Clinical trial NCT02564796
Conditions: Cyanotic Congenital Heart Disease Anemia Cyanosis Congenital Heart Disease
Keywords: Erythropoetin Cyanotic Heart Disease Transfusion Congenital Heart Disease
Sponsor: University of California, San Diego
Start date: 2016-11-01; Completion date: 2020-06-01
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cyanotic congenital cardiac patients require higher hemoglobin concentrations (red blood cell levels) for optimal oxygen delivery to the body. Prophylactic erythropoietin (EPO) and iron can prevent and/or decrease the amount of blood transfusions needed in this population. We seek to investigate if EPO and iron make a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

Detailed description:
Congenital heart disease occurs in about 1% of all live births. Cyanotic cardiac lesions in particular are at risk for significant mortality and morbidity because of their reduced ability to provide adequate oxygenation to the body and the brain. Many experts believe that to have adequate oxygen carrying capacity that these infants should ideally have a hemoglobin level greater than 13 g/dL. Many of these patients require blood transfusions prior to surgery to provide adequate oxygenation. The cause for this is likely multifactorial including normal neonatal physiology, frequent lab draws, and co-morbidities. Although rare, the morbidity due to transfusions can be devastating to this population including transmitted infections, transfusion reactions, extra hospitalizations, and antigen sensitization that would complicate heart transplant if needed.

There are centers in the United States that have developed protocols using erythropoietin to minimize blood product transfusions before and after surgery, also referred to as "bloodless surgery". There have been retrospective studies evaluating the success of these protocols, but there are no randomized controlled prospective studies that the investigators have studying the effects of erythropoietin effects in patients with cyanotic heart disease in regards to transfusion prevention.

Congenital cyanotic cardiac patients require higher hemoglobin concentrations for optimal oxygen delivery. Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. The researchers seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

Arms: arm 1: Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks. arm 2: Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.
Interventions: intervention 1: Epoetin Alfa and Iron intervention 2: Iron
Intervention descriptions: intervention 1: Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks. intervention 2: Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Erythropoietin to Prevent Unnecessary 
Transfusions in Patients with Cyanotic 
CHD - A Prospective Control Trial 
NCT02564796 
Study Protocol – Version Date: 28Jun2018 
 


Erythropoietin to Prevent Unnecessary 
Transfusions In Patients With  Cyanotic 
Congenital Heart Disease – A Prospective 
Randomized Control Trial
Protocol 
University of California, San Diego 
Rady Children’s Hospital, San Diego 
Principal Investigator: David Werho, MD 
Last Edit: 6/28/2018 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
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TABLE OF CONTENTS 
A
INTRODUCTION ............................................................................................................................... 3
A1
STUDY ABSTRACT ......................................................................................................................... 3
A2
PRIMARY HYPOTHESIS ................................................................................................................... 3
A3
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 3
B
BACKGROUND .................................................................................................................................. 3
B1
PRIOR LITERATURE AND STUDIES .................................................................................................. 3
B2
RATIONALE FOR THIS STUDY ......................................................................................................... 4
C
STUDY OBJECTIVES........................................................................................................................ 4
C1
PRIMARY AIM ................................................................................................................................ 4
C2
SECONDARY AIM ........................................................................................................................... 4
C3
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 5
D
INVESTIGATIONAL AGENT .......................................................................................................... 5
D1
PRECLINICAL DATA ....................................................................................................................... 5
D2
CLINICAL DATA TO DATE .............................................................................................................. 6
D3
CLAIM FOR EXCLUSION OF ENVIRONMENTAL ASSESSMENT .......................................................... 6
D4
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 6
E
STUDY DESIGN ................................................................................................................................. 6
E1
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 6
E2
SUBJECT SELECTION AND WITHDRAWAL....................................................................................... 7
2.a
Inclusion Criteria ..................................................................................................................... 7
2.a
Exclusion Criteria ..................................................................................................................... 7
2.b
Ethical Considerations ............................................................................................................. 7
2.c
Subject Recruitment Plans and Consent Process ..................................................................... 7
2.d
Randomization Method ............................................................................................................. 8
2.e
Risks and Benefits ..................................................................................................................... 8
2.f
Early Withdrawal of Subjects ....................................................................................................... 8
2.g
When and How to Withdraw Subjects ....................................................................................... 9
2.h
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9
2.i
Blood transfusion guidelines ......................................................................................................... 9
E3
STUDY DRUG ................................................................................................................................. 9
3.a
Description ............................................................................................................................... 9
3.b
Treatment Regimen ................................................................................................................... 9
3.c
Method for Assigning Subjects to Treatment Groups ..............................................................11
3.d
Preparation and Administration of Study Drug .......................................................................11
3.e
Subject Compliance Monitoring ..............................................................................................11
3.f
Prior and Concomitant Therapy ..................................................................................................11
3.g
Packaging ................................................................................................................................11
3.h
Blinding of Study Drug ............................................................................................................11
3.i
Receiving, Storage, Dispensing and Return .................................................................................11
F
STUDY PROCEDURES ....................................................................................................................12
F1
SCREENING FOR ELIGIBILITY.............................................................................................................12
F2
SCHEDULE OF MEASUREMENTS ........................................................................................................12
F3
VISIT 1 ..............................................................................................................................................12


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F4
VISIT 2 ETC. ......................................................................................................................................12
F5
SAFETY AND ADVERSE EVENTS ........................................................................................................12
5.a
Safety and Compliance Monitoring .........................................................................................12
5.b
Medical Monitoring .................................................................................................................13
i
Investigator............................................................................................................................................ 13
ii
Institutional Data and Safety Monitoring Board ............................................................................... 13
5.c
Definitions of Adverse Events ..................................................................................................13
5.d
Classification of Events ...........................................................................................................13
i
Relationship .......................................................................................................................................... 13
ii
Severity .................................................................................................................................................. 14
iii
Expectedness ....................................................................................................................................... 14
5.e
Grading of Adverse events .......................................................................................................15
5.f
Data Collection Procedures for Adverse Events ..........................................................................15
5.g
Reporting Procedures ..............................................................................................................15
5.h
Adverse Event Reporting Period ..............................................................................................16
5.i
Post-study Adverse Event .............................................................................................................16
5.j
Pure Red Cell Aplasia ..................................................................................................................16
F6
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..............................................................17
G
STATISTICAL PLAN ........................................................................................................................17
G1
SAMPLE SIZE DETERMINATION AND POWER .................................................................................17
G2
INTERIM MONITORING AND EARLY STOPPING ..............................................................................17
G3
ANALYSIS PLAN............................................................................................................................18
G4
STATISTICAL METHODS ................................................................................................................18
G5
MISSING OUTCOME DATA ............................................................................................................19
H
DATA HANDLING AND RECORD KEEPING .............................................................................19
H1
CONFIDENTIALITY AND SECURITY ................................................................................................19
H2
TRAINING......................................................................................................................................19
H3
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................19
H4
RECORDS RETENTION ...................................................................................................................19
I
STUDY MONITORING, AUDITING, AND INSPECTING ..........................................................19
I1
STUDY MONITORING PLAN, AUDITING AND INSPECTING ..................................................................19
J
STUDY ADMINISTRATION ...........................................................................................................20
J1
ORGANIZATION AND PARTICIPATING CENTERS .................................................................................20
J2
FUNDING SOURCE AND CONFLICTS OF INTEREST ..............................................................................20
J3
COMMITTEES .....................................................................................................................................20
J4
SUBJECT STIPENDS OR PAYMENTS ....................................................................................................20
J5
STUDY TIMETABLE ...........................................................................................................................20
K
PUBLICATION PLAN ......................................................................................................................20
L
ATTACHMENTS ...............................................................................................................................21
L1
TABLES .........................................................................................................................................21
L2
INFORMED CONSENT DOCUMENTS.................................................................................................23
STUDY INVESTIGATOR AND SPONSOR ...........................................................................................23
WHAT ARE THE RISKS OF THE STUDY? .........................................................................................25
WHAT ABOUT CONFIDENTIALITY? .................................................................................................27
SUBJECT’S BILL OF RIGHTS ................................................................................................................31
L3
CASE REPORT FORM ......................................................................................................................32
M
REFERENCES ...................................................................................................................................34


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A Introduction
A1 
Study Abstract 
Children with cyanotic heart disease, “blue babies”, have chronically low oxygen levels 
and are at particular risk for death and poor outcomes because of their reduced ability to 
provide adequate oxygen to the body and brain. These infants should ideally maintain 
hemoglobin or red blood cell levels greater than 13 g/dL or a hematocrit >40% (Strauss 
1991, Roseff 2002), to deliver adequate amounts of oxygen to the body. Healthy infants 
often experience a drop in their red blood cell level during their first few months of life, as 
part of the body’s normal maturation process. Children with cyanotic heart disease 
experience this same phenomenon, but are also exposed to additional risks such as 
critical illness and surgical procedures. Thus, newborns with cyanotic heart disease may 
require blood transfusions as part of their care in order to provide adequate oxygen to 
the body. Although rare, the adverse outcomes due to transfusions can be devastating 
to this population. These complications include transmitted infections, transfusion 
reactions, additional hospitalizations, and production of antibodies that could complicate 
heart transplant if needed in the future. Epoetin alfa (EPO) and iron stimulate red blood 
cell production. Studies with EPO have been done in premature infants and children 
prior to surgery in order to assess the drug’s ability to increase red blood cell levels [1-4]. 
They show that early administration of EPO has reduced the use of blood transfusions. 
We seek to investigate, through a prospective randomized controlled trial, if EPO and 
iron make a clinically significant difference in the number of transfusions given to infants 
with cyanotic heart disease. We hypothesize that prophylactic EPO and iron may 
prevent and/or decrease the amount of blood transfusions needed in this population. 
A2 
Primary Hypothesis 
We hypothesize that prophylactic EPO and iron can prevent and/or decrease the amount 
of blood transfusions needed in this population. 
A3 
Purpose of the Study Protocol 
The purpose of this study protocol is to provide a guide and timeline for the completion 
of this prospective randomized controlled trial. 
B Background
B1 
Prior Literature and Studies 
We are not aware of any studies that have investigated this question in this specific 
population. There have been multiple studies looking at the efficacy of EPO in the 
premature infant population (Donato 2005). In these studies, EPO has been shown to 
prevent blood transfusions, however it is not necessarily clinically significant in the long 
term. The clinical significance is different in our study population, because blood 
transfusions may have significant implications for transplant candidacy in the future and 
transplant complications if needed. There is a study involving infants and children with 


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craniosynostosis showing that EPO is safe and can reduce the number of blood 
transfusions in a surgical group that has high risk for bleeding (Fearon 2001). 
B2 
Rationale for this Study 
Congenital heart disease occurs in about 1% of all live births. Cyanotic cardiac lesions in 
particular are at risk for significant mortality and morbidity because of their reduced 
ability to provide adequate oxygenation to the body and the brain. Many experts believe 
that to ensure  adequate oxygen carrying capacity these infants should ideally have a 
hemoglobin level greater than 13 g/dL or hematocrit >40% (Strauss 1991; Roseff 2002). 
Many of these patients require blood transfusions prior to surgery to provide adequate 
oxygenation. The cause for this is likely multifactorial including normal neonatal 
physiology, frequent lab draws, and co-morbidities. Although rare, the morbidity due to 
transfusions can be devastating to this population including transmitted infections, 
transfusion reactions, extra hospitalizations, and antigen sensitization that would 
complicate heart transplant if needed.  
There are centers in the United States that have developed protocols using 
erythropoietin to minimize blood product transfusions before and after surgery, also 
referred to as “bloodless surgery”[4]. There have been retrospective studies evaluating 
the success of these protocols, but there are no randomized controlled prospective 
studies that have studied the effects of erythropoietin in patients with cyanotic heart 
disease in regards to transfusion prevention. There have also been multiple studies 
looking at the efficacy of EPO in the premature infant population (Donato 2005). In these 
studies, EPO has been shown to prevent blood transfusions. However, these findings 
did not represent a clinically significant difference for the study population in the long 
term. The clinical significance is enhanced in our study population, because blood 
transfusions may have significant implications for transplant candidacy in the future and 
transplant complications if needed. Last, there is a study involving infants and children 
with craniosynostosis showing that EPO is safe and can reduce the number of blood 
transfusions in a surgical group that has high risk for bleeding (Fearon 2001). 
C Study Objectives
C1 
Primary Aim 
Congenital cyanotic cardiac patients require higher hemoglobin concentrations for 
optimal oxygen delivery. Prophylactic erythropoietin can prevent and/or decrease the 
amount of blood transfusions needed prior to surgery. We seek to investigate if 
erythropoietin makes a clinically significant difference in the number of transfusions 
given to these patients and the morbidity associated with it during the period in which the 
subjects will be active in the study (from baseline to 14 weeks post initial injection). The 
primary aim will be assessed when all subjects have completed week 14 or discontinue 
early. 
C2 
Secondary Aim 
We will also look to see if administering erythropoietin makes a clinical significance in 
the following outcomes during the period in which the subjects will be active in the study 


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(from baseline to 14 weeks post initial injection): weight gain, oxygen saturations, length 
of initial hospital stay, and hospital readmissions (related to failure to thrive or cyanosis).  
C3 
Rationale for the Selection of Outcome Measures 
Transfusions are currently the treatment of choice for clinically significant anemia in the 
cyanotic congenital heart patient. However, this therapy requires hospitalization and an 
intravenous line which does not come without risk, in addition to the risks associated 
with transfusions which include transfusion reactions from blood type incompatibility, 
antibody sensitization, and infections. Thus, the primary outcome will be to see if the 
number of transfusions can be reduced by administering erythropoietin.  
Although the  hemoglobin level, in and of itself, should not affect  oxygen saturation 
measured by pulse oximetry, our anecdotal experience suggest that  oxygen saturations 
in patients with cyanotic heart disease frequently improve after a blood transfusion to 
increase the amount of hemoglobin. Thus, the secondary outcome of oxygen saturation 
will be looked at for 2 reasons. First, to ensure that the treatment and control arms are 
similar at baseline to prevent bias for  transfusions based on criteria set below. Second, 
to determine if our anecdotal experience has any validity. 
The secondary outcome of weight gain is appropriate in the setting of infants as this 
variable has been used to monitor the ability to thrive and meet the body’s metabolic 
demands. It is well established in pediatrics that the neonate and infant should gain 15-
30 grams per day for optimal growth. Infants who are cyanotic, already have a deficiency 
in meeting their metabolic demands due to a reduced oxygen carrying capacity. This is 
further complicated in the instance of anemia. Thus, infants may  have an increased 
ability to optimize weight gain in the setting of normal, stable hemoglobin levels which 
may be achieved with erythropoietin. 
Often, cyanotic congenital heart defect neonates have prolonged initial hospital stays 
due to the inability to maintain acceptable oxygen saturations, and transition to adequate 
oral intake for appropriate weight gain. If the hospital stay is found to be shortened after 
starting erythropoietin, this may be of clinical and financial significance. 
The number of hospital readmissions (related to failure to thrive or cyanosis) may imply 
the overall clinical stability of a patient. Because these infants are at high risk for 
mortality at home, there are multiple reasons why they may be admitted to the hospital 
including clinically significant anemia which requires blood transfusions, poor weight 
gain, difficulty feeding, inadequate oxygen saturations, and illnesses. Each admission is 
stressful to the patient and their families. Having a normal hemoglobin level may have a 
role in preventing several of these factors, especially regarding failure to thrive or 
cyanosis.  
D 
Investigational Agent  
D1 
Preclinical Data 
Epoetin alfa is approved for use by the US Food and Drug Administration. The current 
labeled use is to treat a lower than normal number of red blood cells (anemia) caused by 


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chronic kidney disease in patients on dialysis to reduce or avoid the need for red blood 
cell transfusions. It should not be used in place of emergency treatment for anemia (red 
blood cell transfusions). It has not been proven to improve quality of life, fatigue, or well-
being. 
Common side effects include joint pain, muscle pain, bone pain, fever, cough, rash 
nausea, vomiting, soreness of mouth, itching, headache, redness and pain in the 
injection site.  
More serious side effects such as stroke, seizures, antibodies to Epoetin alfa, and 
serious allergic reactions have also been reported. 
D2 
Clinical Data to Date  
There is no published clinical data on erythropoietin administration in the cyanotic 
congenital heart defect infant population that we are aware of. 
D3 
Claim for Exclusion of Environmental Assessment 
In accordance with 21 CFR 25.31(e), I, David Werho, MD request a categorical 
exclusion from the requirement for an environmental assessment for the manufacture 
and formulation of epoetin alfa for use in human clinical trials under this IND #129795.  
All waste from the investigational drug will be properly controlled. The amount of wasted 
expected to enter the environment may reasonably be expected to be non-toxic. To my 
knowledge, no extraordinary circumstances exist. 
D4 
Dose Rationale and Risk/Benefits  
500 units/kg/injection (SQ) and oral ferrous sulfate (iron) at 3 mg/kg/day (Donato 2005 & 
Maier 2002) which is an accepted treatment for anemia and prevention of anemia.  
E 
Study Design  
E1 
Overview or Design Summary 
The study will be a prospective randomized controlled trial, to investigate if 
administration of EPO and supplemental iron make a clinically significant difference in 
the number of transfusions given and the morbidity associated with it in infants with 
cyanotic heart disease. There will be 2 arms in the study, a treatment arm (EPO) and an 
observational control arm. The patients will be enrolled in the neonatal period after 
diagnosis and initial palliative procedure (surgical shunt, hybrid procedure, stent in 
patent ductus arteriosus or right ventricular outflow tract to ensure adequate pulmonary 
blood flow). They will be followed for 14 weeks from their enrollment.   Clinical data will 
be obtained as appropriate to study the primary and secondary outcomes. The data will 
be analyzed with a biostatistician to reveal any statistically significant differences 
between the 2 arms of the study.  


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E2 
Subject Selection and Withdrawal  
2.a 
Inclusion Criteria  
 
Newborns less than 4 weeks old at diagnosis 
 
Gestational age >34 weeks 
 
Birth weight 2.2-4kg  
 
Infants with cyanotic heart disease who have had a surgical aorto-pulmonary 
shunt, hybrid procedure (pulmonary artery bands with a patent ductus arteriosus 
stent or PGE-1 to maintain ductal patency) or a catheterization intervention that 
is equivalent to a shunt (patent ductus arteriosus stent, right ventricular outflow 
tract stent).  
 
Baseline hematocrit to be below <40%.
 
Completes at least 1 injection in the study by 8 weeks of age. 
2.a 
Exclusion Criteria  
 
Infants diagnosed at greater than 4 weeks of age 
 
Gestation <34 weeks  
 
Birth weight <2.2 kg or >4kg 
 
Hematocrit >40% 
 
Newborns with acyanotic heart disease 
 
Infants with significant co-morbidities 
o Renal failure (Creatinine > 2 standard deviations above age adjusted 
norm) 
o Hepatic failure (elevated AST/ALT levels > 2 standard deviations above 
age adjusted norm 
o Hemolytic disease 
o Hemoglobinopathies (Sickle-cell disease, Thalassemias)  
2.b 
Ethical Considerations  
There are no ethical concerns in regards to the treatment (EPO) group as this 
medication has been studied for safety, approved by the FDA for use, and has been 
investigated in multiple patient populations including premature infants (Donato 2005) 
and in pediatric craniosynostosis repair (Fearon 2001). There are also no ethical 
concerns to withhold treatment from the control group as there is no definitive study to 
show clinical significance. Because the outcome of the study is not known, a randomized 
prospective control trial is appropriate.  
2.c 
Subject Recruitment Plans and Consent Process 
A partial HIPPA waiver will be obtained to allow for identification of potential subjects for 
the research study. Information to be obtained includes name, date of birth, gestational 
age, weight, and congenital heart diagnosis. Subjects will be identified after birth or 
admission to the hospital by attending physicians (cardiology, NICU, PICU, CVICU), 
clinical fellows (cardiology, NICU, PICU, CVICU), or nurse practitioners in the Acute 
Cardiac Unit. The parents of the potential subject will be approached by the research 
team in the Acute Cardiac Unit. All genders and ethnicities will be recruited as long as 
inclusion and exclusion criteria are met. 


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Informed consent will be obtained by one of the research study members after the initial 
surgical or catheterization procedure. Each member is well informed of the study 
objectives, procedures, risks, benefits, physiology of the disease process and 
mechanism of how the treatment works. The informed consent will be obtained from the 
patient’s parent in a private setting. Details of the study will be presented, and ample 
time will be given to answer any questions. The parent will have until the eligibility period 
expires based on the exclusion criteria outlined above to be included in the study. 
Consent will be obtained in the primary language of the parent. English and Spanish 
versions of the consent documents will be available and official translators will be used 
as appropriate. An appropriate official translator will be used during the entire duration of 
the participant in the study. Informed consent and HIPPA authorization will be 
documented with the study forms that have been drafted and approved for use in the 
study and will be kept in a master research file for the duration of the study in a secure 
area, in a locked drawer by the study team. It will be made clear to the parents that 
participation in the study is voluntary and that decision to be included or excluded will not 
compromise the standard of care that the patient deserves. Patients who meet all 
inclusion criteria except the hematocrit of <40% will be approached and consented, but 
will not be formally enrolled and randomized into a study group (control or EPO) unless 
their hematocrit reaches <40% during their eligibility period. 
2.d 
Randomization Method  
Study subjects will be randomized 1 to 1 by an algorithm determined by the 
biostatistician involved. After a study subject has been enrolled into the study, a 2-digit 
number (1-60) will be assigned. Based on the subject number and predetermined 
randomization provided, a research pharmacist will dispense the study drug if the 
subject is enrolled in the intervention arm. This study will not be blinded. 
2.e 
Risks and Benefits 
There is low risk to the patient in regards to side effects of erythropoietin. In general, 
neonatal population studies have not shown to have significant serious side effects. 
Blood counts will have to be monitored to observe for polycythemia as this would 
increase the risk for blood viscosity and thrombosis. There are rare instances in the adult 
literature with development of Pure Red Cell Aplasia, which is not evident in the 
neonates. There is some discomfort with the injections, however this is of minimal risk. 
Lab draws will be done as part of a routine basis. The benefits to receiving this 
medication are that it may decrease the need of transfusions and hospitalizations in the 
period prior to a more definitive surgery. 
2.f 
Early Withdrawal of Subjects  
As this is a voluntary research study, study subjects will be allowed to withdraw from the 
study before completion at any time. If a withdrawal occurs before initiation of the 
intervention, the subject will be excluded from the study. 


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2.g 
When and How to Withdraw Subjects  
A family may wish to withdraw the study subject from the study at any time. When the 
decision to withdraw is made after discussions with the clinical staff, a member of the 
research team will be notified. The date, time, and reason of the withdrawal should be 
noted by the research member and entered into the database. Families will be 
approached for permission to follow the course of the patient through the proposed study 
period even if the intervention was stopped. 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
Families will be approached for permission to follow the course of the patient through the 
proposed study period even if the intervention was stopped. An intention to treat analysis 
will be applied to the study subject pertaining to the research arm assigned. 
2.i 
Blood transfusion guidelines
Absolute indications: 
 
Hematocrit <30% 
Relative Indications: 
 
Hematocrit <40% AND one of the following 
o Clinical acidosis 
o Low oxygen saturations (<75%) in room air 
o Requires supplemental oxygen  
o Requires respiratory support (Ventilator, positive pressure) 
When a transfusion is needed, a 10 ml/kg aliquot volume should be given.  
E3 
Study Drug  
3.a 
Description  
Epoetin alfa is a recombinant form of human erythropoietin used to stimulate 
erythropoiesis. Iron then helps support proper heme formation with the production of 
hemoglobin. EPO is administered by injections. Iron will be administered orally or 
intravenously if orals are not tolerated. 
3.b 
Treatment Regimen  
Experimental: Epoetin alfa and iron supplements: 
Patients in the treatment group will receive weekly erythropoietin injections for 6 weeks 
starting before 8 weeks of age (at least one week after their surgery) at 500 
units/kg/injection (SQ or IV).(Donato 2005 & Maier 2002 ) Oral ferrous sulfate 3 
mg/kg/day of elemental iron will be given throughout the study if enteral feeds are 
tolerated which is an accepted treatment for anemia and prevention of anemia. If oral 
iron cannot be tolerated and there is laboratory evidence of iron deficiency, intravenous 
iron (either Iron sucrose or Iron dextran) will be used to replace iron stores based on the 
calculated iron deficit: Total replacement dose (mg of iron) = 0.6 x weight (kg) x [100 - 


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(actual Hgb /Desired Hgb x 100)]. This will be given in 5-7 mg/kg every day until the total 
replacement dose is achieved. 
Iron studies (Serum iron, ferritin, total iron binding capacity) will be obtained at baseline 
and at week 14 with the final lab draw. If intravenous iron is used for replacement, iron 
studies will be repeated after replacement to ensure adequate iron stores. 
All injections will be administered by a member of the subject’s care team (bedside 
nurse, nurse practitioner, or physician) with a weekly visit in the cardiology clinic or in the 
hospital if the infant remains hospitalized after being dispensed by the research 
pharmacist. 
A complete blood count will be obtained in the hospital prior to initiation of treatment for 
baseline measurements and to confirm eligibility if not obtained within 48 hours prior to 
the 1st injection as a part of the patient’s standard of care. It will be repeated weekly 
(weeks 2-7) whether inpatient or outpatient, to confirm that there is no over-shoot with a 
hematocrit >45%. Labs will be reviewed prior to treatment.  Treatment will be held for 
hematocrit levels >45%. There will be another lab drawn 14 weeks after the initial 
injection. Outpatient visits and lab draws will be paid for by the study grant. All labs will 
be analyzed by the Rady Children’s Hospital Laboratory. The study drug will be provided 
by the study grant. 
Observational Control: 
An observational group will be used as a control. Thus to keep the integrity of the study 
with minimal bias, strict adherence to the blood transfusion guidelines as listed above is 
required. 
Patients in the control group will have no injections given. This group will receive oral 
ferrous sulfate 3 mg/kg/day of elemental iron for 6 weeks starting before 8 weeks of age 
(at least one week after their surgery).
If oral iron cannot be tolerated and there is laboratory evidence of iron deficiency, 
intravenous iron (either Iron sucrose or iron dextran) will be used to replace iron stores 
based on the calculated iron deficit: Total replacement dose (mg of iron) = 0.6 x weight 
(kg) x [100 - (actual Hgb /Desired Hgb x 100)]. This will be given in 5-7 mg/kg every day 
until the total replacement dose is achieved. 
Iron studies (Serum iron, ferritin, total iron binding capacity) will be obtained at baseline 
and at week 14 with the final lab draw. If intravenous iron is used for replacement, iron 
studies will be repeated after replacement to ensure adequate iron stores. 
A complete blood count will be obtained in the hospital prior to initiation of treatment for 
baseline measurements and to confirm eligibility if not obtained within 48 hours prior to 
enrollment as a part of the patient’s standard of care. A repeat CBC will be obtained at 
week 7 and 14 of the subject’s participation in the study which will be provided by the 
study grant. A CBC may be obtained earlier if indicated by the subject’s care team as a 


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11
part of standard of care. All labs will be analyzed by the Rady Children’s Hospital 
Laboratory. 
3.c 
Method for Assigning Subjects to Treatment Groups  
After a study subject has been enrolled, a 2-digit number will be assigned. Based on the 
number and a pre-randomized allocation scheme devised by the biostatistics 
department, the subject will be placed into the treatment arm or the control arm of the 
study.  
3.d 
Preparation and Administration of Study Drug  
The epoetin alfa that will be used in the study will be obtained through commercial 
means, stored, and prepared by the research pharmacist associated with the study at 
Rady Children’s Hospital. Based on the EPO prescribing information, benzyl alcohol has 
been associated with severe adverse events and death especially in the pediatric 
population. Only benzyl alcohol-free formulations of EPO will be used (multidose vials, 
single-dose vials admixed with benzyl alcohol will not be used.)  When it is time to 
administer the intervention, the clinicians will order a dose of the medication. Based on 
the number assigned to the patient, a dose of epoetin alfa or an empty syringe will be 
prepared. A dedicated administering clinician assigned will then administer the prepared 
syringe either in the inpatient unit or in the cardiology clinic. The pharmacy will store, 
handle and prepare the study drugs according to the approved package inserts. The 
study drug will not be diluted in this trial. Unused portions of the drug in preservative-free 
single use vials will be discarded. 
3.e 
Subject Compliance Monitoring  
Compliance will be documented at each visit as the intervention will be done in the 
hospital or in the clinic setting. A member of the research team will be at each visit to fill 
out the case report form including compliance of iron therapy. The research team will be 
in charge of overseeing that patients return at the proper time for their clinical visits as 
described (see table 1 and table 2) 
3.f 
Prior and Concomitant Therapy  
All patients based on the inclusion criteria will have had a surgical or interventional 
procedure for their cyanotic heart disease. All concomitant therapy that is standard of 
care for the patient will be continued. 
3.g 
Packaging  
Epoetin alfa will be obtained in its normal manufacture packaging. The study 
interventions will be prepared in standard fashion by the pharmacy for administration. 
3.h 
Blinding of Study Drug  
There will be no blinding in this study. 
3.i 
Receiving, Storage, Dispensing and Return  
Ordering, receiving, storage, and dispensing will be done by the pharmacy and research 
pharmacist per hospital standards and protocol. 


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F 
Study Procedures  
F1 
Screening for Eligibility 
Screening for eligibility will be done on the Acute Cardiac Unit at Rady Children’s 
Hospital. When an infant with cyanotic congenital heart disease is identified, the patient 
will be screened for eligibility based on the inclusion and exclusion criteria described 
above. 
F2 
Schedule of Measurements 
The schedule of measurements is listed in Table 1 and Table 2. For the treatment arm, a 
physical exam with oxygen saturation will be recorded weekly from baseline and weeks 
1-7, 14. A complete blood count will be drawn at baseline (if not already obtained for 
clinical use, one week post procedure and ≤ 48 hours prior to 1st injection), weekly from 
weeks 2-7, and at week 14. Iron studies will be drawn at baseline and week 14 unless 
indicated in between. All labs will be analyzed by the Rady Children’s Hospital Clinical 
Laboratory whether inpatient or outpatient. 
The control arm will have a physical exam with oxygen saturations at baseline, week 7 
and 14. A complete blood count will be drawn at baseline (if not already obtained for 
clinical use, one week post procedure and ≤ 48 hours prior enrollment) week 7 and week 
14. Iron studies will be drawn at baseline and week 14 unless indicated in between. All 
labs will be analyzed by the Rady Children’s Hospital Clinical Laboratory whether 
inpatient or outpatient. 
F3 
Visit 1  
Visit 1 will be prior to 8 weeks of age and at least 1 week post procedure while in the 
hospital. After confirmation of eligibility for the study, a physical exam and oxygen 
saturation will be obtained, and the 1st dose of the intervention will be given by the 
subject’s care team if in the EPO arm. 
F4 
Visit 2 etc.  
Visit 2-14 may either be obtained in the hospital or in the clinic setting. A physical exam 
and oxygen saturation will be obtained. A complete blood count will be obtained weekly 
from weeks 2-7 in the EPO arm.  A complete blood count will be obtained in the control 
group at week 7 or earlier if indicated by the subject’s care team. Study injections will be 
given after the lab has been reviewed and confirmed there is no overshoot (Hct >45%). 
There will be a final physical exam and labs at week 14 of the study, which will complete 
the participation of the study. 
F5 
Safety and Adverse Events  
5.a 
Safety and Compliance Monitoring 
Safety and Compliance Monitoring will follow standard principles as outlined below. 


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5.b 
Medical Monitoring  
i 
Investigator 
The research team will review the visits data at least once a week to monitor for adverse 
events, compliance, and progress of the study. The research team will meet with the 
Principal Investigator weekly with a report of adverse events and serious adverse 
events. 
ii 
Institutional Data and Safety Monitoring Board 
The UCSD Data and Safety Monitoring Board (DSMB) has been identified through the 
Clinical and Translational Research Institute. The DSMB is composed of experts in 
biostatistics, clinical trial design, and medicine. The DSMB will meet as subjects are 
enrolled in increments of 5 or annually (whichever is more frequent). .  The DSMB will be 
responsible for monitoring the safety of the study. 
5.c 
Definitions of Adverse Events 
The FDA Final Rule on Investigational New Drug Safety Reporting Requirements 
[http://edocket.access.gpo.gov/2010/pdf/2010-24296.pdf] defines the following terms:  
• Adverse Event:  Any untoward (e.g. unfavorable, negative, or harmful) medical 
occurrence associated with the use of a drug in humans, whether or not the event is 
considered drug related. An event can be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the product.  
• Suspected Adverse Reaction:  Any AE for which there is a reasonable possibility that 
the drug caused the event, meaning the event is possibly, probably, or definitely related 
to the study drug.  
• Adverse Reaction:  An AE for which there is a greater degree of certainty regarding 
causality; meaning the event is probably or definitely related to the study drug. Adverse 
reactions are a subset of Suspected Adverse Reactions. 
5.d 
Classification of Events 
Monitoring adverse events requires that they be classified as to potential relationship, 
severity, and of the study drugs, all of which drive the reporting process. 
i 
Relationship 
Relationship assessment is required in clinical investigations to help determine which 
events require expedited reporting. The following criteria will be used to determine 
relationship:  
1. Not Related: The event is clearly related to other factors, such as the subject’s clinical 
state, or non-study drugs or interventions.  
2. Possibly Related: The event follows a compatible temporal sequence from the time of 
administration of the study drug, but could have been produced by other factors such as 
the subject’s clinical state or non-study drugs or interventions. 


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3. Probably Related: The event follows a reasonable temporal sequence from the time of 
drug administration, and cannot be reasonably explained by other factors such as the 
subject’s clinical state, or non-study drugs or interventions. 
ii 
Severity 
A serious adverse event is one that: 
(a) Results in death, 
(b) Is life-threatening (the subject was, in the view of the Principal Investigator, in 
immediate danger of death from the event as it occurred), 
(c) Requires inpatient hospitalization or prolongation of existing hospitalization, 
(d) Results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, 
(e) 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. 
iii 
Expectedness 
The purpose of reporting is to provide new, important information on serious reactions or 
events previously unobserved or undocumented. Therefore, all adverse events will be 
evaluated as to whether their occurrence was unexpected.  
1. Unexpected: An unexpected adverse event or adverse reaction is one for which the 
nature or severity is not consistent with information in the protocol, consent form, or 
product brochure. An adverse event or adverse reaction also may be categorized as 
unexpected if the event has not previously been observed at the same specificity and/or 
severity.  
2. Expected: An event is considered expected if it is known to be associated with the 
study drugs and/or the disease state. For this protocol, expected events include at least 
the following and may include other symptoms included in the product brochure but not 
listed below: 
o Injection site reactions and pain 
o GI upset symptoms (nausea, vomiting) 
o Fever 
o Swelling 
o Itching 
o Heart attacks 
o Strokes 
o Congestive heart failure: Failure of the heart to pump with normal efficiency 
o Thrombosis of vascular access: Clotting of lines placed in blood vessels 
o Other blood clotting events (i.e. DVT, Pulmonary embolism) 
o Tumor progression or recurrence 
o High blood pressure 
o Serious Allergic reactions: vomiting, low blood pressure, swelling of the tongue 
and face, difficulty breathing, skin rash, hives 
o Pure red cell aplasia: Failure of the body to make any red blood cells 


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o Antibodies to EPO 
o Transmission of viral disease 
o Joint, muscle, or bone pain 
o Dizziness 
o Cough 
o Soreness of mouth 
o Headache 
o Seizures 
o Decreases or increases in the production of other blood cell types 
o High blood sugar 
o Insomnia 
o Depression 
o Trouble swallowing 
o Low potassium levels 
o Weight loss 
5.e 
Grading of Adverse events 
Adverse events will be graded based on the “Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0” as published by the U.S. Department of Health and 
Human Services, National Institute of Health, and National Cancer Institute. This can be 
found at:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
5.f 
Data Collection Procedures for Adverse Events 
In this trial, a primary safety concern as well as one of the secondary end points is to 
capture and compare suspected adverse reactions and adverse reactions associated 
with epoetin alfa administration. In addition, following standard clinical trial procedures, 
information on other adverse events and patient-reported symptoms will be collected.  
Adverse Events will be assessed at baseline and at each study visit. Subjects and 
families will be encouraged to report adverse events to study personnel as soon as the 
event occurs, rather than waiting for scheduled visits. Patient reported symptoms will be 
captured at each of these time points and will be documented by the study coordinators 
or investigators. Assessments at baseline will be obtained while the subject is not taking 
any study drug and is essential to accurate assessment of drug effects. Laboratory 
monitoring will be conducted to assess drug safety as outlined in Table 1 and Table 2. 
Abnormal values will be used to adjust study drug dosage (intervention will be held for 
hematocrit levels >45%), and will not be reported separately as adverse reactions or 
adverse events. However, analysis of safety at the end of the trial will encompass 
adverse reactions, other adverse events, and these laboratory abnormalities, for a 
comprehensive assessment of the safety profile of the study drugs. 
5.g 
Reporting Procedures 
The research investigators will report all adverse events, regardless of expectedness 
and relationship to the study drug according to the following timeframes: 
Classification 
Expectedness 
Relatedness 
Reporting 
Timeframe


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Serious: Fatal life 
Threatening 
Unexpected 
Related 
Within 10 calendar 
days of first 
knowledge of event 
to the IRB 
Serious: Fatal life 
threatening 
Unexpected or 
Expected 
Unrelated 
Within 10 calendar 
days of first 
knowledge of event 
to the IRB 
Serious (Suspected 
Adverse Reactions) 
Unexpected 
Related 
Within 10 calendar 
days of first 
knowledge of event 
to the IRB 
Serious 
Unexpected or 
Expected 
Unrelated 
Within 10 calendar 
days of first 
knowledge of event 
to the IRB 
Not Serious 
Unexpected or 
Expected 
Unrelated or 
Related 
Quarterly to DSMB  
The Investigator or designee will report all serious adverse events to the local IRB 
according to local IRB policies within 10 working days. 
5.h 
Adverse Event Reporting Period 
The adverse event reporting period will begin at the baseline assessment and will 
continue through 30 days after exiting the study. 
5.i 
Post-study Adverse Event 
All adverse events unresolved at the time of the subject's termination from the study will 
be followed by the investigators until the events are resolved, the subject is lost to follow-
up, or the adverse event is otherwise explained or has stabilized. At the last scheduled 
contact, the investigator will instruct each subject or parent/guardian to report any 
event(s) occurring in the next 30 days. Any death or other clinically serious adverse 
event that may be related to the study drugs and that occurs at any time after a subject 
has discontinued study drug or terminated study participation will be recorded and 
reported. 
5.j 
Pure Red Cell Aplasia 
We will be monitoring CBCs weekly. According to the prescribing information, if PRCA is 
suspected with severe anemia (decline in hemoglobin level >0.5 to 1 g/dL per week or 
transfusion requirement once a week to maintain adequate hemoglobin levels), normal 
platelet and white blood cell count, and low reticulocyte count (<10,000/microL) we will 
perform assays for binding and neutralizing antibodies in those subjects by contacting 
the manufacturer. All ESA administration will be permanently discontinued and the FDA 
will be notified within 48 hours. 


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Any unused blood samples from the baseline lab draw through week 14 will be banked 
either at UC San Diego or Rady Children's Hospital San Diego biorepositories under 
appropriate conditions to allow for immunogenicity testing if needed until 6 months after 
an individual subject has completed their last injection.  
F6 
Study Outcome Measurements and Ascertainment 
Ascertainment of the study outcome measurements and adverse events will be obtained 
on a case report form by a study investigator. These will include: 
 
Age/adjusted age 
 
Weight 
 
Oxygen saturation 
 
Compliance of medication 
 
Complete blood count 
 
Transfusions needed 
 
Hospitalizations 
 
Adverse events (Severity, expectedness, and relationship) 
G 
Statistical Plan  
G1 
 Sample Size Determination and Power 
This will be a randomized controlled single center prospective study of up to 60 patients 
to account for drop out rate. There will be a minimum 20 treatment patients and 20 
control patients enrolled. This sample size is based on a 2 proportion population formula 
with the assumption that without treatment about 80% of infants need transfusions 
(based on our experience), and 40% of infants with erythropoietin will need transfusions. 
G2 
 Interim Monitoring and Early Stopping 
Unforeseen inaccuracies in design assumptions, in particular having to do with the 
number of infants who need transfusions without treatment could lead to decreases in 
the trial’s statistical power to detect treatment effects. Accordingly, an analysis will be 
conducted to estimate the variance of the estimated difference, between the two arms in 
regards to number of transfusions. This analysis will be conducted within the intention-
to-treat framework under which the primary analysis of the primary endpoint will be 
conducted. 
To allow time for corrective action if necessary, this analysis will be performed 
approximately after 10 patients have been enrolled in both arms. If necessary, this 
method will be used to obtain a recommended increase in sample size. 
An interim analysis of futility will also be performed to determine if the study should 
continue. This will be done when 10 subjects in each arm have completed the study. The 
study will be terminated if there is no absolute decrease in number of transfusions per 
subject. 


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It is possible that the DSMB may consider it necessary to stop the trial early due to 
safety concerns. To monitor safety, adverse event rates will be compared between the 
two trial arms and reported to the DSMB.  
In addition, the research team will perform an analysis after the first 5 subjects have 
completed at least 1 intervention in the EPO arm for safety. These 5 patients will serve 
as a safety population study. 
An interim analysis of safety will be done after 10 patients have enrolled and completed 
each arm to assess any differences in adverse events between the 2 arms. This will be 
reviewed by the DSMB who will make the determination as to whether any safety 
concerns mandate early trial termination.
G3 
 Analysis Plan 
All primary analyses for efficacy will be performed on an intention-to-treat basis. All 
subjects will be analyzed according to their group assignment regardless of actual 
treatment received. In addition, both groups will be compared for safety at the end of the 
study by comparing adverse events and rates of adverse events. In the safety analysis, 
subjects will only be included if they actually received treatments in that group. (i.e. if a 
patient on the EPO arm did not get EPO, they should not be included in the analysis of 
safety in that arm). 
G4 
 Statistical Methods  
All data will only be gathered during the period in which the subjects will be active in the 
study (from baseline to 14 weeks post initial injection). 
For the primary aim, we will compare the number of blood transfusions (one 10 ml/kg 
aliquot = 1 transfusion) between the two groups with a two-proportion z test. With n = 20 
subjects per group, this test will have 80% power at the α = 0.05 significance level to 
detect a difference. The primary aim will be assessed when all subjects have completed 
week 14. 
We will compare weight gain and the change in oxygen saturation between baseline 
measurements and the 6 week follow-up with a two sample t-test. We will also use a 
linear mixed effects model, with a random intercept included to account for within subject 
correlation, to determine differences in the longitudinal trends in weight and oxygen 
saturation between groups. The length of the initial stay will be compared between 
groups with a two-sample t-test. We will treat the number of re-admissions (in regards to 
failure to thrive and cyanosis) as a categorical variable, and use Fisher’s exact test to 
determine if there is a difference between EPO and control group readmission counts. 
We will consider the Mann-Whitney U test as a robust alternative to the two-sample t-
test if the assumptions of the t-test are not met by the data. 
With a sample size of n = 20 subjects per group, the t-tests described above will have 
80% power at the α = 0.05 level to detect an effect size equal to 0.91 times the common 
standard deviation. For weight change, assuming that the standard deviation of weights 
at baseline and the 6 week follow-up equal 1.22 and 1.53 (respectively), and assuming a 


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19
moderately high correlation between weight measurements within child of ρ = 0.70, this 
translates to a detectable difference of 1.00 kgs. 
G5 
 Missing Outcome Data 
As this study will have an intention to treat model, missing outcome data will default to 
reflect that the subject has received a transfusion. In addition, there may be additional 
analysis only reflecting subjects who have completed the study in its entirety.  
H Data Handling and Record Keeping 
H1 
Confidentiality and Security 
All data will be kept secure through the UCSD REDCap database provided by the 
Clinical and Translational Research Institute. REDCap is a customizable secure Web 
based database. It can only be accessed with a username and password that is 
assigned specifically to each research member. Information entered into the data entry 
system will be by subject study I.D. number. Data will be checked by an automated 
validation tool on REDCap to ensure proper data entry. A project has been created in 
that database for this particular study. 
H2 
Training  
Before the study is started, each member must complete certification requirements to 
conduct research and show demonstration of familiarity with study procedures, methods 
for endpoint measurement, use of the database management system to conduct the 
study.  
H3 
Case Report Forms and Source Documents 
The case report forms (both inpatient and outpatient) will be used as the source 
documents. The case report form that will be used can be found in section L3. 
H4 
Records Retention 
All data will be kept secure through the UCSD RED Cap database. Hard copies of the 
case report forms will be stored in binders that will be kept in secure areas in the 
research office.    
I 
Study Monitoring, Auditing, and Inspecting 
I1 
Study Monitoring Plan, Auditing and Inspecting  
Interim monitoring will be performed as outlined in section G2. In addition, throughout 
the entire study, data will be collected and compiled on a weekly basis. Data will be 
entered into the database at least monthly. The research team will review to ensure that 
the data is being obtained properly, entered into the database properly and to look for 
any missing data at least quarterly. A safety report will be submitted to the DSMB for 
review at least quarterly. 


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J 
Study Administration 
J1 
Organization and Participating Centers 
University of California, San Diego 
Rady Children’s Hospital, Heart Institute 
J2 
Funding Source and Conflicts of Interest 
This study is currently funded by the Academic Enrichment Grant from the Rady 
Children’s Hospital foundation.  
J3 
Committees 
Research team:
David Werho, MD – Principal Investigator (attending cardiologist/intensivist at RCHSD) 
– responsible for recruitment, data collection and analysis, as well as manuscript 
preparation. 
Justin Yeh, MD (Attending cardiologist at Children’s Hospital of Pittsburgh) – will assist in 
analysis of deidentified data and manuscript preparation. 
Jesse Lee, MD (Attending cardiologist at Children’s Hospital of San Antonio)– will assist in 
analysis of deidentified data and manuscript preparation. 
Howaida El-Said, MD, PhD (attending cardiologist at RCHSD)– will assist in recruitment 
therapy administration, in data collection, analysis, and manuscript preparation. 
Stephanie Moriarty RN, MSN, ACNP- (Nurse Practitioner at RCHSD) – will assist in 
recruitment, therapy administration, in data collection, analysis, and manuscript 
preparation. 
Denise Suttner, MD (Attending neonatologist at RCHSD) -- will assist in recruitment 
therapy administration, in data collection, analysis, and manuscript preparation. 
Andrew Ligsay, MD (Pediatric Resident, UCSD) –will assist in recruitment, therapy 
administration, data collection, analysis and manuscript preparation. 
Danica Griffin, MS – Research Coordinator – responsible for all regulatory/IRB 
documents and communications pertaining to the study. 
J4 
Subject Stipends or Payments  
There is no stipend or monetary benefits to the patient or their families. 
J5 
 Study Timetable 
This study is projected to take 4 years. 2 to 2.5 years for recruitment of study subjects 
and obtain all necessary data. 1.5 to 2 years for statistical analysis and manuscript 
preparation. 
K 
Publication Plan  
After the study and analysis is complete, we plan to publish the data to a journal that is 
well recognized in the field of congenital heart disease. 


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L 
 Attachments  
L1 
 Tables 
Table 1 
Treatment Group
Tests and 
Procedures 
Baseline 
(one 
week 
post 
op/cath,≤ 
48 hours 
prior to 
1st
injection)
Week 1 (1 
week post 
op) 
Week 2* 
Week 
3* 
Week 
4* 
Week 
5*  
Wee
k 6* 
Week 
7* 
Week 
14 
Review eligibility 
X 
Informed 
Consent
X 
Physical Exam 
including 
Saturation 
X 
 X 
X 
X 
X 
X 
X 
X  
X 
Epogen Injection 
X 
X 
X 
X 
X 
X 
Iron  
X and 
ongoing for 
12 weeks 
CBC Lab Draw 
X 
X  
X 
 X 
X  
 X 
X 
X 
Iron Studies 
X 
If needed after iron replacement therapy 
X 
*Week 2-7 visits within 5-10 days of last injection. CBC will be reviewed 
prior to each injection. 


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Table 2 
Non-Treatment (Control) Group
Tests and 
Procedure
s 
Baseline 
(one 
week 
post 
op/cath,
≤ 48 
hours 
prior to 
1st
injection
)
Week 
1 (1 
week 
post 
op) 
Week 
2* 
Week 
3* 
Week 
4* 
Week 
5*  
Week 
6 
Week 
7* 
Week 
14 
Review 
eligibility
X 
Informed 
Consent
X 
Physical 
Exam 
including 
Saturation 
X 
As indicated by subject’s care 
team 
X 
X 
Iron 
X and ongoing for 12 weeks 
CBC Lab 
Draw
X 
As indicated by subject’s care team 
X 
X 
Iron 
Studies
X 
If needed after iron replacement therapy 
X 
*Week 7 visits +/- 1 week.  


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L2 
 Informed consent documents 
Rady Children’s Hospital – San Diego 
and University of California, San Diego 
Parent Informed Consent 
Erythropoietin to Prevent Unnecessary Transfusions In Patients 
With Cyanotic Congenital Heart Disease – A Prospective 
Randomized Control Trial 
This is a research study. Research studies include only subjects who choose to 
take part. You are being asked to let your child take part in this study because 
he/she has cyanotic congenital heart disease. Please take your time to make 
your decision. Discuss it with your child and family. Be sure to ask any questions 
that you may have. 
STUDY INVESTIGATOR AND SPONSOR 
Investigator(s): 
David Werho, MD 
Sponsor: 
Division of Cardiology, Department of Pediatrics  
Rady Children’s Academic Enrichment Fund 
WHY IS THIS STUDY BEING DONE?
Cyanotic congenital cardiac patients require higher hemoglobin concentrations (red 
blood cell levels) for optimal delivery of oxygen to the body. Erythropoietin (EPO) is a 
hormone that the human body makes to stimulate the production of red blood cells. It 
has been given to help increase red blood cell levels in patients with low counts. Giving 
EPO and iron may prevent and/or decrease the number of blood transfusions needed in 
this population. We will study if giving EPO and iron is safe, tolerated, and if it decreases 
the need for blood transfusions. 
WHAT MAKES THIS DIFFERENT FROM THE USUAL TREATMENT?
The experimental part of this study is giving EPO and iron to prevent blood transfusions. 
This medication has been shown in some patients to prevent blood transfusions in high 
risk individuals. EPO injections are FDA approved for patients with cancer and chronic 
renal failure, but the use in this population has not been approved. This is a randomized 
controlled trial.  


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Your child will be assigned by chance to a study group (1 group will receive the 
study medication, and one will be observed). Your child has an equal chance of 
being assigned to Group 1 or 2. 
Group 1 (treatment group): 
 
Patients in the treatment group will receive weekly EPO injections and iron 
supplementation for 6 weeks starting before 8 weeks of age, 1 week after their 
first procedure (surgery or heart catheterization). They will be followed for 14 
weeks. 
Group 2 (control group): 
 
Patients in the treatment group will not receive any extra intervention outside of 
standard of care. They will receive iron supplementation for 6 weeks starting 
before 8 weeks of age, 1 week after their first procedure (surgery or heart 
catheterization). They will be followed for 14 weeks. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
We will be enrolling up to 60 subjects to be in this study with a minimum of 20 subjects in 
each group.
HOW LONG WILL YOUR CHILD BE IN THE STUDY?
Your child will be in the study for 14 weeks. 
You can stop your child’s participation at any time. However, if you decide to stop your 
child from participating in the study, we encourage you to talk to the research doctor. 
WHAT IS INVOLVED IN THE STUDY?
This is what will happen if your child participates in this study: 
Group 1 (treatment group): 
 
Patients in the treatment group will receive weekly EPO injections for 6 weeks 
starting before 8 weeks of age (at least one week after their surgery) at 500 
units/kg/injection (SQ) and oral ferrous sulfate (iron) at 3 mg/kg/day of elemental 
iron, which is an accepted treatment for anemia and prevention of anemia.  
 
All injections will be administered with a weekly visit in the cardiology clinic or in 
the hospital if the infant remains hospitalized by a member of the care team. 
 
A complete blood count will be obtained prior to initiation of treatment, after the 
1st dose and weekly during weeks 2 through 7 of the study (to confirm that there 
is no over-shoot, i.e. that the hemoglobin is increased to an abnormally elevated 
level), and week 14. They will be assessed at these time intervals. You will not 
be billed for clinic visits and laboratory tests performed as part of the research 
study. 
 
Any unused blood samples from the baseline through week 14 draw of the study 
will be banked for antibody testing if needed. 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
25
Group 2 (non-treatment group): 
 
Patients in the non-treatment group will not receive injections. They will be 
started on oral ferrous sulfate (iron) at 3 mg/kg/day of elemental iron.  
 
They will be assessed at baseline for enrollment in the study, at week 7 and 14 
after enrollment. A complete blood count (lab draw or heel stick) will be obtained 
at these intervals for comparison with the treatment group. 
 
Additional visits and labs will be done only as indicated by the clinician primarily 
taking care of the infant. 
 
Any unused blood samples from the baseline through week 14 draw of the study 
will be banked for antibody testing if needed. 
WHAT ARE THE RISKS OF THE STUDY? 
The most common side effects seen with erythropoietin injections per the prescribing 
information are:    
o Injection site reactions and pain 
o GI upset symptoms (nausea, vomiting) 
o Fever 
o Swelling 
o Itching 
Over 2200 neonates have been a part of studies involving EPO. No significant adverse 
events have been reported in the literature with neonates receiving EPO. 
Some possible adverse effects for neonates include: 
 Iron deficiency (which can be prevented by ensuring adequate supplementation). 
 Low white blood cell counts (self-correcting after stopping treatment) may 
occasionally occur. 
 Low platelet counts 
 High platelet counts 
 High blood pressure 
 Early use has been associated with more severe eye disease (retinopathy of 
prematurity) if given in extreme premature neonates. 
Side effects seen less often (in adults) are: 
o “Over-shoot” of target red blood cell levels (Abnormally elevated number of red 
blood cells)  
o Decreases or increases in the production of other blood cell types 
o High blood pressure 
o Cough 
o Soreness of mouth 
o Headache 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
26
o Dizziness 
o Low potassium levels 
o Weight loss 
o Transmission of viral disease 
o Joint, muscle, or bone pain 
o Seizures 
o High blood sugar 
o Insomnia 
o Depression 
o Trouble swallowing 
o Heart attacks 
o Strokes 
o Congestive heart failure: Failure of the heart to pump with normal efficiency 
o Thrombosis of vascular access: Clotting of lines placed in blood vessels 
o Other blood clotting events (i.e. DVT, Pulmonary embolism) 
o Tumor progression or recurrence 
o Serious Allergic reactions: vomiting, low blood pressure, swelling of the tongue 
and face, difficulty breathing, skin rash, hives 
o Pure red cell aplasia: Failure of the body to make any red blood cells 
o Antibodies to EPO 
If your child has any illness or discomfort as a result of using the study drug call your 
study doctor immediately. If necessary, the study drug may be stopped and other 
therapy may be started. 
Your child will be assigned to a study group at random (by chance). Your child’s 
assignment is based on chance rather than a medical decision made by the researchers. 
The study group to which your child is assigned to might not be the group you would 
prefer your child to be in. It might also prove to be less effective or have more side 
effects than the other study group(s), or other treatments available for your child’s 
condition. 
Possible side effects from blood drawing or heel stick include: 

Faintness 

Irritation of the vein, such as redness or swelling 

Pain  

Bruising or bleeding at the blood draw site. 

There is also a slight possibility of infection. 

Need for blood transfusions because of more frequent lab monitoring 
If your child uses the numbing cream for blood draws there may be skin irritation, the 
skin may temporarily turn red, white or develop a rash.  
Other risks in this study include the following: 
o Your child’s condition may not improve; it may stay the same; or it may worsen 
while participating in this study. 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
27
o There may be side effects or discomforts associated with this study, which are 
not yet known. 
o The researchers in this study have determined to target a red blood cell level 
(hematocrit) that is higher than the recommended amount of 33% as listed in the 
prescribing label for EPO. The EPO prescribing information is based on and 
includes data of various adult populations which suggest that targeting a 
hematocrit level above 33% is associated with increased severe adverse events. 
Specifically, when higher targets of hematocrit levels of 42% were used in clinical 
trials, the risk of death, blood clotting events, and other adverse events were 
seen in the higher target groups, in adult patients with chronic kidney disease as 
well as cancer. This has not been replicated in pediatric studies especially 
neonates. There are some studies in pediatric patients showing that a higher 
hematocrit level may not be necessary to ensure adequate oxygen delivery to the 
body, however given what we know about “blue” (cyanotic) heart conditions, 
these patients require a hematocrit level of 40-45% to ensure adequate delivery 
of oxygen to the body.  A blood transfusion is often considered when the 
hematocrit level is below 40% in this population in our practice. EPO has been 
used safely in premature infants, however safe hematocrit target levels in 
pediatric patients has not been well studied or well established. We will be 
targeting a hematocrit level between 40-45%.  
o Possible risk of loss of confidentiality associated with participant study data. The 
study doctor and the study staff will take care to de-identify any information about 
your child, including using a subject number rather than your child’s name, as 
one of the ways that his/her personal information will be protected. 
For more information about these risks and side effects, ask your child’s study doctor.  
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There may or may not be any direct benefit to your child by participating in the study. 
However knowledge can be obtained to help infants in the future as well as provide a 
platform for more research in this area. 
WHAT OTHER OPTIONS ARE THERE?
The alternative to study participation is to not be included in the study. Your child will 
continue to have standard of care treatment without erythropoietin which may include 
blood transfusions, but will not be included in the study data. Your child’s care will not be 
compromised. 
WHAT ABOUT CONFIDENTIALITY? 
Your child will be given a study identification (ID) number. All study records and 
questionnaires will be labeled with this number and not your child’s name or 
other personal data. This information will be kept on a password-protected 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
28
computer, will be kept separately from the study data, and will not be shared with 
researchers outside the study center.  
While your child is in this study all related records may be made available to: 
 The UCSD Institutional Review Board (for the protection of human 
subjects in research) 
 Other regulatory agencies responsible for overseeing research, such as 
the federal Office for Human Research Protections 
 The Food and Drug Administration (FDA)
A copy of this permission form, and the HIPAA authorization form that you will 
sign, will be placed in your child’s medical record. Your child’s records and 
information will not be released without your permission unless required by law.
Under California law, we must report information about known or reasonably 
suspected incidents of abuse or neglect of a child including physical, sexual, 
emotional, and financial abuse or neglect. If any investigator has or is given such 
information, he or she may be required to report such information to the 
appropriate authorities. 
If the study results are published or presented, your child will not be identified. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Website will not include information that can 
identify your child. At most the Website will include a summary of the results. You 
can search this Website at any time.
WHAT ARE THE COSTS?
Labs (CBC) during an inpatient hospitalization are a part of acceptable standard of care 
and you or your health plan/insurance company will have to pay for these. Outpatient clinic 
visits and labs (i.e. CBC) that are not considered part of acceptable standard of care and 
pertain to this research will be covered by the research study funds. You will not be billed 
for clinic visits and laboratory tests performed as part of the research study. The study 
drug erythropoietin will be supplied at no cost while your child takes part in this study 
You and/or your health plan/insurance company will need to pay for all of the other costs of your child’s condition not 
specifically related to the research. 
WHAT IF YOUR CHILD IS INJURED IN THE STUDY?
If your child is injured as a direct result of participation in this research, Rady Children’s 
Hospital – San Diego or the University of California will provide any medical care needed 
to treat those injuries. Neither Rady Children’s Hospital – San Diego nor the University 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
29
will provide any other form of compensation to you if your child is injured. You may call 
the Human Research Protections Program Office at (858) 246-4777for more information 
about this, to inquire about your child’s rights as a research subject or to report research-
related problems. 
WILL YOU OR YOUR CHILD BE COMPENSATED?
There is no compensation for participation and completion of this study.
WHO DO YOU CALL IF YOU OR YOUR CHILD HAS QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury during business hours, contact 
the research coordinator: 
David Werho, MD 
(858) 966-5855  
For questions after normal business hours or on weekends, please call (858) 576-1700
and ask for the cardiology physician on call. 
WHAT ARE YOUR CHILD’S RIGHTS AS A RESEARCH SUBJECT?
Taking part in this study is voluntary. You may choose not to let your child take part or 
you or your child may choose to leave the study at any time. Your decision will not result 
in any penalty or loss of benefits to which your child is entitled. If you have questions 
about your child’s rights you may call: 
University of California, San Diego 
Human Research Protections Program 
(858) 246-4777 
You will be told about any new information that may affect your child’s health, welfare, or 
willingness to stay in this study.  
SIGNATURE AND CONSENT TO BE IN THE STUDY:
Your signature below means that you have read the above information about the study 
and have had a chance to ask questions to help you understand what your child will do 
in this study and how your child’s information will be used. 
You or your child can change your minds later if you want to. You will be given a copy of 
this consent form and a copy of the Subject’s Bill of Rights. By signing this consent form 
you are not giving up any of your or your child’s legal rights. 
You agree to allow your child to participate in this research study. 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
______________________________________________________________________________________ 
30
NAME OF PARTICIPANT 
 
AGE 
________________________________________________ 
PRINTED NAME OF PARENT OR GUARDIAN 
 
________________________________________________ 
_______________ 
SIGNATURE OF PARENT OR GUARDIAN  
DATE 
_________________________________________________ 
PRINTED NAME OF WITNESS (person explaining this form) 
_________________________________________________ 
_______________ 
SIGNATURE OF WITNESS (person explaining this form)  
DATE  


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
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31
SUBJECT’S BILL OF RIGHTS 
It is important that the purpose and procedures of the research study are fully 
understood and that consent is offered willingly. A subject in a research study or 
someone, who is asked to give consent on behalf of another person for such 
participation, has the right to the following: 
1. 
Be informed of the nature and purpose of the research. 
2. 
Be given an explanation of all procedures to be followed and of any drug or 
device to be used. 
3. 
Be given a description of any risks or discomforts, which can be reasonably 
expected to result from this research study. 
4. 
Be given an explanation of any benefits, which can be reasonably expected to 
the subject as a result of this research study. 
5. 
Be informed of any appropriate alternative procedures, drugs, or devices that 
may be advantageous and of their relative risks and discomforts. 
6. 
Be informed of any medical treatment, which will be made available to the 
subject if complications should arise from this research. 
7. 
Be given an opportunity and encouraged to ask any questions concerning the 
study or the procedures involved in this research. 
8. 
Be made aware that consent to participate in the research may be withdrawn and 
that participation may be discontinued at any time without affecting continuity or 
quality of medical care. 
9. 
Be given a copy of the signed and dated written consent form. 
10. 
Not be subjected to any element of force, fraud, deceit, duress, coercion, or any 
influence in reaching the decision to consent or to not consent to participate in 
the research. 
If you have any further questions or concerns about your child’s rights as a research 
subject, please contact your research doctor or the UCSD Human Research Protections 
Program at (858) 246-4777. 


UCSD/Rady Children’s Hospital  
Epoetin alfa trial protocol 
June 28, 2018 
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32
L3 
 Case report form 
Erythropoietin to Prevent Unnecessary Transfusions In Patients With Congenital Cyanotic 
Heart Disease – A Prospective Control Trial 
Patient ID: ____________________ 
 
Date of Visit: __________________ 
Trial Week (circle one):  1    2    3    4    5    6    7    8    9    10    11    12    13    14     
Cardiac diagnosis/Surgical history:  
_____________________________________________________________________________ 
_____________________________________________________________________________ 
Age:  __________    Adjusted Age: __________    Weight: _______(kg)      SpO2 _______%
Injection dose: #  1    2    3    4    5    6    Iron Sulfate:                (mg) ;                      (mg/kg);    
Is patient compliant ?  Y/N 
Other medications:____________________________________________________________ 
CBC:   WBC _____    HgB ______    Hct ______  Plt _______ 
Transfusions needed (circle one):  YES    /   NO 
If Yes, # units/ml and date:   __________________________________________________   
Hospitalization needed (circle one):  YES    /   NO 
# of Days: _______________ 
If Yes, Dates and Primary reason:
_____________________________________________________________________________ 
Adverse events: Check off if subject has the following since the last visit 
o Injection site reactions and pain 
o GI upset symptoms (nausea, vomiting) 


UCSD/Rady Children’s Hospital  
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June 28, 2018 
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33
o Fever 
o Swelling 
o Itching 
o Heart attacks 
o Strokes 
o Congestive heart failure: Failure of the heart to pump with normal efficiency 
o Thrombosis of vascular access: Clotting of lines placed in blood vessels 
o Other blood clotting events (i.e. DVT, Pulmonary embolism) 
o Tumor progression or recurrence 
o High blood pressure 
o Serious Allergic reactions: vomiting, low blood pressure, swelling of the tongue 
and face, difficulty breathing, skin rash, hives 
o Pure red cell aplasia: Failure of the body to make any red blood cells 
o Antibodies to EPO 
o Transmission of viral disease 
o Joint, muscle, or bone pain 
o Dizziness 
o Cough 
o Soreness of mouth 
o Headache 
o Seizures 
o Decreases or increases in the production of other blood cell types 
o High blood sugar 
o Insomnia 
o Depression 
o Trouble swallowing 
o Low potassium levels 
o Weight loss 
o “Over-shoot” of target red blood cell levels (Abnormally elevated number of red 
blood cells) 
o Other Adverse Events: _________________________________________


UCSD/Rady Children’s Hospital  
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June 28, 2018 
______________________________________________________________________________________ 
34
M 
References 
1. Donato H, Rendo P, Vivas R, Schvartzman G, Digregorio J, Vain N. 
Recombinant human erythropoietin in the treatment of anemia of prematurity: a 
randomized, double- blind, placebo-controlled trial comparing three different 
doses. International Journal of Pediatric Hematology/ Oncology 1996;3:279–85.  
2. Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R, et al. Early 
treatment with erythropoietin beta ameliorates anemia and reduces transfusion 
requirements in infants with birth weights below 1000 g. Journal of Pediatrics 
2002;141(1):8–15.  
3. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell 
transfusion in preterm and/or low birth weight infants. Cochrane Database of 
Systematic Reviews 2014, Issue 4. Art. No.CD004863. DOI: 10.1002/14651858. 
CD004863.pub4. 
4. Hugo Donato (2005) Erythropoietin: an update on the therapeutic use in 
newborn infants and children, Expert Opinion on Pharmacotherapy, 6:5, 723-734 
5. Naguib AN, Winch PD, Tobias JD et al. A single-center strategy to minimize 
blood transfusion in neonates and children undergoing cardiac surgery. Pediatr 
Anesth 2015; 25: 477–486. 
6. Roseff, S.D., Luban, Naomi, Manno, Catherine, Guidelines for assessing 
appropriateness of pediatric transfusion. Transfusion, 2002. 2002 (42): p. 1398 -
1413. 
7. Fearon, JA, Weinthal, J. The Use of Recombinant Erythropoietin in the Reduction 
of Blood Transfusion Rates in Craniosynostosis Repair in Infants and Children. 
Plast Reconstr Surg. 2002 Jun; 109(7): 2190-6. 
8. Roseff SD, Luban NL, Manno CS. Guidelines for assessing appropriateness of 
pediatric transfusion. Transfusion 2002 Nov; 42: 1398 -1413. 
9. Strauss RG. Transfusion Therapy in Neonates. Am J Dis Child. 1991:145 (8) 
904-911.
10. Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams 
N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel 
TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure 
red-cell aplasia and epoetin therapy.
N Engl J Med. 2004;351(14):1403.

ICF_001.pdf: 
 
 
 
Erythropoietin to Prevent Unnecessary 
Transfusions in Patients with Cyanotic 
CHD - A Prospective Control Trial 
NCT02564796 
IRB-Approved Informed Parent Consent – Version: 2.0 29Nov2018 
 




#160871 
IRB #160871 
Version 2.0 | 11/29/18 
Page 2 of 10
Human Research 
Protections Program 
Approved 
Current Approval: 
 06/13/2019 
Do not use after 
 07/04/2020 
risk individuals. EPO injections are FDA approved for patients with cancer and chronic 
renal failure, but the use in this population has not been approved. This is a randomized 
controlled trial.  
Your child will be assigned by chance to a study group (1 group will receive the study 
medication, and one will be observed). Your child has an equal chance of being assigned 
to Group 1 or 2. 
Group 1 (treatment group): 
! Patients in the treatment group will receive weekly EPO injections and iron 
supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first 
procedure (surgery or heart catheterization). They will be followed for 14 weeks. 
Group 2 (control group): 
! Patients in the treatment group will not receive any extra intervention outside of 
standard of care. They will receive iron supplementation for 6 weeks starting before 
8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). 
They will be followed for 14 weeks. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
We will be enrolling up to 60 subjects to be in this study with a minimum of 20 subjects in 
each group.
HOW LONG WILL YOUR CHILD BE IN THE STUDY?
Your child will be in the study for 14 weeks. 
You can stop your child’s participation at any time. However, if you decide to stop your 
child from participating in the study, we encourage you to talk to the research doctor. 
WHAT IS INVOLVED IN THE STUDY?
This is what will happen if your child participates in this study: 
Group 1 (treatment group): 
! Patients in the treatment group will receive weekly EPO injections for 6 weeks 
starting before 8 weeks of age (at least one week after their surgery) at 500 
units/kg/injection (SQ) and oral ferrous sulfate (iron) at 3 mg/kg/day of elemental 
iron, which is an accepted treatment for anemia and prevention of anemia.  
! If oral iron cannot be tolerated and there is laboratory evidence of iron deficiency, 
intravenous iron will be used to replace iron stores 
! All injections will be administered with a weekly visit in the cardiology clinic or in the 
hospital if the infant remains hospitalized by a member of the care team. 
! Iron studies (Serum iron, ferritin, total iron binding capacity) will be obtained at 


#160871 
IRB #160871 
Version 2.0 | 11/29/18 
Page 3 of 10
Human Research 
Protections Program 
Approved 
Current Approval: 
 06/13/2019 
Do not use after 
 07/04/2020 
baseline and at week 14 with the final lab draw. If intravenous iron is used for 
replacement, iron studies will be repeated after replacement to ensure adequate 
iron stores. 
! A complete blood count will be obtained prior to initiation of treatment, after the 1st
dose and weekly during weeks 2 through 7 of the study (to confirm that there is no 
over-shoot, i.e. that the hemoglobin is increased to an abnormally elevated level), 
and week 14. They will be assessed at these time intervals. You will not be billed 
for clinic visits and laboratory tests performed as part of the research study. 
! Any unused blood samples from the baseline through week 14 draw of the study 
will be banked for antibody testing if needed. 
Group 2 (non-treatment group): 
! Patients in the non-treatment group will not receive injections. They will be started 
on oral ferrous sulfate (iron) at 3 mg/kg/day of elemental iron.  
! If oral iron cannot be tolerated and there is laboratory evidence of iron deficiency, 
intravenous iron will be used to replace iron stores 
! Iron studies (Serum iron, ferritin, total iron binding capacity) will be obtained at 
baseline and at week 14 with the final lab draw. If intravenous iron is used for 
replacement, iron studies will be repeated after replacement to ensure adequate 
iron stores. 
! They will be assessed at baseline for enrollment in the study, at week 7 and 14 
after enrollment. A complete blood count (lab draw or heel stick) will be obtained at 
these intervals for comparison with the treatment group. 
! Additional visits and labs will be done only as indicated by the clinician primarily 
taking care of the infant. 
! Any unused blood samples from the baseline through week 14 draw of the study 
will be banked for antibody testing if needed. 
If you consent to this study, there is a chance that your child may not become eligible for 
enrollment if his/her hematocrit never falls below the minimum threshold. In this case, your 
child will continue to receive the standard care during their hospitalization. 
WHAT ARE THE RISKS OF THE STUDY? 
The most common side effects seen with erythropoietin injections per the prescribing 
information are:    
! Injection site reactions and pain 
! GI upset symptoms (nausea, vomiting) 
! Fever 
! Swelling 
! Itching 
Over 2200 neonates have been a part of studies involving EPO. No significant adverse 
events have been reported in the literature with neonates receiving EPO. 


#160871 
IRB #160871 
Version 2.0 | 11/29/18 
Page 4 of 10
Human Research 
Protections Program 
Approved 
Current Approval: 
 06/13/2019 
Do not use after 
 07/04/2020 
Some possible adverse effects for neonates include: 
! Iron deficiency (which can be prevented by ensuring adequate supplementation). 
! Low white blood cell counts (self-correcting after stopping treatment) may 
occasionally occur. 
! Low platelet counts 
! High platelet counts 
! High blood pressure 
! Early use has been associated with more severe eye disease (retinopathy of 
prematurity) if given in extreme premature neonates. 
Side effects seen less often (in adults) are: 
! “Over-shoot” of target red blood cell levels (Abnormally elevated number of red
blood cells)  
! Decreases or increases in the production of other blood cell types 
! High blood pressure 
! Cough 
! Soreness of mouth 
! Headache 
! Dizziness 
! Low potassium levels 
! Weight loss 
! Transmission of viral disease 
! Joint, muscle, or bone pain 
! Seizures 
! High blood sugar 
! Insomnia 
! Depression 
! Trouble swallowing 
! Heart attacks 
! Strokes 
! Congestive heart failure: Failure of the heart to pump with normal efficiency 
! Thrombosis of vascular access: Clotting of lines placed in blood vessels 
! Other blood clotting events (i.e. DVT, Pulmonary embolism) 
! Tumor progression or recurrence 
! Serious Allergic reactions: vomiting, low blood pressure, swelling of the tongue and 
face, difficulty breathing, skin rash, hives 
! Pure red cell aplasia: Failure of the body to make any red blood cells 
! Antibodies to EPO 
If your child has any illness or discomfort as a result of using the study drug call your study 
doctor immediately. If necessary, the study drug may be stopped and other therapy may 


#160871 
IRB #160871 
Version 2.0 | 11/29/18 
Page 5 of 10
Human Research 
Protections Program 
Approved 
Current Approval: 
 06/13/2019 
Do not use after 
 07/04/2020 
be started. 
Your child will be assigned to a study group at random (by chance). Your child’s
assignment is based on chance rather than a medical decision made by the researchers. 
The study group to which your child is assigned to might not be the group you would prefer 
your child to be in. It might also prove to be less effective or have more side effects than 
the other study group(s), or other treatments available for your child’s condition. 
Possible side effects from blood drawing or heel stick include: 
#
Faintness 
#
Irritation of the vein, such as redness or swelling 
#
Pain  
#
Bruising or bleeding at the blood draw site. 
#
There is also a slight possibility of infection. 
#
Need for blood transfusions because of more frequent lab monitoring 
If your child uses the numbing cream for blood draws there may be skin irritation, the skin 
may temporarily turn red, white or develop a rash.  
Other risks in this study include the following: 
! Your child’s condition may not improve; it may stay the same; or it may worsen 
while participating in this study. 
! There may be side effects or discomforts associated with this study, which are not 
yet known. 
! The researchers in this study have determined to target a red blood cell level 
(hematocrit) that is higher than the recommended amount of 33% as listed in the 
prescribing label for EPO. The EPO prescribing information is based on and 
includes data of various adult populations which suggest that targeting a hematocrit 
level above 33% is associated with increased severe adverse events. Specifically, 
when higher targets of hematocrit levels of 42% were used in clinical trials, the risk 
of death, blood clotting events, and other adverse events were seen in the higher 
target groups, in adult patients with chronic kidney disease as well as cancer. This 
has not been replicated in pediatric studies especially neonates. There are some 
studies in pediatric patients showing that a higher hematocrit level may not be 
necessary to ensure adequate oxygen delivery to the body, however given what we 
know about “blue” (cyanotic) heart conditions, these patients require a hematocrit 
level of 40-45% to ensure adequate delivery of oxygen to the body.  A blood 
transfusion is often considered when the hematocrit level is below 40% in this 
population in our practice. EPO has been used safely in premature infants, however 
safe hematocrit target levels in pediatric patients has not been well studied or well 
established. We will be targeting a hematocrit level between 40-45%.  
! Possible risk of loss of confidentiality associated with participant study data. The 
study doctor and the study staff will take care to de-identify any information about 
your child, including using a subject number rather than your child’s name, as one 


#160871 
IRB #160871 
Version 2.0 | 11/29/18 
Page 6 of 10
Human Research 
Protections Program 
Approved 
Current Approval: 
 06/13/2019 
Do not use after 
 07/04/2020 
of the ways that his/her personal information will be protected. 
For more information about these risks and side effects, ask your child’s study doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There may or may not be any direct benefit to your child by participating in the study. 
However knowledge can be obtained to help infants in the future as well as provide a 
platform for more research in this area. 
WHAT OTHER OPTIONS ARE THERE?
The alternative to study participation is to not be included in the study. Your child will 
continue to have standard of care treatment without erythropoietin which may include 
blood transfusions, but will not be included in the study data. Your child’s care will not be
compromised. 
WHAT ABOUT CONFIDENTIALITY? 
Your child will be given a study identification (ID) number. All study records and 
questionnaires will be labeled with this number and not your child’s name or other 
personal data. This information will be kept on a password-protected computer, will be 
kept separately from the study data, and will not be shared with researchers outside the 
study center.  
While your child is in this study all related records may be made available to: 
! The UCSD Institutional Review Board (for the protection of human subjects in 
research) 
! Other regulatory agencies responsible for overseeing research, such as the federal 
Office for Human Research Protections 
! The Food and Drug Administration (FDA)
A copy of this permission form, and the HIPAA authorization form that you will sign, will be 
placed in your child’s medical record. Your child’s records and information will not be
released without your permission unless required by law.
Under California law, we must report information about known or reasonably suspected 
incidents of abuse or neglect of a child including physical, sexual, emotional, and financial 
abuse or neglect. If any investigator has or is given such information, he or she may be 
required to report such information to the appropriate authorities. 
If the study results are published or presented, your child will not be identified. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 


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required by U.S. Law. This Website will not include information that can identify your child. 
At most the Website will include a summary of the results. You can search this Website at 
anytime.
WHAT ARE THE COSTS?
Labs (CBC) during an inpatient hospitalization are a part of acceptable standard of care and 
you or your health plan/insurance company will have to pay for these. Outpatient clinic visits 
and labs (i.e. CBC) that are not considered part of acceptable standard of care and pertain 
to this research will be covered by the research study funds. You will not be billed for clinic 
visits and laboratory tests performed as part of the research study. The study drug 
erythropoietin will be supplied at no cost while your child takes part in this study 
You and/or your health plan/insurance company will need to pay for all of the other costs 
of your child’s condition not specifically related to the research. 
WHAT IF YOUR CHILD IS INJURED IN THE STUDY?
If your child is injured as a direct result of participation in this research, Rady Children’s
Hospital – San Diego or the University of California will provide any medical care needed 
to treat those injuries. Neither Rady Children’s Hospital – San Diego nor the University will 
provide any other form of compensation to you if your child is injured. You may call the 
Human Research Protections Program Office at (858) 246-4777 for more information 
about this, to inquire about your child’s rights as a research subject or to report research-
related problems. 
WILL YOU OR YOUR CHILD BE COMPENSATED?
There is no compensation for participation and completion of this study.
WHO DO YOU CALL IF YOU OR YOUR CHILD HAVE QUESTIONS OR PROBLEMS?
For questions about the study or a research-related injury during business hours, contact 
the research study doctor: 
Dr. David Werho at 858-966-5855 
For questions after normal business hours or on weekends, please call (858) 576-1700
and ask for the cardiology physician on call. 
WHAT ARE YOUR CHILD’S RIGHTS AS A RESEARCH SUBJECT?
Taking part in this study is voluntary. You may choose not to let your child take part or you 
or your child may choose to leave the study at any time. Your decision will not result in any 


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penalty or loss of benefits to which your child is entitled. If you have questions about your 
child’s rights you may call:
University of California, San Diego 
Human Research Protections Program 
(858) 246-4777 
You will be told about any new information that may affect your child’s health, welfare, or
willingness to stay in this study.  


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SIGNATURE AND CONSENT TO BE IN THE STUDY:
Your signature below means that you have read the above information about the study 
and have had a chance to ask questions to help you understand what your child will do in 
this study and how your child’s information will be used. 
You or your child can change your minds later if you want to. You will be given a copy of 
this consent form and a copy of the Subject’s Bill of Rights. By signing this consent form
you are not giving up any of your or your child’s legal rights.
You agree to allow your child to participate in this research study. 
NAME OF PARTICIPANT  
AGE 
________________________________________________ 
PRINTED NAME OF PARENT OR GUARDIAN 
________________________________________________ _______________ 
SIGNATURE OF PARENT OR GUARDIAN 
 
DATE 
_________________________________________________ 
PRINTED NAME OF WITNESS (person explaining this form) 
_________________________________________________ 
_______________ 
SIGNATURE OF WITNESS (person explaining this form) 
 
DATE  


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SUBJECT’S BILL OF RIGHTS
It is important that the purpose and procedures of the research study are fully understood 
and that consent is offered willingly. A subject in a research study or someone, who is 
asked to give consent on behalf of another person for such participation, has the right to 
the following: 
1. 
Be informed of the nature and purpose of the research. 
2. 
Be given an explanation of all procedures to be followed and of any drug or device 
to be used. 
3. 
Be given a description of any risks or discomforts, which can be reasonably 
expected to result from this research study. 
4. 
Be given an explanation of any benefits, which can be reasonably expected to the 
subject as a result of this research study. 
5. 
Be informed of any appropriate alternative procedures, drugs, or devices that may 
be advantageous and of their relative risks and discomforts. 
6. 
Be informed of any medical treatment, which will be made available to the subject if 
complications should arise from this research. 
7. 
Be given an opportunity and encouraged to ask any questions concerning the study 
or the procedures involved in this research. 
8. 
Be made aware that consent to participate in the research may be withdrawn and 
that participation may be discontinued at any time without affecting continuity or 
quality of medical care. 
9. 
Be given a copy of the signed and dated written consent form. 
10. 
Not be subjected to any element of force, fraud, deceit, duress, coercion, or any 
influence in reaching the decision to consent or to not consent to participate in the 
research. 
If you have any further questions or concerns about your child’s rights as a research
subject, please contact your research doctor or the UCSD Human Research Protections 
Program at (858) 246-4777.