo. 
Although to date, this has not been associated with significant regurgitation,15 ongoing dilation 
may eventually result in aortic insufficiency that is less well tolerated by those in the RVPAS 
group given their history of a right ventriculotomy.  
For the SVR III study, measurements of function and anatomy will be obtained using CMR 
and echo. While the primary outcome measure for the proposed study is RVEF measured by 
CMR, some eligible subjects will be unable to undergo CMR because they have a pacemaker or 
cannot cooperate in the scanner. The inclusion of echo measurements as secondary outcomes 
allows cardiac function to be evaluated in a greater percentage of the SVR cohort. Knowledge 
of the relationship between CMR and echo measures will be valuable for the clinical care of 
patients with HLHS and other single RV disorders, particularly given that serial echoes are 
performed routinely in single ventricle patients, 
 
3.4.2 Measurement of Exercise Intolerance:  
Adolescents with Fontan physiology are recognized to have reduced aerobic exercise 
capacity.18-22  Causes of lower exercise capacity include reduced systolic and/or diastolic 
function, limited ability to maintain adequate preload to the systemic ventricle, chronotropic 
incompetence, or even the mildest elevation in pulmonary vascular resistance.  Consistent with 
previous findings, the Fontan Cross Sectional Study showed a percent predicted VO2 max of 
only 66% at 12 years of age.20 To the extent that RV function deteriorates in the RVPAS group 
at older ages, exercise performance may be even further compromised.  
3.4.3 Incidence of Arrhythmias: 
Abnormalities of cardiac rhythm, including both tachy- and brady-arrhythmias, are common 
after the Fontan procedure.  Supraventricular tachycardia (SVT), most commonly intra-atrial re-
entrant tachycardia (IART), occurred in 9.4% of the Fontan Cross Sectional cohort with 
increasing incidence with age.23 Atrial stretch, which can result from ventricular dysfunction and 
high ventricular end diastolic pressure, can exacerbate atrial arrhythmias.24 Progressive 
ventricular dysfunction or even stable but reduced ventricular function in the RVPAS group 
could therefore increase the incidence of atrial arrhythmias.  
The potential for promotion of ventricular arrhythmias from scarring around the RVPAS 
conduit insertion site is even more concerning.  Ventricular arrhythmias occurred in 3.5% of 
Fontan patients in the Cross-Sectional study,23 and the use of the RVPAS could increase this 
rate considerably. Both atrial and ventricular rhythm abnormalities can lead to diminished 
exercise tolerance, lower quality of life, higher risk of thromboembolic events and protein-losing 
enteropathy, and a possible increase in the incidence of sudden death.  
 
3.4.4 Measurement of Neurodevelopmental (ND) Outcomes:  
Children with single ventricle lesions frequently have developmental disabilities. The 
etiology of ND morbidity is multifactorial and includes low birth weight,25-27 prolonged cyanosis,28 
congestive heart failure,29 unstable hemodynamics during the pre-operative period, need for 
multiple cardiac catheterizations, and a series of operations culminating with Fontan palliation.30 
Impaired cerebral blood flow, even in utero,31,32 as well as structural abnormalities of the brain33-
37 and the presence of genetic and other associated congenital abnormalities,26,38 also appear to 
contribute to concerning outcomes reported in numerous studies in infancy and early childhood.  
Most findings on ND in this high-risk group of children have derived from single-center or 
cross-sectional studies. To date, the relationship between early developmental assessments 
and measures of development for school-age children with HLHS and other forms of single RV 
remains unknown. The SVR and SVR Extension (SVR II) studies included neurodevelopment 
as an important outcome11,26,27 because of its critical role in determining quality of life and 

 
 
 
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informing optimal treatment approaches. The measurements of the SVR cohort to date are 
limited by the young age at which in-person testing was performed (14 months) and by the use 
of home questionnaire instruments in SVR II.  An in-person evaluation at age 11 years using a 
multifaceted battery will allow a richer understanding of ND outcomes in this cohort, refining our 
ability to discriminate differences based on earlier shunt strategy, as well as to discern other 
factors influencing long-term neurodevelopment, school function, and quality of life. Given the 
importance of these outcomes to patients and families, we anticipate excellent motivation to 
participate in this study.  
4. STUDY / TRIAL DESIGN 
 
4.1 Overview of Study Design  
The SVR III study is a prospective follow-up study of an existing cohort of children with 
HLHS and other single RV anomalies enrolled in early infancy in a randomized clinical trial of 
Norwood procedure with MBTS versus RVPAS. We seek to determine if the shunt assignment 
at the time of the Norwood operation is associated with cardiac function, transplant free survival, 
exercise function, and neurodevelopmental outcomes. Families of surviving SVR participants 
will be contacted and asked to return for multidisciplinary evaluation including performance of a 
CMR study, echo, exercise testing, and neurocognitive evaluations. All testing will be performed 
at an SVR enrollment site, either where the Norwood was performed or a site that is closer to 
the subject’s home.  Both CMR and echoes will be interpreted in core laboratories by 
investigators blinded to Norwood shunt type.  
4.2 Procedures to Minimize Bias 
The eligible SVR III study cohort is defined by the participants in the SVR trial.  All eligible 
subjects will be encouraged to participate, regardless of distance, demographic factors, or 
earlier medical history.  To avoid bias in measures for ventricular function, those performing 
measurements in the CMR and echo core labs will be masked to the shunt type at the time of 
the Norwood operation.  The psychologist or their surrogate conducting the ND evaluation will 
also be masked to the original treatment group assignment.  
4.3 Study Measures  
 
The battery of evaluations will require approximately two days. Careful coordination will 
ensure that evaluations are completed efficiently, effectively, and safely.  
 
4.3.1 Measures Related to Primary Aim  
 
4.3.1.a  Cardiac Magnetic Resonance Imaging (CMR) 
CMR will be performed in all participants without pacemakers or other contraindications. 
Sedation or anesthesia will not be used for CMR scans performed solely for this research study. 
To maximize subject participation, a focused, basic CMR protocol will be performed to 
assess ventricular morphology and systolic function, with an estimated study length of 10-15 
minutes. An expanded research CMR protocol to assess Fontan and collateral flows, systemic 
arterial anatomy, and Fontan pathways, including pulmonary artery and pulmonary vein size, 
will be performed when possible in subjects able to comply with an additional 45 minutes of 
scan time.  All CMR studies will be performed on 1.5 T magnets that are available at all sites 
and will be performed in a free breathing state without anesthesia or intravenous access.  To 
ensure that all measures are performed consistently, and to enhance the precision of study 
results, CMR images will be analyzed at the CMR core lab.  

 
 
 
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We have chosen to use CMR as the primary measure of RVEF for this study. CMR is a 
better, more reproducible method of measuring RVEF than 2D or even 3D echo.41 Lai and 
colleagues found that 2D echo measurement of RVEF is particularly limited in the face of a 
dilated right ventricle, a common finding for patients with HLHS.42 Comparison of 2D echo to 
CMR as part of the Fontan Cross Sectional Study demonstrated that CMR is accurate and more 
reproducible for measurement of RV volume, mass, and ejection fraction.43 Lower inter-observer 
variability of measures performed using CMR result in improved power/smaller sample size 
needs.43 One potential limitation of CMR in this population is its incompatibility with electronic 
pacemakers. In the Fontan Cross-Sectional cohort, the incidence of pacemakers was 13% at 
the time of the initial study and overall 9% in those with a systemic RV.44   The prevalence of 
pacemakers increases with age; in the Fontan Cross Sectional study 7-8% of the those 10-11 
years of age had undergone pacemaker placement.44   We anticipate therefore, that at 11 years 
of age, no more than 5-10% of the SVR cohort will have pacemakers. 
Of note, if a clinical CMR was performed within the study window using the study protocol, 
these data will be acceptable for submission to the CMR core lab. If a clinical study has 
required sedation or anesthesia but otherwise is consistent with the study protocol, then the 
technique will be noted but the data may still be submitted to the core lab.    
The battery of CMR measures will include: 
1. Evaluation of ventricular morphology and systolic function (all participants):  
• 
RVEF=(RVEDV-RVESV)/RVEDV 
• 
Right ventricular end-diastolic volume (RVEDV) and RVEDVi (RVEDV 
indexed to BSA) 
• 
RV end-diastolic mass and end-diastolic mass indexed to BSA 
• 
Right ventricular end-systolic volume (RVESV) and RVESVi (RVESV 
indexed to BSA) 
 
2. Evaluation of Fontan flows and collaterals by phase contrast imaging:  
• 
Cardiac output based on inferior vena cava (IVC) and superior vena cava 
(SVC) flows 
• 
Comparison of right versus left lung perfusion through pulmonary artery 
and pulmonary vein flow measurements,  
• 
Degree of neo-aortic regurgitation 
• 
Tricuspid regurgitation measured by comparison of TV inflow or right 
ventricular stroke volume with neo-ascending aorta flow  
• 
Aorto-pulmonary collateral flow percents: [neo-ascending aorta-(SVC 
+IVC)]/neo-ascending aorta 
• 
Fenestration shunt: (SVC+IVC)-(LPA+RPA)/(SVC+IVC) 
3. Assessment of systemic arteries (using 3 D Steady State Free Precession (SSFP) 
navigator-gated   imaging) 
• 
Neo-aortic arch orthogonal dimensions 
• 
Descending aortic orthogonal dimensions 
4. Assessment of Fontan pathways (using 3D SSFP navigator-gated imaging) 
• 
Right pulmonary artery (RPA) diameter and area 
• 
Left pulmonary artery (LPA) diameter and area 
• 
Pulmonary vein assessment (qualitative evaluation for stenosis)  
  
4.3.1.b Two Dimensional Echo  

 
 
 
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Two-dimensional echocardiograms will be performed on each participant. It is anticipated 
that all study participants will undergo an echocardiogram within the study window. All images 
will be sent to the Echo Core Lab, where detailed measures will be performed. Measures of RV 
systolic, diastolic, and global function will be performed. In addition, measures of anatomy (e.g., 
neo-aortic root diameter) and measures of physiology affecting RV function (e.g., degree of neo-
aortic insufficiency) will be assessed.  Subjects will not be sedated for echocardiograms 
performed solely for research.  In the event that an echo was performed clinically within the 
study window, these data will be included as long as the clinical echo adhered to the echo study 
protocol.  
While the primary outcome measure for the proposed study is RVEF measured by CMR, 
some eligible subjects will not be able to undergo CMR because they have pacemakers or 
cannot cooperate with even the basic CMR protocol. The inclusion of echo measurements as 
secondary outcomes allows the cardiac function related outcomes to be measured in a greater 
percentage of the SVR cohort. The inclusion of echo measurements will allow for important 
comparison of echo to CMR measurements in those participants who do undergo both 
assessments. While the ideal study window is 2 years, 11 years +/- 1 year, we will aim for the 
CMR and echo to be performed within 6 months of each other.  If a cardiac procedure that could 
affect the correlation between these two imaging studies is performed between the two tests 
(e.g., a pacemaker is placed after CMR but before echo), or if the CMR and echo are performed 
more than 6 months apart, we will eliminate that subject from analyses that compare results of 
these two test modalities.  
The battery of echo measures will include:  
1. 
Measures of RV systolic function 
• 
RVEF (by modified Simpson’s method) 
• 
RVEDV 
• 
RVESV 
• 
RV percent area change 
• 
RV change in pressure/change in time 
• 
Doppler Tissue Imaging (DTI) peak annular systolic velocity 
• 
Tricuspid annular peak systolic excursion 
• 
Peak longitudinal regional and global systolic strain and strain rate 
• 
Peak circumferential regional and global systolic strain and strain rate 
2. 
 Measures of RV diastolic function 
• 
Tricuspid inflow (peak E velocity, peak A velocity and E/A ratio) 
• 
Annular DTI (e’ velocity, a’ velocity, E/e’ ratio) 
• 
Presence and duration of pulmonary vein reversal  
3. Global function indices 
• 
Systolic/diastolic time ratio from tricuspid regurgitant jet 
• 
Myocardial Performance Index (Tei index) 
4. Anatomic measures 
• 
RVEDV, RVESV, Right ventricular end-diastolic (RVED) area, Right 
ventricular end-systolic (RVES) area 
• 
RV shape eccentricity index 
• 
Neo-aortic indexed annular area 
• 
Neo-aortic root diameter 
• 
Ascending aortic diameter 
• 
Tricuspid indexed annular area 

 
 
 
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5. Physiologic measures 
• 
Degree of tricuspid regurgitation (TR) (regurgitant orifice area, largest 
vena contracta diameter, qualitative assessment) 
• 
Degree of neoaortic regurgitation (regurgitant orifice area, largest vena 
contracta diameter, qualitative assessment) 
• 
Neo-aortic peak distal arch gradient 
• 
Dyssynchrony (defined as standard deviation of time to peak longitudinal 
regional strain, and standard deviation of time to peak circumferential 
regional strain) 
 
4.3.2  Measures Related to Secondary Aims 
 
4.3.2.a  Annual Vital Status and Medical History 
Through the SVR II study, families have been contacted to assess vital status and interim 
medical history. This process will be continued through the duration of the SVR III study. 
Through annual contact with families (e.g., at the time of in-person hospital visits, via telephone 
or email), vital status will be assessed and medical history including need for cardiac 
transplantation, need for other surgical procedures or development of a new diagnosis such as 
stroke, protein losing enteropathy or arrhythmia (atrial or ventricular), will be assessed. Medical 
records will be obtained from the primary cardiologists to verify medical history.  Of note, we will 
assess vital status for all consenting survivors of the SVR study. 
While medical record review and contact with families will serve as the primary means to 
measure vital status, searches of publicly available death indexes will be performed for all 
participants who are lost to follow-up. Prior to completion of any of the study evaluations, a 
medical history will be performed by the study coordinator using a semi-structured interview and 
standardized data forms. Parents/guardians will be queried related to the interim history since 
their last SVR/SVR II assessment. Questions will include any additional cardiac operations or 
interventions (including pacemaker placement), any interim cerebral vascular events, seizures, 
and diagnosis of atrial or ventricular arrhythmias (See section 4.3.2.c).  
An additional touchpoint will occur in 2024-2025 to identify vital status for all eligible to 
participate; all SVR survivors will be contacted to identify vital status, current contact information 
and location of current medical care. Information related to planning for longer term follow-up 
will be shared with the patient and family who will also be queried about potential questions they 
would like answered through further study. Information related to the conversation will be kept at 
the study center. Information related to vital status will be shared with the DCC. For any 
participant over the age of 18 years, if appropriate and required by the local IRB, consent for 
this portion of SVR III will be requested. 
 
4.3.2.b. Exercise Testing  
Cardiopulmonary exercise testing will be performed with a standard ramp cycle ergometry 
protocol.45,46  Inclusion in this portion of the study will require participants be able to comfortably 
reach the pedals enough to effectively pedal the cycle ergometer”. This typically, but not always 
correlates with a height of >/=130 cm. 
Electrocardiographic monitoring and breathing by using expiratory gas analysis will be 
performed throughout the exercise test. Heart rate, blood pressure and oxygen saturation will be 
monitored continuously. Baseline inspiratory and expiratory flow volume loops will be 
performed. Subjects will then perform hyperventilation for 10 seconds (3 times for 
reproducibility) to measure maximal voluntary ventilation. Participants will then pedal in an 
unloaded state for 3 minutes. Workload will then be increased continuously with exercise watts 
ramped to achieve each predicted maximal work rate in watts after 10 to 12 minutes of cycling. 

 
 
 
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All subjects will be encouraged to exercise to exhaustion. This method is safe and allows for 
adjustment of work rate to optimize performance potential for each individual within 10-12 
minutes. VO2 max will be defined as the highest VO2 achieved by the subject during the exercise 
stress test. Maximal aerobic effort will be defined as a peak respiratory exchange ratio 
(VCO2/VO2) of ≥ 1.10. VO2 max will be indexed to body weight and expressed as a predicted 
value for healthy age/gender matched subjects per Cooper and Weiller–Ravell.47  
In addition to VO2 max, oxygen pulse (maximum VO2/peak heart rate), and ventilator 
aerobic threshold (VAT) determined by V-slope method and confirmed by the dual criteria 
measurements of the ventilatory equivalents of CO2 and O2 (VE/ VCO2 and VE/ VO2), will be 
measured/calculated. The battery of exercise measures will include:  
1. Maximal work rate: expressed in Watts 
• 
The maximal work rate reached during exercise test 
2. Oxygen consumption (VO2): expressed in ml/kg/min 
• 
Resting 
• 
Maximal –defined as highest oxygen consumption achieved during the 
exercise test when averaged over 10 second intervals 
3. VAT will be measured by V slope method and confirmed with ventilator equivalent 
method 
• 
VO2 at VAT 
• 
Percent of achieved maximal oxygen consumption (VO2 at VAT/ max VO2) x 
100 
4. Oxygen Pulse measured at rest, VAT and Max VO2 
5. Pulse Oximetry measured at rest, VAT and maximal exercise 
6. Heart Rate measured at rest, VAT and maximal exercise 
7. Blood Pressure measured at rest and maximal exercise 
8. Minute Ventilation measured at rest, VAT and maximal exercise 
9. Tidal Volume measured at rest, VAT and maximal exercise 
10. Respiratory Rate measured at rest, VAT and maximal exercise 
11. Ventilator Equivalents of Carbon Dioxide (VE/VCO2) measured at rest, VAT, and 
maximal exercise 
 
If a ramped cycle exercise test has been performed for clinical reasons within the study 
window, these data will be included if the exercise test protocol was performed using the SVR III 
exercise test protocol.  
 
4.3.2.c. Incidence of Atrial and Ventricular Arrhythmias  
Medical record review and semi-structured interviews, will be employed to determine the 
percent of participants with atrial and with ventricular tachyarrhythmias.  
Participants will be categorized as having had an atrial tachyarrhythmia if they have a 
history of IART or SVT documented by any type of electrocardiographic recording, have 
required treatment with an antiarrhythmic, or have required cardioversion at any time for an 
atrial tachyarrhythmia.  
Participants will be considered to have had a ventricular arrhythmia if >5 beat run of 
ventricular tachycardia has been recorded, if the participant has been treated with an 

 
 
 
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antiarrhythmic for a ventricular arrhythmia, or if a pacemaker or defibrillator has been placed 
secondary to a ventricular arrhythmia.  
 
4.3.2.d. Neurodevelopmental and Quality of Life Evaluation  
Neurodevelopmental assessment will be performed by a licensed psychologist or 
supervised psychometrician at each site.  Multiple areas will be assessed including intellectual 
functioning, academic (reading and math) functioning, language, memory, attention/executive 
functioning, visual spatial, fine motor, social functioning, adaptive skills, emotional/behavioral 
functioning, and quality of life. A sub-group of instruments included in the battery are based on 
parent and/or teacher report, including the Behavior Rating Inventory of Executive Function 48 
(BRIEF), the Behavioral Assessment System for Children, 2nd Edition (BASC- 2),49 the Connors 
3rd Edition Rating Scale, ADHD Index (Conners 3),50 the Adaptive Behavior Rating Scale – 3rd 
Edition (ABAS-3), 51 the Autism Spectrum Rating Scale (ASRS), 52 and the Peds QL (generic 
and cardiac modules).53  These will be completed by a parent either before or during the child’s 
evaluation (see details of Consent /Assent Process within Section 5.5  for informed consent 
procedures related to completion of questionnaires before the in-person evaluation). Teacher 
report instruments will be mailed to the study site either prior to or following the in-person 
evaluation.  The in-person battery will begin in the morning and will require approximately 5 
hours. Breaks will be provided for snacks/lunch as appropriate for the participant. Parents will 
be given a summary of their child’s test results that will be scored based on age-based norms. 
ND evaluations will need to occur at least 6 weeks after any hospitalization. The psychologist 
and/or his designate at each site will be blinded to the shunt type at the time of the Norwood 
operation. The full battery (Table 1) will be extremely valuable to facilitate understanding of long 
term outcomes; in addition, all measured outcomes will be compared between shunt groups to 
discern any potential effect of shunt type on ND outcomes. 
 
 

 
 
 
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Table 1: Neurodevelopment Battery 
Area 
Specific Instruments 
In-Person 
Testing Time 
Parent/ 
Teacher Time 
Intelligence 
Wechsler Intelligence Scale for 
Children-V 
65-80 min 
 
Math  
Wechsler Individual Achievement III 
Tests- 
Math Problem Solving 
Numerical Operations 
15 min 
15 min 
15 min 
 
Reading  
Wechsler Individual Achievement III 
Word Reading 
Reading Comprehension 
Pseudoword Decoding 
6 min 
20 min 
6 min 
Language Function 
NEPSY-II  
   Comprehension of Instructions 
Oromotor Sequence  
8 min 
5 min 
Executive Function 
Delis-Kaplan Executive Function 
System Verbal fluency 
Tower 
Trail Making 
BRIEF-Parent Report 
BRIEF-Teacher Report 
 
10 min 
10 min 
15 min 
 
 
 
 
 
15 min 
15 min 
Visual Spatial Skill 
Developmental Test of Visual-
Motor Integration-6 (VMI-6) and  
Visual perception  
5 min 
3 min 
Motor Function 
Lafayette Grooved Pegboard 
5 min 
 
Memory 
Wide Range Assessment of Memory and Learning 
45 min 
 
Social Skills 
NEPSY II Theory of Mind and Affect 
Recognition 
Autism Spectrum Rating Scale Parent Report 
 
11 min 
 
 
 
7 min 
Behavior Evaluation 
ADHD specific measure 
BASC-2  Parent Report 
BASC-2 Teacher Report 
Conners 3rd Edition ADHD Index Parent Forms 
Conners 3rd Edition ADHD Index Teacher Forms 
 
20 min 
20 min 
8 min 
8 min 
Quality of Life 
PedsQL Parent and self report, generic 
and cardiac modules. 
 
15 min 
Adaptive Function  
ABAS-3 Parent Report 
 
20 min 
 
Instruments in bold text are parent and teacher completed instruments and thus will not contribute to the time the 
participant needs to work directly with the psychometrician/psychologist. 
In person evaluation-approximately 4.5 hours; parent forms 1.5 hours (85 minutes); teacher forms 0.75 hours (43 
minutes). 
 
Of note, based on current AHA/AAP guidelines for neurodevelopmental testing in children 
with congenital heart disease, it is possible that participants will have undergone a clinical ND 
assessment within the study window.  Repetition of the same ND test administered twice within 
6 months can affect the score of the second test.  For this reason, scores from tests that overlap 
with our research battery will be incorporated into the research database if the research 
evaluation takes place within 6 months of the clinical testing.  In this circumstance, we will 
complete the SVR III ND research battery by performing only those research ND tests that were 

 
 
 
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not done as clinical testing.  If more than 6 months has elapsed between clinical and research 
testing, we will perform the entire research battery, including tests that had been administered 
earlier for clinical purposes.   
A certification process for team members performing the neurodevelopmental battery will 
include review by the neurodevelopmental consultants of a recording of the team member 
performing the testing battery on a patient or volunteer of a similar age to the study participants.  
 
4.3.2.e Biorepository 
Participants and their parents who have not yet contributed to the SVR Extension 
biorepository will be offered the opportunity to provide saliva for extraction and storage of DNA. 
If study participants have consented to participate in the biorepository through the SVR 
Extension study but not yet contributed a sample, they will be asked to contribute at the time of 
the SVR III participation. Families who were not previously approached, or who declined 
participation in the biorepository earlier, may be offered the opportunity to participate at the time 
of the SVR III participation.  
 
4.3.3. Covariate Measures 
The unique nature of this large inception cohort presents the opportunity to examine events 
that commonly occur in this population as both risks and outcomes.  To that end, a number of 
events will be collected as covariate measures. Covariates that are available from the SVR trial, 
SVR II and annual visit forms include: 
SVR and SVR II:   
• 
Pre-Stage I: prenatal diagnosis, genetic syndrome, socioeconomic status, birth 
weight/gestational age, occurrence of neonatal shock.   
• 
Stage I hospitalization: mechanical ventilation time, cardiopulmonary bypass and 
deep hypothermic circulatory arrest/regional cerebral perfusion times, 
ICU/hospital length of stay, delayed sternal closure, use of extracorporeal 
membrane oxygenation (ECMO), unplanned surgical/catheter interventions.   
• 
Interstage, post stage II and post stage III: unplanned surgical/catheter 
interventions, cardiac arrest, ECMO.   
• 
Stage II/Stage III: mechanical ventilation time, cardiopulmonary bypass and deep 
hypothermic circulatory arrest/regional cerebral perfusion times, ICU/hospital 
length of stay, delayed sternal closure, use ECMO, and unplanned 
surgical/catheter interventions. 
 
Medical history data:  
• 
Treatment with heart failure medications, (angiotensin converting enzyme 
inhibitors, angiotensin receptor blockers, beta-blockers), treatment for pulmonary 
hypertension, use of anticoagulants.   
• 
New diagnoses: stroke, plastic bronchitis and protein losing enteropathy will be 
recorded.  
• 
Weight and height will be measured at the time of the CMR and/or the exercise 
test. 
 
Procedural history data:   
• 
Unanticipated interventions: catheterization or surgery, (pacemaker implantation, 
stent implantation, Fontan revision, etc.), use of mechanical circulatory support, 
and lack of Fontan completion will be noted. 
 

 
 
 
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Socioeconomic (SES) data from the SVR and SVR II studies will be included as possible 
covariates in models for survival and ND outcomes.  Educational status of the child, family 
structure, and language spoken in the home will be collected.  In addition, maternal education 
level and current address information to determine census block variables such as percent 
within the census block living below the poverty level, will be collected at the time of ND 
evaluation to allow us to determine and adjust for the contribution of these factors to survival 
and ND outcomes at 11 years of age.   
 
4.3.4. Schedule of Measurements 
Table 2 
Measurement 
11 ± 1 
years* 
Annually to 16 years 
One time visit after 
turning 16 years 
Vital Status/Medical History 
including incidence of rhythm 
abnormalities 
 
X 
X 
 
CMR 
X 
 
 
 
Echo  
 
X 
 
 
Ramped Cycle Exercise Test 
 
X 
 
 
ND Battery  
 
X 
 
 
Biorepository Sample 
 
 X** 
 
 
Vital status  
 
 
X 
** or at study enrollment if >12 years at enrollment 
* Included only if no prior adequate sample  
 
 
4.4 Study Visits 
All measures specifically performed for the SVR III protocol will be performed at study 
enrollment, ideally within a 2 year window defined by 11 years of age ± 1 year; however 
subjects can be enrolled at any time there is interest in participation up until September 30, 
2020. As described above, the optimal window for the CMR and echo is within six months of 
one another, and comparison of these measures will only be performed if there has been no 
intervening cardiac operation or interventional catheterization. For those subjects who choose to 
complete the in-person evaluations within two consecutive days, Figure 1 demonstrates a 
reasonable schedule for accomplishing this.  
 
Figure 1: Preferred Schedule of In-Person Evaluations 
 
 
8A 
9A 
10A 
11A 
12P 
1P 
2P 
3P 
4P 
Day 1 
Cardiac MRI           Exercise Test       Lunch                               Echo 
Day 2       ND Battery                                          Lunch               ND Battery cont.  
 
Vital status and medical history will be performed annually beginning at age 10 years and 
through the conclusion of the study. The oldest participants will be 16 years of age at the time 
that the youngest participants reach the conclusion of the study window.  An additional visit will 

 
 
 
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occur in 2024-2025 to identify vital status for all eligible to participate; all SVR survivors will be 
contacted to identify vital status, current contact information, location of current medical care, 
and potential questions they would like answered through further study.  
 
4.5 Repeat Study Evaluations 
If any of the evaluations are deemed incomplete either at the clinical site if the relevant 
imaging core lab assesses and finds that the images are inadequate, the evaluation may be 
repeated by the site if the patient, family and site personnel all agree to repeat the assessment.  
 
5. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
5.1 Subject Inclusion: 
 
All SVR study cohort members will be contacted to assess for vital status. Transplant free 
survivors will be approached to participate in the in-person assessment.   
 
5.2 Subject Exclusion:  
We will exclude patients who have undergone cardiac transplantation or biventricular 
conversion from all outcomes other than vital status. Those with pacemakers will be excluded 
from the CMR, and patients unable to comfortably reach the exercise bike pedals enough to 
effectively pedal the cycle ergometer will be excluded from the exercise test. 
 
5.3 Subject Withdrawal Criteria 
Subjects may withdraw from the study at any time if: 
• 
Subject, parent, or legal guardian declines further participation. 
• 
The investigator or physician judges that it is in the subject’s best interest to withdraw 
from the study.  
If the subject refuses to continue with the study visits, every attempt should be made to 
continue contact by telephone, written communication, or record review of vital status and 
medical history outcomes unless the subject specifically refuses such follow-up.  
 
5.4 Subject Availability 
Through the SVR and SVR II studies vital status has been collected annually for the entire 
SVR cohort. As of June 2014, 352 subjects were alive, 18 had undergone cardiac 
transplantation, and 3 had undergone biventricular conversion, leaving 331 transplant-free 
survivors with single ventricle physiology. Conservatively assuming only 80% retention of this 
cohort secondary to additional mortality, transplantation or loss to follow-up, we anticipate at 
least 264 participants will be available for this study to participate in the proposed protocol.  
5.5 Recruitment/Enrollment Procedures 
The ideal study window will extend from 10 to 12 years of age for each participant (11 years 
± 1 year), but subjects can be enrolled at any time there is interest in participation up until 
September 30, 2020. The Principal Investigator (PI) at each site, his or her designees, and the 
study coordinator will be responsible for subject recruitment. Parents/guardians of participants 
will be contacted by the team up to 6 months prior to the opening of the study window to 
introduce families to the study and to coordinate participation in all relevant portions.  

 
 
 
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Consents for the SVR and SVR II studies include ongoing permission to contact the families 
up to patient age 11 years. A letter will be mailed out to the families of eligible participants briefly 
describing the SVR III study. After approximately 2 weeks, we will telephone or email potential 
participants to discuss the study and address questions. The consent document will be mailed 
out to each family who has expressed interest in SVR III participation and the information will be 
reviewed subsequently by phone by the site PI and /or the research coordinator. Subjects may 
also be contacted in person at the time of a clinic visit at the study center. Data on all screened 
subjects will be entered into the screening log.  
Initial consent, enough to schedule the evaluations, will be granted by interested families 
over the phone or in-person if contacted through the clinic.  Neurodevelopmental questionnaires 
can be completed in advance of the study visit based upon this initial phone consent. If an in-
person signature is required prior to completion of parent and /or teacher questionnaires by a 
site, then these questionnaires can be completed at or after the in-person evaluation.  The 
written consent and assent documents will be reviewed in person with the parent/guardian and 
patient by the site PI/study coordinator and will be signed in person. If the interested subject/ 
families are interested in remote participation only, consent will take place over the phone or 
virtually depending on the sites approved procedures. 
 
Figure 2: Approach to Consent and Study Retention 
 
 
 
 
 
 
 
 
Contact eligible SVR subjects/families 
for vital status and SVR III study 
participation. Can make contact starting 
at patient age 9.5 years   
Vital Status and Medical History  
If not eligible for in-person evaluation, 
consent for annual follow-up will be 
obtained/renewed  
Written informed consent /assent documented 
Phone/ Virtual informed consent/ assent 
In-Person evaluations 
ND evaluation, echo  
ramped cycle exercise test, CMR  
Annual Contact  
All participants through study completion 
to obtain vital status and medical history  
Schedule in-person evaluations for 
interested participants 
Send questionnaires if allowed with 
phone consent 
Remote participation 
ND evaluation/ questionnaires   

 
 
 
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Details of the Consent/Assent Process: 
 
The consent process may vary slightly depending on the specific site. In general, we anticipate a 
multistep process: 
1) A letter will be mailed to each survivor of the SVR cohort to briefly describe the SVR III 
study and plans for contact.  
2) After two weeks, the family will be contacted via telephone or email to address questions 
and assess general interest in SVR III.  
3) If the participant has undergone a transplant, consent will be mailed to renew the plans 
for annual follow-up for vital status. 
4) If the participant is eligible and interested for the in-person SVR III study, appointments 
will be scheduled for the in-person evaluation in accordance with the needs of the family, 
and dependent on the institutions guidelines for in-person visits based on the COVID-19 
pandemic.  
5) If the participant is eligible and interested in remote participation in SVR III study, phone/ 
virtual consent and discussion on what study events to be done remotely (ND 
Questionnaires, annual follow-up for vital status) will be held. 
6) All questions from the parent/guardian and participant related to study participation will be 
thoroughly addressed by the site PI, his or her designees, and/or the study coordinator 
prior to signing and documentation of the informed consent/assent documents. 
7) All signatures and dates will be accurately documented. Any errors will be noted in a note 
or memo. If mistakes have occurred re-consent/ re-assent may be performed if necessary. 
8) Neurodevelopmental questionnaires can be completed before the actual visit and 
delivered to the study team at the time of the in-person evaluation based on phone 
consent.  They can also be completed at or after the time of the in-person visit and mailed 
to the study team. 
 
6. SAFETY ASSESSMENTS AND MONITORING 
 
6.1 Specification of Safety Parameters 
All individuals eligible for participation have single ventricle physiology and are recognized 
to be at risk for exercise intolerance, declining ventricular function, and arrhythmias. The small 
increased risk to study participation is described in detail in Section 11.  Any complication during 
a study evaluation or change in function occurring within 24 hours of a study evaluation, will be 
considered an adverse event and reported as described below.   
6.2 Recording and Reporting Adverse Events 
 
This study is not an intervention study. However, a major component of safety monitoring is 
ascertainment and reporting of adverse events (AE), including adverse reactions to study 
procedures. The approach to these activities for this study is summarized in the sections that 
follow.  
 
6.2.1 Definitions of Adverse Event, Suspected Adverse Reaction and Adverse Reaction  
 
For the purposes of this study, adverse events will include any untoward event that occurs 
to the child participant during or within 24 hours of any study-related evaluation including the 
CMR, echo, ramped cycle exercise test or battery of neurodevelopmental assessments.   
 
 

 
 
 
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6.2.2. Classification of Adverse Events 
 
Monitoring AEs requires that they be classified as to seriousness, 
expectedness, and potential relationship to the study, of which drive the reporting 
process. 
 
a. Seriousness  
A serious adverse event (SAE) is one that: 
• 
Results in death, 
• 
Is life-threatening (the subject was, in the view of the PI, in immediate danger of death 
from the event as it occurred), 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization,  
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
Is an important medical event that may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the serious adverse event outcomes. 
 
The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 MedDRA 12.1 
(http://ctep.cancer.gov) provides a grading system that is used to categorize the severity of 
adverse events, as follows: 
Grade 1 Mild 
transient, requires no special treatment or intervention,  
does not interfere with daily activities 
Grade 2 Moderate 
alleviated with simple treatments, may limit daily  
activities 
Grade 3 Severe 
requires therapeutic intervention and interrupts daily  
activities 
Grade 4 Life-threatening 
Or disabling 
 
Grade 5 Death 
 
 
A SAE, as defined above, encompasses CTCAE grades 4 and 5, and any Grade 3 event 
that requires or prolongs hospitalization, or that substantially disrupts the ability of the subject to 
conduct normal life functions.   
 
b. Expectedness  
The purpose of reporting is to provide new, important information on serious reactions or 
events previously unobserved or undocumented.  Therefore, all AEs will be evaluated as to 
whether their occurrence was unexpected, using the following definitions:  
• 
Unexpected:  An unexpected AE or adverse reaction is one for which the nature or 
severity is not consistent with information in the protocol, or consent form.  An AE or 
adverse reaction also may be categorized as unexpected if the event has not previously 
been observed at the same specificity and/or severity.    
• 
Expected:  An event is considered expected if it is known to be associated with the 
particular evaluation. Expected adverse events could include 1) falling from the bicycle 
exercise test, 2) developing an arrhythmia during exercise testing, 3) anxiety during the 
CMR, and 4) frustration at the time of the neurodevelopmental testing.      
 
c. Causality 
Causality assessment is required to determine which events require expedited reporting. The 
following criteria will be used to determine causality: 

 
 
 
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• 
Not Related:  The event is clearly related to other factors, such as the subject’s clinical 
state, or non-study drugs or interventions. 
• 
Possibly Related:  The event follows a compatible temporal sequence from the time of 
study evaluation, but could have been produced by other factors such as the subject’s 
clinical state or non-study drugs or interventions. 
• 
Probably Related:  The event follows a reasonable temporal sequence from the time of 
study evaluation, and cannot be reasonably explained by other factors such as the 
subject’s clinical state, or non-study drugs or interventions. 
 
6.2.3. Identification and Data Collection Procedures 
 
AEs that are not considered adverse reactions or suspected adverse reactions will be 
identified when they are reported to the clinical center or during scheduled study visits by study 
coordinators and investigators. AEs will be assessed using self-report, physical examination 
data, and medical record review.  
 
6.2.4. Reporting Procedures (Table 3) 
 
Fatal or life-threatening AEs are to be reported to the Data Coordinating Center (DCC) 
within 24-hours of first knowledge of the event.  Those that are unexpected and considered 
possibly, probably, or definitely related to the study will be reported by the DCC to the Data 
Safety and Monitoring Board (DSMB) Chair, the Medical Monitor (MM), the National Heart, 
Lung, and Blood Institute (NHLBI), and all study Investigators as soon as possible, but no later 
than 7 calendar days after first knowledge of the event, followed by a complete report within 15 
calendar days.  All other fatal or life threatening events that are unrelated to the study will be 
reported semiannually to the DSMB and the NHLBI. 
All other SAEs (i.e., non-fatal or not life-threatening) that are unexpected and considered 
possibly, probably, or definitely related to the study will be reported to the DCC within 24-hours 
of learning of the event.  The DCC will report the event to the NHLBI, DSMB and all study 
Investigators within 15 calendar days after first knowledge of the event.   
All other AEs not meeting the criteria for expedited reporting will be reported to the DCC 
within 7 calendar days of first knowledge of the event.  The DCC will report these AEs quarterly 
to NHLBI. 
Table 3.   Reporting of Adverse Events 
Seriousness 
Reporting Timeframe 
Fatal or life threatening 
Within 24-hours of learning of the event 
Serious, but not fatal or life 
threatening, and pregnancy 
Within 24-hours of learning of the event 
All other 
Within 7 calendar days of learning of the event 
 
 
6.2.5. Reporting Adverse Events to Institutional Review Boards (IRB) for National 
Institutes of Health (NIH)-Supported Multi-Center Clinical Trials 
 
The site Investigator or designee is responsible for reporting all serious adverse events to 
the local IRB in accordance with local policies and procedures.  
 

 
 
 
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6.2.6. Follow-up of Subjects after Adverse Events 
 
For AEs with a causal relationship to the study conduct, follow-up by the PI is required until 
the event or its sequelae resolve or stabilize at a level acceptable to the PI. 
 
6.3 Safety Monitoring 
 
The Data and Safety Monitoring Plan for this trial will follow standard PHN monitoring 
principles.  Oversight of data and safety is provided by the PHN DSMB, appointed by NHLBI.  
The DSMB meets at least twice a year to review data on AEs, adverse reactions, suspected 
adverse reactions, patient-reported outcomes, data quality, and study recruitment at regular 
intervals, and makes recommendations about study conduct to the Director, NHLBI.   
The DSMB and NHLBI are assisted by a MM in reviewing serious adverse events in PHN 
studies.  The PHN MM is the NHLBI’s designee for determining causality and expectedness of 
all SAEs.   
 
7. STATISTICS 
 
7.1 Analysis Plan  
The surviving participants and non-participants will be compared to assess 
representativeness of the SVR III cohort. The primary comparison of outcomes between shunt 
types will be performed according to the intention-to-treat principle. Secondary analyses of each 
aim will be performed using non-intention to treat, defined as the shunt in place at the end of the 
Norwood operation.  
 
7.1.1. Analysis of the Primary outcome for Primary Aim: To compare cardiac function at 
11 years of age between subjects randomized to receive either of a RVPAS vs. a MBTS at 
the time of the Norwood operation 
 
RVEF as measured by CMR is the primary outcome for this study. Descriptive statistics will 
be presented across all patients and by randomized shunt type.  Distribution of the RVEF will be 
examined with histogram and compared by shunt type with either a Student’s t-test or a 
Wilcoxon rank sum test as appropriate. If the distribution of RVEF is found to be skewed or 
otherwise non-normal, non-parametric tools will be used or RVEF will be transformed 
appropriately to obtain a close to normal distribution.  
 
7.1.2. Analyses of Secondary Outcomes 
 
7.1.2.a  Additional Measures of the Primary Aim 
For all additional CMR and echo measures related to Aim 1, the distribution of each 
measure will be assessed. Continuous measures will be compared between randomized shunt 
types with either a Student’s t-test or a Wilcoxon rank sum test as appropriate. Categorical 
measures will be compared with a Fisher exact test, Chi-square test or the Mantel-Haenszel test 
for trend.     
In addition, subjects with CMR and echo performed within a 6 month window without an 
intervening cardiac procedure will be selected to assess the agreement between the two 
techniques. The continuous measures will be compared using Bland-Altman limits of agreement 
and Pearson’s correlation coefficient. The Kappa statistic will be used to evaluate the 
agreement in the categorical measures in Echo and CMR.   
 

 
 
 
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7.1.2.b Secondary Aim 1: To compare the long-term death/transplant rates of subjects 
randomized to receive either a RVPAS vs a MBTS 
Transplant-free survival rate will be calculated using the Kaplan-Meier method. The logrank 
test will be performed to determine if time since randomization to the composite endpoint of 
death or transplantation is different between the two shunt types. Cox proportional hazard 
regression will be used to model the time to death or transplant by shunt type; to determine if 
the shunt difference varies by time and to identify risk factors of the endpoint.  
In addition, nonparametric competing-risks methodology will be used to estimate the cumulative 
incidence rate of death and transplant. Proportional subdistribution hazards model will be fit to 
assess the effect of covariate on death and transplant in a competing risk setting. 
 
7.1.2.c Secondary Aim 2: To compare exercise tolerance between those randomized to 
receive a RVPAS vs a MBTS 
 VO2 max, work rate VAT and items 4-11 from section 4.3.2.b, from ramped cycle ergometry 
will be compared between the two shunt groups. The distribution of the variable will be 
determined with descriptive statistics. If the variable is normally distributed, Student’s t-test will 
be used to compare shunt groups. If non-parametric, then Wilcoxon Rank-Sum will be used.  
 
7.1.2.d Secondary Aim 3: To compare the incidence of atrial and ventricular arrhythmias 
between those randomized to receive a RVPAS vs a MBTS at the time of the Norwood 
operation 
Arrhythmias will be classified as atrial tachyarrhythmias or ventricular tachyarrhythmias. 
The rate of atrial and of ventricular tachyarrhythmias will be compared between the shunt 
groups with the Fisher exact test.  
 
7.1.2.e Secondary Aim 4: To compare neurodevelopmental outcomes at 11 years of age 
in subjects randomized to a RVPAS vs MBTS 
Descriptive statistics will be performed for each scale included in the ND battery. Student’s 
t-test will be used to compare normally distributed measures, Wilcoxon Rank-Sum for non-
parametric continuous measures and Fisher exact test for all dichotomous measures. 
Adjustment will be included for measures of socioeconomic status.  
 
7.1.2.f Secondary Aim 5: To determine if early perioperative events other than type of 
systemic to pulmonary artery shunt are related to long-term outcomes 
 To determine if early events after the Norwood operation are related to long-term 
outcomes, comprehensive models will be explored for each of the primary outcome measures 
for each aim (RVEF by CMR, transplant-free survival at 11 years, VO2 max at ramped cycle 
ergometry, incident atrial tachyarrhythmias, incident ventricular tachyarrhythmias, Wechsler full 
scale IQ, and Language and Math Achievement Tests). Candidate predictors for these models 
will include previously collected early events and additional medical and surgical variables since 
the last SVR/SVR II contact. 
 
7.2 Number of Subjects to be Enrolled 
 
The proposed study is a prospective observational design of a previously determined, fixed 
cohort. Out of the 549 subjects randomized in the original SVR trial, 334 subjects are currently 
alive, free from heart transplant and 331 have single ventricle physiology. Study sample size will 
depend on the ability to contact families and on the consent rate for contacted subjects. 
Conservatively assuming 80% retention of this cohort (N=265) and 10% excluded from the 
primary measure of RVEF by CMR, either because CMR is not possible due to a pacemaker or 
because CMR data are not obtainable without general anesthesia or sedation, we anticipate the 

 
 
 
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primary outcome will be collected and adequate for 239 participants. If there is 90% retention 
and 10% without CMR, the primary outcome will be obtained in 269 participants. 
 
7.3 Level of Significance 
 
We anticipate that by 11 years of age the overall rate of transplant free survival will be 
approximately even between the two shunt groups. However, if even 60% of survivors are from 
one shunt group, with 239 total eligible participants there is 85.5% power to detect a 4% 
absolute difference in RVEF between the two groups (Table 4). If total N=269, there is 80% 
power to detect a 3.5% mean absolute difference in RVEF between groups. If the transplant-
free survival rates in the two shunt groups are closer, then all power estimates in Table 4 
increase by 1 percentage point. Thus, the proposed study has ample power to detect effect 
sizes smaller than one-half of a standard deviation, which is typically considered to be a 
minimum clinically significant effect. 
The exercise aim will also be amply powered; utilizing the above assumptions and a SD=16 
for percent predicted VO2max there is approximately 85% power to detect a 6% point difference 
between groups (e.g., 57% for RVPAS vs. 63% for MBTS).  
The key secondary outcome of long-term transplant-free survival is hypothesized to be 
lower in the RVPAS group, although the difference may not be large. The size of the original 
SVR trial cohort limits our ability to detect true survival differences that are very small. The 
proposed study, with 10-16 years follow-up per participant depending on time of enrollment into 
the original trial will have approximately 80% power using a logrank test to detect a hazard ratio 
of 0.67. For example, after accounting for loss to follow-up and shunt crossover, a transplant-
free survival difference of 13% (50% vs. 63%) at study end will be detectable. 
 
Table 4.  Power to Detect RVEF Mean Differences of 0.5-3% points by Shunt Type 
(Assuming Total Evaluable RVEF Sample Sizes of N=239 and N=269, SD=10*, Two-
Sided α=0.05). 
Group N 
Mean RVEF 
Power 
MBTS 
RVPAS 
MBTS 
RVPAS 
 
Assuming 80% retention, 10% without CMR 
143 
96 
55 
50.0 
96.5% 
143 
96 
55 
50.5 
92.5% 
143 
96 
55 
51.0 
85.5% 
143 
96 
55 
51.5 
75.2% 
143 
96 
55 
52.0 
62.0% 
Assuming 90% retention, 10% without CMR 
161 
108 
55 
50.0 
98.0% 
161 
108 
55 
50.5 
95.0% 
161 
108 
55 
51.0 
89.3% 
161 
108 
55 
51.5 
80.1% 
161 
108 
55 
52.0 
67.1% 
*SD based on Fontan Cross-Sectional Study data, RV subgroup 
 
 
7.4 Interim Analyses and Stopping Rules for Termination of the Study 
 
As this is an observational study and inclusion of the entire cohort will be valuable, there 
are no preconceived stopping rules for early termination of the study.  However, we would like to 
reserve the right to look at an interim analysis at some time point such as when all participants 
have reached 10 years of age (2018). Premature termination of this study may occur because of 
a regulatory authority decision, or withdrawal of study approval by clinical site IRBs, In addition, 

 
 
 
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NHLBI retains the right to discontinue the study prior to the inclusion of the intended number of 
subjects, but intends to exercise these rights only for valid scientific or administrative reasons.  
 
7.5 Spurious Data Procedures  
Consistency checks and range checks will be built into the data management system. This 
will allow many errors to be identified and corrected at the time of data entry. Queries regarding 
any problems with data will be sent to site coordinators regularly throughout the course of the 
study. Sites will also be monitored during the study. Therefore, spurious data are expected to be 
rare. Any data which are judged by the MM to be definitely incorrect, and which cannot be 
resolved, will be set to missing.  
The study report will indicate the number of subjects who have missing data on each study 
endpoint.  For covariate-adjusted analyses, the number of subjects who have missing data on 
the covariates will be reported. 
Throughout the study, the rate, timing, and reasons for subject withdrawal will be monitored 
by site and treatment arm. Any site with a pattern of differential withdrawal by treatment arm will 
be queried. If necessary, retraining will take place or the site may be barred from enrolling 
additional subjects to the study. 
 
7.6 Deviation Reporting Procedures 
 
Any modifications or deviations from the statistical plan described in this protocol will be 
documented in a "Revised Statistical Plan" document.  
 
7.7 Subjects to be Included in Analyses  
 
All participating subjects will be included in the appropriate analyses, though only 
participants who have undergone CMR will be included in the analysis for the primary outcome 
measure of CMR RVEF. The participants who have not had a CMR will be included in analyses 
related to the secondary outcomes of the primary aim.  
 
 
8. DATA MANAGEMENT 
 
An Electronic Data Capture (EDC) system will be used for the study that is designed to 
support reliable and secure data entry for clinical research purposes. The system also provides 
seamless integration of eCRFs and paper-based CRFs within a single protocol if desired; 
implementation of protocol amendments; and SAS and XML study data exports. 
 
8.1 Data Entry 
Data can be entered directly from multiple study sites via a fully validated and 21 CFR Part 
11 compliant, secure Web application and stored centrally.  A configurable sample-based 
double data entry system is available. Data are entered by subject study identification number; 
names will not be linked with subject data in the database. Study sites will maintain records in 
secure areas linking the subject name with the identification number assigned for the study. 
Study sites will have full access to their own data and be able to view these data remotely. 
Study staff will not be able to view subject data associated with other sites.  
 

 
 
 
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8.2 Data Validation and Monitoring 
Integrated into the data entry system are real time validations, including both inter- and 
intra-instrument data checks.  Inconsistent or questionable values are flagged during entry, and 
an edit report is automatically generated to the data entry client.  These edit reports provide the 
information necessary to investigate any data entry errors or resolved questions regarding out-
of-range or questionable values.  Second level query tracking allows monitors and data 
managers real time access to unresolved queries as well as the date and time of query 
generation and resolution.  
 
8.3 Data Security and Integrity 
All data changes are written to an audit trail. The audit trail identifies the data item by table, 
column and key field. The entry includes the user, date and time, as well as the old value and 
new value. Both patient related data as well as trial configuration data are written to the audit 
trail. Data are saved at regular intervals during data entry to prevent loss of information in the 
event of a disruption of the Internet connection. In the unlikely event of a major disruption, a 
backup connection allows full access to the DMS.  
 
Several levels of security are employed to ensure privacy and integrity of the study data, 
including the following: Study access requires use of assigned user names and passwords. 
Individual roles and access levels are assigned by the study data manager. Passwords are 
changed regularly. Web-based entry uses secure socket layer data encryption.  Data will not be 
stored on laptop computers. 
 
9. QUALITY CONTROL AND QUALITY ASSURANCE (QC/QA) 
The DCC has primary responsibility for QC/QA activities of the phenotypic data.  The DCC 
also requires that the sites complete certain QC activities, most of which are monitored by the 
DCC.   
The key QC/QA activities are: 
• 
Development of a Study Manual; 
• 
Clearly formatted and carefully constructed Data Forms with clear, up-to-date 
manuals of instruction; 
• 
Sign-Off Procedures for all CRFs; 
• 
Central protocol training and certification of all site data collection staff with the use 
of standardized checklists; 
• 
Data management training and certification of site personnel completing data entry 
      and/or data management; 
• 
Verification of patient eligibility;  
• 
On-going monitoring of all protocols/data collection activities; 
• 
Completion of reliability and/or pilot studies for key measurements as appropriate;  
• 
Inclusion of repeat measurements, as feasible, in the course of the study; and 
• 
Monitoring visits to sites as required with pre-specified goals and/or remote 
      monitoring activities. 
The DCC may conduct site visits to the Core Laboratories to review QA and QC procedures 
and data transfer to the DCC.  Review of central laboratory-related reports will be conducted at 
least monthly to identify overall or site-specific problems in data or specimen acquisition and 
reporting of results.    

 
 
 
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10. ETHICS AND HUMAN SUBJECTS CONSIDERATIONS 
10.1 Potential Risks and Protection Against Risks 
 
Clinical data collection: CMR, Echo, Exercise test, ND battery 
For the CMR protocol, procedural risks will be reduced by avoiding use of anesthesia/ 
sedation or intravenous access. Participants may experience anxiety or claustrophobia in the 
CMR scanner. This will be limited by availability of entertainment/distraction whenever possible.  
The exercise protocol risks are limited, but there is a very small risk of arrhythmia or of low 
cardiac output related to strenuous exercise. A trained exercise technician will be present 
throughout the exercise test and cardiac monitoring of the rhythm will be performed throughout 
the course of the exercise test.  
There is no procedural risk to echocardiography or to neurodevelopmental testing.  All of 
the evaluations will require time and thus pose some inconvenience. It is also possible that the 
participant may become frustrated with the neuropsychological battery, however subjects will be 
given breaks as needed, and the battery will be administered by an individual trained in the 
testing of children from a full developmental range and under the supervision of a psychologist.  
Biorepository samples will be obtained from saliva samples and thus there will be no 
physical risk of bruising, bleeding or discomfort.  
There is some inconvenience and burden of completing ND questionnaires and some 
families may feel uncomfortable answering questions. The parent-completed questionnaires will 
require approximately 85 minutes to complete. In addition, teachers will be contacted and asked 
to complete two questionnaires. We will aim for questionnaires to be completed prior to the in-
person assessment; however, there will be little time pressure required for the completion of the 
instruments by the parents and teachers as they will be mailed out to parents approximately 3 
months prior to the appointment for the in-person evaluation, after initial telephone informed 
consent. 
Clinical testing, including CMR, echo, exercise testing and the administration of the ND 
battery will be performed by professionals trained to avert risks. 
 
10.2 Confidentiality  
 
Investigators will take all reasonable measures to protect the confidentiality of subjects and 
their families, including the following: 
a) Each subject is assigned a subject identification number (SID).  All interview and clinical 
research data are stripped of identifiers and labeled with the SID. The enrollment log 
with participant identifiers will be maintained at each site in a secured, locked location 
available only to the study staff. The informed consent form states that study data will 
be made available to the DCC and NIH/NHLBI to ensure study safety and QC. The 
subject’s name and any other identifying information will not appear in any presentation 
or publication resulting from this study.  
b) All echoes and CMRs sent to core labs for analyses will be de-identified prior to the 
data leaving the clinical site. If an incidental finding is found on a study clinical test such 
as a CMR, or echo, the PI or other qualified member of the research team will take full 
responsibility for disclosing the findings to the patients/parents, communicating with 
their primary cardiologist with permission, or making appropriate cardiology referrals as 
indicated.  The subject may choose to seek a second opinion and/or appropriate clinical 
care.  This might change the subject's insurability and employability as it relates to the 
clinical finding only.  The presumption is that detection of a potentially clinically 
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c)  Parents will be asked for permission to approach their child’s teacher. In the cover letter 
accompanying the questionnaire instruments, minimal diagnostic/personal information 
will be shared about the child to explain the benefit of the teacher’s participation. By 
allowing contact, and providing the teacher’s name, parents will be granting permission 
for sharing of this information.   
Confidentiality of biorepository samples will be protected as follows: 
a) Biological specimens (DNA) will be assigned a repository identification number without 
other identifying information. All research related information will be maintained in a 
system completely separate from the hospital’s medical record system. Informed 
consent will state that the subject’s data will be made available to the DCC, NIH/NHLBI, 
IRB and DSMB if necessary for assessment of study safety.  
b) To help to protect the privacy of subjects participating in the biorepository, we have a 
Certificate of Confidentiality. With this Certificate, the researchers of this study cannot be 
forced to disclose information that may identify a subject, even by a court subpoena, in 
any federal, state, or local civil, criminal, administrative, legislative or other proceedings. 
The Certificate cannot be used to resist a request for information from the United States 
government when it is used for evaluating federally funded study projects or for 
information that must be disclosed to meet the requirements of the Food and Drug 
Administration (FDA). A Certificate of Confidentiality does not prevent a subject or 
his/her family from voluntarily releasing information about the subject’s involvement in 
the research. If an insurer, employer, or other person obtains a subject’s or family’s 
written consent to receive research information, then the researchers will not use the 
Certificate to withhold information.  
c) Information from DNA analyses and clinical studies or medical records may be placed 
into a central biorepository in the future such as the National Center for Biotechnology 
Information (NCBI) repository. The purpose of a central data biorepository is to help 
researchers work together to learn about ways in which genes affect disease. The NCBI 
or a similar repository makes data accessible through the Internet. The NCBI repository 
has two databases, open access and controlled access. The open access database is 
available to anyone on the Internet and includes DNA sequence traces that are not 
linked to medical or personal information. The controlled access database includes de-
identified medical information and more detailed analyses of de-identified samples that 
are made available to researchers with IRB approval to conduct human genetic studies 
and who have received approval from an NIH Data Access Committee. 
d) The results of the future tests will not be released to the subject/family. At the end of the 
study, the results of the genetic testing may be published for all the subjects as a group, 
but it will not be possible to provide results for an individual subject and medical 
management will not be changed based on individual results. There is a reasonable 
possibility that no findings will result from this research effort. If findings are detected it 
may be years before any utility of these findings are realized. Further if samples are 
“anonymized” prior to release to other investigators for research, it may not be possible 
to trace the results back to the subject. 
Global Unique Identifiers:  A unique subject number, called a Global Unique Identifier or 
GUID, will be assigned to each study participant.  The GUID is a universal subject ID that 
allows researchers to share data specific to a study participant without exposing personally 
identifiable information (PII) and at the same time be able to match participants across labs, 
databases or research studies.  Personal information does not leave the research site, only 
a unique set of encrypted codes that are then decrypted to determine if the subject already 

 
 
 
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exists within the data repository.  The GUID is then sent to the enrolling site.  This process is 
the same one used by the National Database for Autism Research.   The GUID will allow 
data from this study to be combined with data from other research studies or databases in 
an effort to improve outcomes in children and young adults with heart disease. 
 
10.3 Potential Benefits 
It is possible that the clinical assessments obtained for research purposes, including the 
CMR, echo, exercise test, and ND evaluation, may reveal important clinical findings.  Families 
will receive a written report on the ND evaluation that will explain the results and will include 
recommendations for follow-up if appropriate. Such findings may lead to valuable intervention to 
improve outcomes for the participant. Results of each of the evaluations will be reported to the 
subject’s cardiologist, and the subject’s family will be informed about the transfer of information.  
There might be an indirect benefit from the awareness that study results may help to 
improve the care of children with similar problems in the future.  Families may derive a sense of 
altruism, accomplishment, and contribution to furthering understanding of the problem through 
their participation.  
Currently, there is no known direct benefit from provision of biospecimens by the subject 
and family.  The indirect benefit comes from the potential knowledge about the relationship 
between genetic factors or biomarkers and longer-term cardiac and neurodevelopmental 
outcomes.  This information may help physicians provide better answers to families’ questions 
regarding causes, risk, and recurrence risks.  It may also inform the development of future 
interventions and/or treatments. 
The research using samples and data from the biorepository may result in inventions or 
discoveries that could create new tests and medicines that have commercial value. Although 
subjects and their families will not receive compensation now or in the future for their samples or 
data, income that may be derived from future research or sales of the grouped data may be 
used to support biomedical research, providing societal benefit and thus may be a benefit to 
participants and families. 
 
10.4 Risk/Benefit Ratio and Importance of Information to be Obtained 
The risk/benefit ratio is favorable for this study, for the following reasons:  
1. The baseline risk is minimal because there are no therapeutic interventions. In addition, 
although an individual subject may not benefit from participation, the results of this study will 
make important contributions to the design of an optimal management algorithm for infants 
with single ventricle.  
2. The assessments of RV function address important long-term concerns regarding the 
potential negative effects of a ventriculotomy on the single right ventricle following the RV-
to-PA shunt.  
3. Extending the length of follow-up of the SVR study up to 11 years to assess right ventricular 
function and to obtain the incidence of death or cardiac transplantation is crucial to 
evaluating the potential survival and functional benefit of the RV-to-PA connection.  
4. Neurodevelopment and functional status are critical determinants of the child’s well-being 
and have never been studied in such a large population of children with single ventricle, or 
in a longitudinal fashion.  The in-person evaluation proposed in this study, compared to the 
questionnaires used at the 6-year evaluation, will provide more accurate and richer 
information about development for use by families and schools. 

 
 
 
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5. The assessment of the incidence of arrhythmias will address important long-term concerns 
regarding the potential promotion of ventricular arrhythmias by the ventriculotomy required 
for the placement of the RV-to-PA shunt.  
6. The assessment of exercise capacity will address long-term concerns related to the potential 
effects of the ventriculotomy on the function of the single right ventricle. 
7. Data generated from this study will be unique in terms of the breadth and depth of the 
guidance that can be provided to parents and medical care providers of children with 
univentricular hearts who have undergone the Norwood procedure.  
 
11. STUDY LIMITATIONS 
The study of the long-term outcomes of this well-defined inception cohort is essential and 
imperative to discern the optimal shunt type at the Norwood operation for children with HLHS 
and other related single RV anomalies. Nonetheless there are some limitations to this study that 
are important to recognize. The primary outcome measure for this study is ventricular function 
measured by CMR. We anticipate that approximately 7-8% of the SVR cohort will have had 
pacemakers placed by the age of 10.5 years and will therefore be unable to undergo CMR. 
Despite the fact that this group will be excluded from the primary aim, we anticipate that we will 
still have 85% power to detect a 4% absolute group difference in RVEF. In addition, 2D echo will 
also be utilized to assess RV function. While this is an imperfect tool, no participants will be 
excluded from the potential in participating in this portion of the evaluation.  
To avoid bias, all team members responsible for measurement/interpretation will be blinded 
to the assigned shunt type at the Norwood. It is possible that Echo and MRI Core Lab readers 
will be able to deduce which shunt was used based on review of images. 
This study will require the coordination of multiple evaluations and the return of participants 
to their original surgical site for 1.5-2 days. While this will require a significant commitment for 
families, this cohort of children with HLHS and their families are invested and motivated; a 
survey of this cohort revealed that at least 88% of families are interested in returning for follow-
up for assessment in a SVR related study (9% responded they were unsure and only 3% denied 
interest; Lynn Sleeper-personal communication, 8-5-2013), and have expressed interest in 
returning to the surgical site even in cases when travel will be essential. 
 
 

 
 
 
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12. REFERENCES 
 
1. Norwood WI, Kirkland JK, Sanders SP. Am J Cardiol 1980; 45(1):87-91.  
2. Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart 
syndrome. N Engl J Med 1983; 308(1):23-6.  
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