Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Follow-up Study
Conditions: Anemia, Sickle Cell
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

  
 
 
 
 
 
 
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
 
FOLLOW-UP OBSERVATIONAL STUDY 
 
 
 
 
 
 
 
 
 
PROTOCOL 
 
Revision 2 
January 2010 
 
 
 
 
 
 
 
 
 
NOTICE 
 
The contents of this document 
are confidential and are not to be 
cited or discussed except with 
individuals to whom it has been 
distributed.   
 
Prepared by: 
 
 
 
 
 
 
 
Clinical Trials & Surveys Corp.  
             10065 Red Run Boulevard, Suite 250 
 
 Owings Mills, MD 21117  
 
 
 
 
 
 
 

 
 
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
TABLE OF CONTENTS 
 
Chapter 
 
 
 
 
 
 
 
 
 
 
Page 
 
 
1 
BACKGROUND AND STUDY RATIONALE 
 
 
 
 
1-1 
 
 
1.1 
Overview 
 
 
 
 
 
 
 
 
1-1 
 
 
2 
OBJECTIVES AND DESIGN OF THE STUDY 
 
 
 
 
2-1 
 
 
2.1 
Introduction 
 
 
 
 
 
 
 
 
2-1 
 
 
2.2 
Specific Aims  
 
 
 
 
 
 
 
2-4 
 
 
2.3 
Design of the Study 
 
 
 
 
 
 
 
2-5 
 
 
3 
CHILD ELIGIBILITY, RECRUITMENT, ORIENTATION, AND INFORMED 
 
 
CONSENT 
 
 
 
 
 
 
 
 
 
3-1 
 
 
3.1 
Introduction 
 
 
 
 
 
 
 
 
3-1 
 
 
3.2 
Family Orientation 
 
 
 
 
 
 
 
3-1 
 
 
3.3 
Informed Consent 
 
 
 
 
 
 
 
3-2 
 
 
3.4 
Informed Consent Template  
 
 
 
 
 
3-4 
 
 
 
4 
STUDY ENDPOINTS  
 
 
 
 
 
 
 
4-1 
 
 
4.1 
Introduction 
 
 
 
 
 
 
 
 
4-1 
 
 
4.2 
Follow-up Endpoints  
 
 
 
 
 
 
4-1 
 
 
 
4.2.1 Growth, Development and Education 
 
 
 
4-1 
 
 
 
4.2.2 Hematologic and Clinical Events 
 
 
 
 
4-2 
 
 
 
4.2.3 Central Nervous System 
 
 
 
 
 
4-2 
 
 
 
4.2.4 Spleen  
 
 
 
 
 
 
 
4-3 
 
 
 
4.2.5 Kidney  
 
 
 
 
 
 
 
4-4 
 
 
 
4.2.6 Fetal Hemoglobin 
 
 
 
 
 
 
4-5 
 
 
 
4.2.7 Stored Blood Sample  
 
 
 
 
 
4-5 
 
 
4.3 
Statistical Analyses Overview 
 
 
 
 
 
4-6 
 
 
4.4 
Statistical Considerations in Design and Study Size  
 
 
4-7 
 
 
 
4.4.1 Primary Treatment Comparisons 
 
 
 
 
4-7 
 
 
 
4.4.2 Spleen Endpoint 
 
 
 
 
 
 
4-8 
 
 
 
4.4.3 Data Analysis  
 
 
 
 
 
 
4-10 
 
 
 
 
4.4.3.1 Introduction 
 
 
 
 
 
 
4-10 
 
 
 
 
4.4.3.2  Regression Analysis and Adjustment 
 
 
4-12 
 
 
 
 
4.4.3.3  Longitudinal Data Analysis  
 
 
 
4-13 
 
 
 
 
4.4.3.4  Missing Data Analysis 
 
 
 
 
4-13 
 
 
 
4.4.4 Interim Monitoring 
 
 
 
 
 
 
4-14 
 
 
 
4.4.5 Safety Related Outcomes 
 
 
 
 
 
4-15 
 
 
 
 
 
 
 
 

 
TABLE OF CONTENTS (Continued) 
 
Chapter 
 
 
 
 
 
 
 
 
 
 
Page 
 
 
 
5 
OPEN-LABEL TREATMENT WITH HYDROXYUREA 
 
 
 
5-1 
 
 
5.1 
Overview 
 
 
 
 
 
 
 
 
5-1 
 
 
5.2 
Dose Titration of Open-Label Hydroxyurea  
 
 
 
5-1 
 
 
5.3 
Monitoring for Toxicity 
 
 
 
 
 
 
5-2 
 
 
 
6 
LABORATORY ANALYSES AND SPECIMENS 
 
 
 
 
6-1 
 
 
6.1 
Overview 
 
 
 
 
 
 
 
 
6-1 
 
 
6.2 
Pitted Cell Laboratory  
 
 
 
 
 
 
6-1 
 
 
6.3 
Cystatin C Laboratory  
 
 
 
 
 
 
6-1 
 
 
6.4 
VDJ/DNA Mutation Core Laboratory  
 
 
 
 
6-1 
 
 
6.5 
HJB Core Laboratory  
 
 
 
 
 
 
6-2 
 
 
6.6 
NHLBI Specimen Repository  
 
 
 
 
 
6-2 
 
 
 
6.6.1 Specimen Storage 
 
 
 
 
 
 
6-3 
 
 
 
6.6.2 Obtaining Storage Specimens 
 
 
 
 
6-3 
 
 
6.7 
Hemoglobin F, BUN and Microalbumin:Creatinine Ratio 
 
 
6-4 
 
 
 
Core Laboratory 
 
 
7 
GUIDELINES FOR STANDARD CLINICAL CARE  
 
 
 
7-1 
 
 
7.1 
Introduction 
 
 
 
 
 
 
 
 
7-1 
 
 
7.2 
Immunizations 
 
 
 
 
 
 
 
7-1 
 
 
7.3 
Prophylactic Medications 
 
 
 
 
 
 
7-1 
 
 
8 
SPECIAL STUDIES AND READING GROUPS 
 
 
 
 
8-1 
 
 
8.1 
Introduction 
 
 
 
 
 
 
 
 
8-1 
 
 
8.2 
Liver-Spleen Scans 
 
 
 
 
 
 
 
8-1 
 
 
8.3 
Pitted Cell Counts and Howell Jolly Bodies (HJB) 
 
 
 
8-1 
 
 
8.4 
Clinical Events 
 
 
 
 
 
 
 
8-2 
 
 
8.5 
Creatinine Clearance and Cystatin C  
 
 
 
 
8-2 
 
 
8.6 
Abdominal Ultrasound 
 
 
 
 
 
 
8-2 
 
 
8.7 
Transcranial Doppler (TCD)  
 
 
 
 
 
8-3 
 
 
9 
FOLLOW-UP PROCEDURES 
 
 
 
 
 
 
9-1 
 
 
9.1 
Introduction 
 
 
 
 
 
 
 
 
9-1 
 
 
9.2 
Follow-up Visits 
 
 
 
 
 
 
 
9-1 
 
 
 
9.2.1 Passive Follow-up Group 
 
 
 
 
 
9-1 
 
 
 
9.2.2 Active Follow-up Group 
 
 
 
 
 
9-2 
 
 
 
9.2.3 Collection of Laboratory Data  
 
 
 
 
9-2 
 
 
 
9.2.4   Adverse Event Reporting 
 
 
 
 
       
9-3 
 
 
10 CLOSE-OUT PROCEDURES 
 
 
 
 
 
 
10-1 
 
 
10.1 
Overview 
 
 
 
 
 
 
 
 
10-1 
 
 
10.2 
Debriefing Contact 
 
 
 
 
 
 
 
10-1 
 
 
10.3 
Final Study Data and Dissemination of Results 
 
 
 
10-2 

 
TABLE OF CONTENTS (Continued) 
 
Chapter 
 
 
 
 
 
 
 
 
 
 
Page 
 
 
 
11 ORGANIZATIONAL STRUCTURE AND PARTICIPATING UNITS  
 
11-1 
 
 
11.1 
Introduction 
 
 
 
 
 
 
 
 
11-1 
 
 
11.2 
Clinical Center Staff  
 
 
 
 
 
 
11-1 
 
 
11.3 
Monitoring and Endpoint Evaluation  
 
 
 
 
11-1 
 
 
 
Exhibit 11.1 
BABY HUG Follow-up Study Organizational Chart  
 
11-2 
 
 
Exhibit 11.2 
Participating Clinical Centers  
 
 
 
 
11-3 
 
 
REFERENCES 
 
 
 
 
 
 
 
 
 
R-1 
 
 
APPENDIX A 
Schedule and Volume of Blood and Urine Collection and 
 
 
 
 
Schedule of Special Studies  
 
 
 
 
A-1 
 
 
APPENDIX B 
BABY HUG Follow-up Study Data Collection Sheet  
 
B-1 
 

 
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 Page 1-1  
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 1 
BACKGROUND AND STUDY RATIONALE 
 
1.1   
OVERVIEW 
 
The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was designed as a Phase 
III, two-year study treatment, double-blind, randomized placebo-controlled trial including 200 
children at 14 clinical centers.  The final child was randomized into the BABY HUG Treatment Study 
in September 2007.  At the end of their child’s two years of study treatment, all parents/guardians 
will be offered the opportunity for their child to be treated with open-label hydroxyurea (HU) therapy, 
without regard to and without knowledge of their child’s randomized treatment assignment.  When 
originally consenting to participation in BABY HUG, parents/guardians were told explicitly of the 
investigators’ intention to request permission to follow their child for many years, to evaluate 
possible long-term effects of treatment.   
 
The purpose of the BABY HUG Follow-up Study is to provide structured follow-up of the 
children enrolled in the BABY HUG Treatment Study, in order to characterize the long-term 
toxicities and unexpected risks (if any) associated with treatment with hydroxyurea at an early age.  
Ideally this unique group of children should be intensively followed for growth, development, and 
clinical status at least through puberty or early adulthood to document any alterations in the natural 
history of sickle cell disease (SCD) associated with early HU therapy.  This protocol is the initial 
installment in that effort.  
All parents/guardians of BABY HUG participants will be offered enrollment of their child into 
the BABY HUG Follow-up Study, regardless of their original randomized treatment assignment.  All 
children enrolled will be followed to a common termination date of December 31, 2011 or longer as 
funding permits.  This plan will potentially provide approximately 2 to 6 years of follow-up after the 

 
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BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
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original randomized treatment on all children.  Although all parents/guardians will be offered 
treatment with open-label hydroxyurea for their child after completing the BABY HUG randomized 
trial, participation in the follow-up study will not be contingent upon their subsequent treatment 
choice.   
In the BABY HUG Follow-up Study, parents/guardians will be asked to consent to periodic 
reporting of clinically obtained information on their child including growth parameters, blood test 
results, transcranial Doppler (TCD) or other clinically obtained routine “screening” studies, and 
details of sickle cell disease related hospitalizations and health events.  Collection and ongoing 
evaluation of growth and clinical data are essential  to the determination of long-term effects of 
hydroxyurea.  Blood cells, serum, and urine will be collected at follow-up study entry and on a 
second occasion four years later or at study exit (4 years/exit) whichever comes first.  This will 
provide samples for surrogate markers of toxicity and clinical efficacy, such as measures of renal 
and spleen function and markers of DNA damage (see Appendix A).  The stored blood sample will 
be separated, aliquots made and stored for future studies.  An application for storage of 
biospecimens will be made to BioLINCC (www.biolincc.nhlbi.nih.gov).  If storage of specimens is 
approved, they will be available for future studies with links to the clinical database of the BABY 
HUG Treatment Study.  It is anticipated that essentially all BABY HUG families will agree to this 
“passive” follow-up plan.  Personal identifying information will be removed from the database.  
Studies may be conducted by BABY HUG investigators and other researchers investigating sickle 
cell disease and related disorders. 
In addition, parents/guardians will be invited to participate in one optional “active” 
reassessment two years after exit from the BABY HUG Treatment Study.  At that time, age-
appropriate neuropsychological testing, abdominal ultrasonography, and a radionuclide liver-spleen 
scan will be done.  In addition, a blood sample for fetal hemoglobin, Howell Jolly Bodies (HJB), 
pitted cells, Cystatin C, and HPLC creatinine (see Appendix A) will be collected.  Testing will be 
conducted at central laboratories.  There will also be an additional neuropsychological test four 

 
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years after exit from the BABY HUG Treatment Study.  These studies will allow simultaneous 
assessment of unexpected nephrotoxicity or splenic enlargement and possible prolonged protection 
from organ dysfunction.   
Data collected in this follow-up study will be descriptively analyzed according to the original 
treatment assignment (HU versus placebo), as well as the subsequent independent decision by 
families concerning use of open-label HU in the follow-up period.  Data collected in the passive 
follow-up portion will determine whether early hydroxyurea treatment is associated with long-term 
toxicities and provide limited data regarding long-term efficacy.  Data collected in the active follow-
up portion will identify long-term effects on organ dysfunction, and determine if duration of treatment 
and age of initiation (early vs. late) affect hydroxyurea’s efficacy and toxicity.  Information obtained 
from this follow-up study is vitally important to understanding the risks and benefits of early 
treatment, and ultimately for creation of an optimal paradigm for hydroxyurea therapy in young 
children with sickle cell anemia.   
 
 
 
 
 
 
 
 

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 2 
 
OBJECTIVES AND DESIGN OF THE STUDY 
 
2.1  
INTRODUCTION 
The purpose of this observational study is to perform long-term clinical follow-up of children 
enrolled in the original Pediatric Hydroxyurea Phase III (BABY HUG) Clinical Trial, after they have 
completed their period of randomized study treatment.  This long-term follow-up study was 
envisioned at the conception of the BABY HUG Treatment Study, and parents/guardians as well as 
local Institutional Review Boards (IRB) were made aware of this intent in the consent forms 
obtained at the BABY HUG Treatment Study enrollment.  The overall goal of the BABY HUG 
Follow-up Study is to define more accurately the long-term risks and benefits of early HU treatment. 
All of this information is needed to determine the optimal use of HU in very young children with 
sickle cell anemia (SCA).   
Long-term follow-up of BABY HUG participants treated with HU is critical for several 
reasons.  First, certain HU toxicities identified during the BABY HUG Treatment Study may persist 
during the follow-up period, while other toxicities may decline in incidence or severity, and still other 
new toxicities may arise.  The profile of these events may also be different in children starting HU 
treatment at 9 to 18 months of age (in the randomized treatment study) as opposed to children 
starting treatment at 33 months of age or later (by parent or guardian choice during the open-label 
follow-up study).  Serious toxicities, particularly those concerning growth and development, could 
become evident only years after initial HU exposure and treatment.  Children not treated with HU 
during the randomized treatment study, or at all represent an important comparison group and 
should be followed in the same manner. 
Previous studies have provided limited assessment of late toxicities associated with HU 
therapy in a small number of young children with SCA.  In the HUSOFT extension study (Wang et 

 
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al, 2001; Hankins et al, 2005), 17 infants (age 7 to 25 months) completed four years of treatment 
with HU and eleven completed six years.  Hoppe (Hoppe et al, 2000) described eight children with a 
mean age of 3.7 years (range 2 to 5 years) treated with HU for an average of 2.6 years.  While no 
unique adverse side effects and no apparent growth toxicities were reported in these two small 
series involving open-label HU treatment, longer follow-up on larger groups is required to support 
evidence-based decision making.  Long-term follow-up of the 200 children enrolled in the BABY 
HUG Treatment Study will provide a critical and unparalleled opportunity to evaluate late toxicities 
associated with early HU exposure in a large number of well-characterized very young children with 
SCA and to specifically assess the potential spectrum and severity of growth, development, 
hematological and organ toxicities experienced.  Ongoing concern about long-term effects on 
growth and development, as well as data regarding the possible mutagenicity/carcinogenicity of HU, 
can only be addressed in this long-term follow-up study. 
Secondly, in conducting this follow-up study, it is important to document any long-term 
clinical and laboratory effects associated with HU therapy in this young age group.  Clearly toxicities 
must be identified, but benefits identified during the BABY HUG Treatment Study may persist during 
the follow-up period, others may decline in magnitude, and still other new benefits may arise.  
Hematological effectiveness of HU therapy in terms of maintaining elevated levels of HbF was 
shown in HUSOFT, but confirmation of this benefit and its persistence with long-term treatment in a 
larger group of placebo-controlled children is needed.  While it would be ideal to prospectively 
assess the beneficial effects of HU therapy in preventing or ameliorating chronic organ damage with 
“gold-standard” testing at several times over many years, simple less invasive measures of organ 
damage and function are likely to be validated as useful surrogates in the BABY HUG Treatment 
Study.  Accordingly, we will collect blood and urine samples at study entry and 4 years/exit (which 
ever comes first) for all children enrolled in the BABY HUG Follow-up Study, for surrogate measure 
(pitted red blood cell [pit count], quantitative Howell Jolly Bodies [HJB], glomerular filtration rate 
[GFR] estimation from the Schwartz equations, Cystatin C, and urine microalbumin: creatinine ratio 

 
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[microalbuminuria]) assessment, VDJ recombination event assessment of genotoxicity, and 
storage.  In addition, all children will be offered an optional active re-evaluation two years after the 
end of randomized treatment to include studies with more direct organ measurement 
(neuropsychological testing, abdominal ultrasonography, liver-spleen scan and GFR estimates) and 
one additional neuropsychological test at four years after the end of randomized treatment.  Only 
with surrogate and direct measures of toxicity and organ function can we establish appropriate HU 
treatment paradigms for young children with SCA.  
In addition, clinical benefits from long-term HU treatment, such as a decrease in vaso-
occlusive pain crises or episodes of acute chest syndrome, may be observed during this follow-up 
study.  The HUSOFT follow-up study (Hankins et al 2005) suggested that HU resulted in a decrease 
in the frequency of acute chest syndrome (ACS) events, but was limited by the small number of 
children.  Follow-up of a group of 200 infants for 2 to 6 additional years, when clinical events are far 
more common than in early infancy, will allow determination of the role of HU in ameliorating the 
clinical complications of SCA  in young children and provide insight into the risks and value of early 
initiation of such therapy. 
Attempts to identify early clinical and laboratory characteristics that predict major 
complications and organ injury later in life have been only modestly successful.  However, markers 
(early dactylitis, severe anemia, and leukocytosis) identified by the Cooperative Study of Sickle Cell 
Disease (CSSCD) to increase the risk of death, stroke, and recurrent pain and acute chest 
syndrome later in life are parameters likely to be impacted by the early use of hydroxyurea.  Based 
on historical analyses, one might anticipate 20-30 deaths and 10 to 20 strokes in a cohort of 200 
infants followed through the first two decades. (Miller et al, 2000; Quinn et al, 2004)  At the end of 
this follow-up study we may begin to see a difference in natural history based on treatment with HU.  
Although long-term outcome may be somewhat obscured by the use of HU at the end of the blinded 
study, any discernible differences on modification of these late major sickle cell-related problems by 

 
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early, ever or never therapy with hydroxyurea would be of great significance to subsequently born 
subjects and their families. 
The determination of the overall risk-to-benefit ratio for treatment with HU in this unique 
group of young children is likely to be complex.  Regardless of the outcome of the BABY HUG 
Treatment Study, the safety and efficacy of HU treatment in SCA cannot be defined without 
collection of clinical and at least limited long-term laboratory follow-up data.  Treatment 
recommendations for primary and secondary prevention based on observational data and expert 
opinion can be notoriously incorrect (Manson et al, 2003; Wasserthiel-Smoller et al, 2003).  A 
modest treatment effect in the BABY HUG Treatment Study may become more apparent and 
compelling during long-term follow-up.  Alternatively, the BABY HUG Treatment Study may provide 
evidence of benefit in preventing chronic organ damage in children with SCA, but long-term follow-
up may demonstrate that the toxicity associated with HU treatment and/or time-limited organ 
protection (postponement rather than prevention of injury) make its use unwarranted.  BABY HUG 
cannot clarify the role of HU in the treatment of very young children with SCA until the long-term 
risks and benefits are studied and better understood.  
In summary, determination of the long-term risks and benefits of treatment with HU in infants 
and toddlers with SCA is absolutely essential to perform at this time.  The participants in the BABY 
HUG Treatment Study represent a unique and “never-to-be-repeated” resource from which to 
address these issues.  The BABY HUG Follow-up Study will allow more accurate characterization of 
the role and optimal timing of treatment with HU in young children with SCA.  Follow-up of all 
participants for as long as possible is proposed. Initially, all children will be followed for at least two 
years to a common termination point of December 31, 2011 for clinical events and routine clinically 
obtained laboratory values.  Ultimately, even longer-term follow-up will be proposed to allow a more 
complete assessment of the risks and benefits of early treatment with HU for children with SCA.  
2.2 
SPECIFIC AIMS 
 
The specific aims of this follow-up study are: 

 
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1. 
To identify and define possible long-term toxicities in children who receive treatment 
with HU. 
2. 
To determine if prolonged treatment with HU changes the risk and benefits of its use. 
3. 
To investigate the optimal age for initiation of treatment with HU (early vs. late).  
2.3 
 DESIGN OF THE STUDY 
 
 After completion of active participation in the BABY HUG Treatment Study, each family will 
be asked to consent to have their child participate in this long-term follow-up study.  If applicable, 
their child’s retrospective data will be collected beginning with the exit visit from the BABY HUG 
Treatment Study.   Follow-up of these children will continue to a common termination point on 
December 31, 2011, and beyond if further funding permits.  Depending on the parents/guardians 
choice of “passive” or “active” follow-up, we will collect some or all of the following parameters that 
may not be part of routine clinical care: fetal hemoglobin (Hb F); pitted cell counts; HJB; liver-spleen 
scan, abdominal ultrasound; estimation of the GFR from the Schwartz equations and Cystatin C 
measurements; microalbuminuria; and neuropsychological testing.  The plan for the performance of 
these tests is shown in Appendix A.   
All children enrolled in the BABY HUG Treatment Study who participated for at least 18 
months are eligible for the follow-up study regardless of their initial treatment assignment, their 
current treatment status, their prescribed dose and perceived compliance, or the follow-up group 
(passive versus active) selected.  At the completion of the BABY HUG treatment study, all families 
will be offered the option to place their child on open-label HU, based on discussions with their local 
physicians and other health care providers.  This decision will be made without knowledge of the 
primary study results or an individual child’s treatment assignment, and will not influence the 
opportunity to participate in this follow-up observational study.  Based on the initial 40 child pilot 
sub-study, approximately 2/3’s of the children/families exiting the BABY HUG Treatment Study will 
choose open-label HU treatment.   

 
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Although the BABY HUG Follow-up Study is intended to monitor the longer-term risks of HU 
therapy, it will also test the hypothesis of an early versus late effect of starting HU.  Experience from 
the MSH study (Steinberg et al. 2003) suggests that important covariates to be studied in the BABY 
HUG Follow-up Study include the unrandomized comparisons of ever used HU versus never used 
HU, and a time-dependent covariate indicating whether a child is “on” or “off” HU treatment during 
follow-up.  The assessment of this last variable will require careful collection of HU treatment 
information over the course of the follow-up study and enumeration of significant clinical adverse 
events.  We believe that these data can be collected by the current dedicated study personnel at 
each Clinical Center, using semi-annual review of the child’s medical record and structured 
reporting forms.  It is likely that children in the BABY HUG Treatment Study will continue to be 
medically followed at their Clinical Center by physicians and nurses knowledgeable about and 
dedicated to the goals of the treatment study, making the probability of long-term local data 
submission feasible   Since continued HU treatment will not be randomized, it will not be possible to 
itemize all of the treatment and response trajectories that may occur in this study and statistically 
assess each possibility.  Instead, the follow-up study statistical design will have a generalized and 
comprehensive analytical plan that will allow investigators to detect changes in these trajectories 
and associations as the follow-up study continues.    

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 3 
 
CHILD ELIGIBILITY, RECRUITMENT, ORIENTATION, AND INFORMED CONSENT  
 
3.1 
INTRODUCTION  
 All children who have completed at least 18 months of the BABY HUG Treatment Study will 
be eligible for this follow-up study.  A new informed consent from parents or guardians will be 
required for participation.  When families consented to enrollment in the BABY HUG Treatment 
Study, parents/guardians were made aware that the investigators wished to maintain contact with 
the child after the treatment study ended, and because most children were clinically followed in the 
same Clinical Center where they participated in the BABY HUG Treatment Study, this was felt to be 
realistic.  Information about the concept of a follow-up study was repeated during the course of the 
study and consent will be requested at the child’s 24-month (exit) visit from the treatment study.  
During the follow-up study, passive data collection with retrospective data abstraction (including 
information from other health providers when necessary) will be carried out for all children whose 
parents/guardians give consent to be in the follow-up study.  In addition, blood cells, serum, and 
urine will be collected for measurement of important surrogate markers of efficacy and toxicity at 
follow-up study entry and 4 years/exit.  Some of the optional “active” assessment studies are more 
than minimal risk, but will allow ongoing evaluation of organ function both for absence of new 
toxicities as well as potential for preservation of function that would usually be lost by children with 
sickle cell disease in early childhood. These additional studies will objectively assess the 
developmental safety of early HU use, and provide information about the duration of BABY HUG 
Treatment Study primary organ endpoints.   
3.2 
FAMILY ORIENTATION 
 
At the end of the BABY HUG Treatment Study all children will be offered treatment with 
open-label HU by their child’s physician.  Parents/guardians will make this decision without knowing 

 
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their child’s randomized BABY HUG treatment study assignment.  Given the staggered exit of 
children from the treatment study, it is not practical to inform families of the treatment assignment, 
and to do so could result in potential unmasking of the primary study. 
The rationale and the importance of the follow-up study will be presented and explained to 
the parents/guardians.  They will be given a list of the passive follow-up data to be collected and the 
active assessment evaluations and tests that would be performed (see Appendix A).  They will be 
advised that they are required to sign a new consent form in order to participate in the follow-up 
study.  Open-label HU treatment will be managed according to local clinical care standards.  
Information about HU treatment will be collected on follow-up study forms.  Parents/guardians will 
be advised that the follow-up study will not be paying for open-label HU treatment. 
Families may continue to participate in the study even if they move out of the area of the 
Clinical Center.  They will be encouraged to notify the coordinator in advance of the move so that 
plans for passive data collection in their new location can be developed.  
3.3 
INFORMED CONSENT 
Individual Clinical Center consent forms will be prepared based on the model informed 
consent form presented below.  The model consent form will be approved by the Observational 
Safety Monitoring Board (OSMB) prior to its release to the Clinical Centers for submission to the 
local IRBs.  Each final consent form will be reviewed by Medical Coordinating Center (MCC) staff, 
NHLBI Program staff and a member of the OSMB, to ensure all required elements of the consent 
form have been addressed. 
  
The Clinical Center Principal Investigator (PI) will attempt to obtain consent from each family 
in the BABY HUG Treatment Study by contacting the parent/guardians at the end of the treatment 
study.  The family will be given adequate time and privacy to review the consent form.  They will 
have the opportunity to have all of their questions and concerns addressed by the PI.  An 
ombudsman, required for the BABY HUG Treatment Study consent process, may be present but is 

 
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not required.  A copy of the signed consent form will be given to the parent/guardians and placed in 
the child’s medical record. The original will be maintained in study files by the Principal Investigator. 
 

 
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INFORMED CONSENT TEMPLATE    
PURPOSE, PROCEDURES AND LENGTH OF STUDY 
We are asking you to agree to your child’s participation in the BABY HUG Follow-Up Study.   
This study in 14 Clinical Centers will follow the nearly 200 children enrolled in the BABY HUG 
Treatment Study to learn about the long-term effects of study treatment.  This study is sponsored by 
the National Institutes of Health: National Heart, Lung, and Blood Institute (NIH-NHLBI).  If you 
agree to allow your child to enroll in the BABY HUG Follow-up Study, we will collect medical 
information on your child until at least December 31, 2011. 
The BABY HUG Treatment Study was designed to see if treatment with the drug 
hydroxyurea (also called HU) in children with sickle cell anemia could prevent organ damage, 
especially in the spleen and kidneys.  There was also a chance that treatment could prevent painful 
crises, lung disease, stroke, and blood infection.   When your child exits (exited) BABY HUG, 
you and your child’s doctor will decide (decided) whether or not to give HU from the 
pharmacy.  The main goal of the follow-up study is to study the long-term safety of HU.  If 
treatment with HU provides a benefit or if a safety problem is discovered, it will be important to 
determine if the age that HU was started is important.  Follow-up of your child will provide us 
important information about whether HU treatment should be given to infants and if so, the best age 
to begin treatment.  We would like your child to join the follow-up study whether or not you 
choose for him or her to take HU from the pharmacy now or ever. 
 
You may choose to let your child participate in the BABY HUG Follow-up Study in one of 
two ways. The first is “passive” follow-up.  As your child is seen for clinical care of sickle cell 
disease, we will collect information from routine tests ordered by your child’s clinical sickle 
cell doctors.  These tests usually include a complete blood count and measurement of your child’s 
height, weight and head circumference at each visit.  At least twice a year we will also collect 
information about illnesses that your child has had since the last visit and how they were medically 

 
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treated. We will also record the results of TCD (transcranial Doppler or brain ultrasound) tests, 
imaging by CT or MRI and clinical consultations if ordered by your child’s doctor.   
 
We will collect two teaspoons of blood and a urine sample from your child at the 
beginning and end (or after four years on study, whichever comes first) of this follow-up 
study.  These samples will be used to assess spleen and kidney function as well as changes in 
your child’s genetic material or DNA.  The blood samples will be stored for use as new 
laboratory evaluations become available for future research on sickle cell disease and 
related disorders.  We will store these blood samples forever. 
  
The second way you may choose to have your child participate is known as “active” follow-
up.  The same blood and urine samples will be collected as outlined in the above paragraph.  Your 
child’s health information will be collected and submitted to the BABY HUG coordinating center at 
least twice per year as with passive follow-up.  In addition, you agree to allow at one time in two 
years one more blood sample, imaging studies, and behavioral testing as were done at the 
beginning and end of the BABY HUG Treatment Study.  You also agree to allow an additional 
behavioral test at your child’s four-year visit. 
 
If you choose to participate in either group, we will collect information from your child’s 
medical record since he/she exited the BABY HUG Treatment Study. 
 
Family notification of their child’s BABY HUG treatment will be sent to the family on 
or about December 2009.  We will inform families about the BABY HUG Treatment Study results 
as the data are analyzed.  At the end of the follow-up study, your family will be informed of the 
results and any new recommendations from the study doctors. 
STUDY TESTS TO BE PERFORMED  
Passive Follow-Up Group 
 
We will collect information from your child’s medical record including height, weight, 
and the results of physical examinations and laboratory tests performed as part of routine 

 
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clinical care.  If your child has had any major health problems, imaging studies, or medical 
consultations between clinic visits, including the usual complications of sickle cell disease 
and especially those that require hospitalization, we will collect and submit that information.  
If your child has already completed the BABY HUG Treatment Study before the time that you 
consent to join this follow-up study, we will collect medical information back to the date he 
or she exited the treatment study.  If TCD testing has been ordered clinically by your child’s 
doctor, we will review the images and results of that testing.  In the follow-up study, all data 
collection will end on December 31, 2011. 
 
The information collected from testing your child’s blood samples will be added to the BABY 
HUG Treatment Study data file for analysis.  The laboratory tests performed as part of the follow-up 
study are not diagnostic tests for clinical disease.  The results will be used as part of a large group 
analysis without identifying your child.  You will not receive the research results from your 
child’s individual sample.  Knowledge of the test results will not change your child’s current 
medical care.  
 
If your family moves from this area, the study coordinator will contact you by telephone or in 
writing about every 6 months to obtain information about your child’s growth and development and 
clinical events.  We will request any information relevant to the follow-up study regarding your 
child’s health from other health care providers.  We will ask you to sign a release for us to obtain 
that information. 
Active Follow-up Group 
 
If you agree to have your child in the active follow-up group, the same clinical information, 
blood and urine specimens as in the passive follow-up group will be collected, but there will 
be additional blood and urine tests, as well as tests to check the function of your child’s 
brain, spleen and kidneys. These additional tests will be performed only once, approximately 
two years from now.  Each of these tests may require a separate visit.    

 
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There will also be a behavioral test, called the Vineland Adaptive Behavior Scale, 
performed at the four-year visit.  A test requiring a small dose of radiation to evaluate the 
function of the spleen will be performed in exactly the same way it was done in the BABY HUG 
Treatment Study.  For this test, small doses of radioactive material will be given through your child’s 
vein.  We will use a camera sensitive to radioactivity to take pictures of your child’s spleen.  The 
radioactive material will leave your child’s body in urine or stool by the next day.  In order to monitor 
your child’s brain growth and development, neuropsychological testing will be performed.  Your 
child will also have an ultrasound (sound wave) imaging test of spleen and liver size.  These are the 
same tests that were performed twice in the BABY HUG Treatment Study.  An extra blood sample 
will be collected to assess spleen and kidney function.  
RISKS 
 
The needle used to take blood may cause a sharp pain as it goes into the skin.  Sometimes 
a bruise will form at the place the needle goes into the skin.   
 
If your child is enrolled in the active follow-up group, he or she will have one medical 
imaging study. The liver-spleen scan test requires that an IV be started in your child’s vein 
and that a small amount of radiation (like the amounts that people encounter naturally in daily life 
from space) is injected into your child’s body. Like the blood draw, the risks of the needle stick for 
the IV are pain and bruising.  Your child will receive about the same amount of radiation as he or 
she would get from living in our natural surroundings for about nine days.  The radiation dose is 
what your child will receive from the follow-up study only and does not include any exposure he or 
she may have received or will receive from other tests. 

 
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BENEFITS 
At this time no one knows whether HU will help your child.  The results of this follow-up 
study, along with those from the BABY HUG Treatment Study, will help doctors decide in the future 
if and when to give HU to young children with sickle-cell anemia and how long to give it. 
 
FREE CHOICE 
 
Your child’s participation in the follow-up study is up to you.  You are free to take 
your child out of this study at any time.  You are free to start or stop HU from the pharmacy, 
after talking with your child’s doctor at any time.  You are free to choose to have your child’s 
information included in the data file, decide if your child’s blood sample can be saved indefinitely, 
and to choose which active follow-up tests your child should have.  You are free to change your 
mind about the active follow-up tests you will allow your child to have up until the tests are 
performed.  If you take your child out of the study or do not take part in the study, we would still like 
to provide medical care for your child.  That is, you may choose not to be part of the follow-up study, 
not allow us to collect information from that care, and just allow your child to receive standard care 
for sickle cell disease in this hospital and clinic.  You and your child’s doctor may plan to use or not 
use hydroxyurea.  Other treatments may be possible for your child.  These treatments include blood 
transfusions and stem cell or bone marrow transplantation.  Your choice to continue in the follow-up 
study will not change the way your child is treated in this hospital or the treatments available to your 
child.  In or outside of the study, we want to give the best care for your child.  
COSTS 
All costs that are considered part of routine clinical care will not be paid by the study. 
Routine care will be billed, as before, to you and/or your health insurance provider. Costs related 
to the blood and urine samples obtained just for this study (at entry and exit), and 
procedures performed in the active follow-up group, will be paid for by the study.  If you 

 
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decide to have your child take hydroxyurea, the costs of the medication and the laboratory 
studies to monitor its effects will be billed to you and/or your health insurance provider. 
PAYMENT 
  
If you chose to allow your child to participate in the active follow-up group you will 
receive $100 for the extra clinic visits required.  Payment will be made when you arrive at the 
clinic for the start of the active group tests.  This is to cover your costs of parking, travel, meals 
and other expenses to get your child to the clinic for these extra tests.  Payment will not be given for 
your child’s regular clinic visits. 
PRIVACY 
 
Your child has a right to privacy.  All information in this study that can single out your child or 
your family will remain private.  A numbering system that does not allow anyone outside this Clinical 
Center to know your child’s name will be used to identify your child.  Your child will not be named in 
reports of results from this study.  Your child’s medical reports and family data will be kept private. 
CONSENT FOR A DATA FILE 
  
At the end of the follow-up study, a computer file of the study results will be made for future 
use by researchers studying sickle cell and related diseases.  The information collected from your 
child’s participation in the follow-up study, all testing done during the study, and the saved blood 
samples will be linked to the child’s participant number in the follow-up study data file.  This data file 
will not have your child’s name, your name or any facts that could be linked to your child or family 
directly.  The computer file may be used by other doctors to study sickle cell anemia or related 
disorders.  Data may be given to the National Institutes of Health, the Food and Drug Administration 
(FDA) or other U.S. or state agency as required. 
I  
 agree 
  
 do not agree   ______  for the data file to include my child’s information.  
  
 
 
 
         Initials  

 
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CONSENT FOR STORED BLOOD SAMPLES 
These are the blood samples taken at study entry and exit. 
I  
 agree 
  
 do not agree   ______  to the saving of my child’s blood samples  
 
 
  
 
         Initials  indefinitely. 
  
 
 
 
     
I  
 agree 
  
 do not agree   ______  to the use of my child’s blood samples for future   
  
 
 
 
         Initials  
research on sickle cell disease and related disorders. 
 
CONSENT 
 
I agree for my child to participate in the 
 ______passive follow-up group. 
  
 
 
 
                                  Initials 
 
OR  
I agree for my child to participate in the  
 ______ active follow-up group. 
  
 
 
 
                         
Initials 
 
LIMITATIONS  
 
The <<insert Clinical Center name>> will not provide compensation for children who may 
incur injuries as a result of being in this research except as is required by law.  This means that 
while all study doctors will do everything possible to provide careful medical care and 
safeguards in the conduct of this research, the medical center will not offer to pay for injury 
resulting solely from the research itself.  The study sponsor, The National Heart, Lung, and 
Blood Institute, does not offer financial compensation or payment if you are injured as a 
result of participating in this research study.  
 
You can discuss the rights of children who participate in research with the Chairman of the 
Medical Center’s Institutional Review Board, telephone number (                   ).  This board is 
composed of doctors and lay people who have reviewed and approved this study. Dr. 
____________________, Principal Investigator of this study, is also willing to talk about any of your 
concerns about the study at telephone number (                     ).  
 
 

 
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COPY OF CONSENT 
If you agree to have your child take part in this research study, you will receive a signed copy of this 
consent form. 
FOR SUBJECT FAMILIES WHO HAVE ALREADY SIGNED A CONSENT AND HAVE 
ENROLLED THEIR CHILD INTO THE ACTIVE GROUP BUT HAVE NOT HAD THE 24 
MONTH VISIT YET 
 
The only change to the BABY HUG Follow-up Study for your child is that the 24 month 
special studies visit will no longer include a DTPA/GFR test and an additional neuropsychology test, 
called the Vineland Adaptive Behavior Scale, will be done at the four year visit. 
PARENT, INVESTIGATOR AND WITNESS SIGNATURES 
 
I have read all of the consent form.  I have been given a chance to ask questions and have 
received answers about areas I did not understand.  I willingly give my consent for my child to join 
this study.   
 
I understand that I may withdraw my child from the study at any time.  In doing this, I will, in no way, 
change my child’s ongoing medical care at this medical center or elsewhere.   
 
 
 
_________________________  
________________________________       _____   _____ 
Child’s name  
 
  
Signature of parent or legal guardian  
(Date)  (Time) 
 
 
 
 
 
 
 
 
________________________________ 
_____  _____ 
 
 
 
 
 
  
Signature of parent or legal guardian  
(Date)  (Time) 
 
 
_________________________ 
________________________________ 
_____  _____ 
Investigator’s name 
 
  
Signature of Investigator 
 
 
(Date)  (Time) 
 
_________________________ 
________________________________ 
_____  _____ 
Witness’ name 
 
  
Signature of Witness  
 
 
(Date)  (Time) 
 

 
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PEDIATRIC PHASE III CLINICAL TRIAL (BABY HUG) 
FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 4  
 
STUDY ENDPOINTS 
 
4.1 
INTRODUCTION 
The primary objective of the follow-up study is to monitor the continued safety of HU 
treatment.  Safety of HU will be assessed by ongoing clinical monitoring of growth and 
development, age-appropriate neuropsychological evaluation, serial hematologic parameters, and  
the frequency of expected and unexpected clinical events related to sickle cell disease.  For this 
reason follow-up should continue as long as practically possible.  Disease and treatment-related 
effects on the spleen will be measured by a liver-spleen scan, pitted cell counts and HJB 
enumeration. With the deletion of the DTPA/GFR, kidney function will now be measured by GFR 
estimation from the Schwartz formulae or Cystatin C measurements and the urine 
microalbumin:creatinine ratio.  These evaluations will also allow us to monitor the effectiveness of 
ongoing HU therapy.  We will also seek to study how early treatment with HU changes the child’s 
disease trajectory as open-label HU becomes available after the child’s participation in the BABY 
HUG Treatment Study.  
4.2  
FOLLOW-UP ENDPOINTS   
4.2.1 Growth, Development, and Education 
 
Height, weight, physical examination parameters (for example the presence of a palpable 
spleen or liver) are routinely assessed at clinical care visits which usually occur every 3-4 months 
through the first five years of life and every 6-12 months at older ages in children with sickle cell 
anemia.  Children will be carefully monitored for height or weight percentile and compared to 
standardized growth curves.  In particular, the growth curves of children ever exposed will be further 
divided into those who have taken HU both in the treatment study and follow-up study versus those 
treated with HU only in the follow-up study and compared to those never on HU.  (HU children in the 

 
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trial whose parents elect not to have their child take HU in the follow-up study will be excluded from 
this analysis.) 
 
Careful evaluation of the BABY HUG participants through young adulthood for growth, 
school performance, development of pubertal characteristics (menarche and Tanner Score), and 
fertility is beyond the scope of resources currently available to this follow-up study, but is highly 
desirable.  During the period demarcated for the follow-up study, the first children may complete the 
second grade, although the majority will not yet have entered formal education.  We will collect self-
reported data about school placement (special education placement and/or repeated grades vs. 
those continuing without such assistance) and the presence or absence of parental concern about 
language development and behavior.  
4.2.2  Hematologic and Clinical Events 
Complete blood counts (CBC) will be collected for all children at their regular clinic visits in 
accordance with standard clinical practice.  Creatinine and hepatic transaminase values will be 
routinely recorded for children on hydroxyurea.  The investigators will continue to compare children 
on and off of treatment with HU to assess the effect of HU treatment on the absolute neutrophil 
count, white blood cell count, mean cell volume, reticulocyte count and platelet count.   
For any children having serious clinical events, these events will be recorded including, but 
not limited to, stroke, splenic sequestration events (and presence of a palpable spleen), 
transfusions, and hospitalizations.  This information will be collected by structured, retrospective 
review of the medical record at the semi- and annual reporting periods.  
4.2.3  Central Nervous System 
Neuropsychological evaluation with the Wechsler Preschool and Primary Scale of 
Intelligence (WPPSI) and the Vineland Adaptive Behavior Scale tests will be performed once each, 
with the other active assessments, at two years and four years (respectively) after enrollment in the 
BABY HUG Follow-Up Study.  Results will be analyzed with the previously collected Bayley and 

 
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Vineland tests in the BABY HUG Treatment Study to carryout an analysis of covariance.  
Longitudinal profiles will not be analyzed because the neuropsychological scales must be changed 
as the child ages, which will prevent the creation of a neuropsychological trajectory based on a 
common measurement. 
4.2.4  Spleen 
The liver-spleen scan will be performed on subjects in the active follow-up group two years 
after completion of the treatment study.  The results of this scan will be compared to the two scans 
performed at initial screening and exit from the BABY HUG Treatment Study.  Thus, pre-treatment, 
post-treatment and follow-up scans performed at time zero, two and four years respectively from 
entry in the treatment study will be available for review and comparison.  The follow-up scan will be 
categorized by the same panel of nuclear medicine specialists who read the previous scans.  Once 
again these reviewers will be masked to all treatments received by the subject and will not be 
involved in the acquisition of the images.   
Children will be compared between groups for the continued presence of a spleen with 
sufficient function to take up the radionuclide.  A functional spleen can be seen as both having 
potential for toxicity (the child remains at risk for splenic sequestration, a potentially fatal 
complication that children with sickle cell anemia usually do not develop after 3-5 years of age) as 
well as demonstration of HU’s ability to preserve organ function.   
Pit counts and HJB quantitation will be performed once for all subjects, four years after exit, 
which is approximately six years after enrollment in the BABY HUG Treatment Study.  Children who 
agree to active follow-up will have an additional pit count and HJB measurement at the time of the 
other active organ assessments.  The results of the pit counts will be compared with those serially 
performed during the BABY HUG Treatment Study. This will provide an assessment of changes that 
have occurred over the entire period of study.  The results for the HJB will be compared with those 
performed at screening and completion of the BABY HUG Treatment Study.  This will provide an 

 
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assessment of serial changes in surrogate measures of spleen function.  The non-invasive markers 
of spleen function will be compared to the results of the liver-spleen scans (when available) to 
continue to assess their reliability in providing the same information about ongoing risk from a 
functional spleen as the radionuclide scan. 
4.2.5  Kidney  
Central laboratory measurement of serum creatinine will be performed in order to estimate 
the GFR according to the Schwartz formula, GFR=kL/Pcr, where L = the body length in centimeters, 
Pcr = the serum creatinine concentration in mg/dl, and k = 0.55 mg creatinine/100 min x cm x 1.73 
m2.  Blood Urea Nitrogen (BUN) and Cystatin C will also be collected to obtain a recently reported 
Schwartz GFR. The newly developed Schwartz formula is: GFR(ml/min per 1.73 m(2))=39.1[height 
(m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height 
(m)/1.4](0.188).1 
 
Measurement of serum Cystatin C will also be used to estimate the GFR.  Cystatin C 
measurement was added to the BABY HUG Treatment Study in October 2006 due to its apparent 
superiority over creatinine-based estimates of GFR (Alvarez et al, 2006).  This may be especially 
true in individuals with sickle cell anemia due to their substantial tubular secretion of creatinine.  
This measurement is being obtained, to the extent possible, on residual samples of serum stored 
from creatinine measurement done with entry and exit DTPA scans early in the treatment study.  It 
was performed on all children entering or exiting the treatment study after this change in protocol.  
Measurement of Cystatin C (by blood sample) will continue to be performed by the Clinical 
Chemistry Laboratory at St. Jude Children’s Research Hospital and will be performed at entry into 
this study (if not done at exit from the treatment study) and four years after exit from the treatment 
study.  Subjects in the active follow-up group will have an additional determination, two years after 
follow-up study entry, coincident with other organ function assessments.  For most of the children 
who will enter the follow-up study immediately after exiting the treatment study, this measurement 

 
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will be available for comparison to the Cystatin C value collected in the follow-up study as well as 
the serum creatinine measurement.  These two methods will be compared for their prediction of 
GFR for HU treatment groups, based on early vs. later or ever use of HU.  As discussed in the 
BABY HUG Treatment Study protocol, the development of hyperfiltration is one of the earliest 
lesions in sickle cell nephropathy.  Evaluation of renal function, particularly raw creatinine and/or 
Cystatin C values, will also allow assessment of any unexpected detrimental effects of HU therapy.  
Microalbuminuria, assessed by the urinary microalbumin to creatinine ratio, may also be 
regarded as an early sign of sickle nephropathy (Darnidharka 1998). This ratio will be measured in 
all children at entry to this study and at exit from this study.  Assessment of this parameter will 
provide additional information about the toxic or beneficial effects of HU on kidney function in young 
children with sickle cell anemia.  For example, even if HU therapy prevents the rise in GFR of 
hyperfiltration, it may make other aspects of renal function, such as microalbuminuria, worse.  Again 
this assessment will allow determination of the true spectrum of toxicity or benefit conveyed with 
early use of HU. 
4.2.6  Fetal Hemoglobin 
 
Maintenance of an elevated fetal hemoglobin with hydroxyurea therapy is one of the 
secondary endpoints of the BABY HUG Treatment Study.  Fetal hemoglobin will be measured once 
in conjunction with the active follow-up assessment two years after entry into the follow-up study.  
The levels of fetal hemoglobin observed will be compared to the serial values available from the 
BABY HUG Treatment Study data to evaluate the persistence of a beneficial effect from 
hydroxyurea. 
4.2.7  Stored Blood Samples 
We will collect, separate and store components from a five milliliter blood sample from all 
follow-up study participants at entry into the study and  at four years or exit.  These samples will be 
linked to the treatment study and follow-up study datasets and will be available to researchers for 

 
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future studies of sickle cell and related diseases.  It is likely that in the future, as with the addition of 
the Cystatin C and urinary microalbumin:creatinine assessments, novel investigations for toxicities 
or organ function effects of HU will be proposed.  These samples will also be used and stored 
indefinitely.  Storage of samples with known periods of exposure to HU will be an invaluable 
resource for these investigations.  To this end, Investigators have agreed that saved serum samples 
will be shipped to a central repository at the NHLBI. 
4.3 
STATISTICAL ANALYSES OVERVIEW 
 
The BABY HUG MCC staff will continue to assess the number of non-functioning spleens, 
according to assigned treatment, four years after the children were enrolled in the treatment study.  
The alpha level for the spleen test will be set at 0.05. 
 
A review of the other endpoints and treatment variables to be analyzed shows three different 
treatment-variable constructs, and four classes of endpoint analyses, to be performed in the BABY 
HUG Follow-up Study.  As mentioned in Chapter 2, the primary independent variables to be studied 
in the BABY HUG Follow-up Study are: 1) the BABY HUG Treatment Study treatment assignment, 
2) a variable indicating whether a child has ever received HU (either as study treatment during the 
treatment study and/or open-label follow-up), and 3) a time-dependent covariate indicating HU 
treatment or no HU treatment over the BABY HUG follow-up interval.  The last variable is not a 
variable per se but a treatment trajectory that will be assessed for its association with SCA-related 
symptoms and adverse events.  The endpoint analyses to be considered in the follow-up study, 
consist of longitudinal data analyses of continuous endpoints (e.g., CBC results, fetal hemoglobin 
values, and quantitative spleen and renal evaluations), longitudinal analyses of qualitative 
evaluations (e.g., spleen activity as evaluated by two masked nuclear medicine physicians), time to 
event analyses (e.g., the time to the occurrence of adverse events), an analysis of covariance (the 
analysis of the four-year WPPSI score), and multivariate analyses e.g., (Vineland Adaptive Behavior 
Scale). 

 
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Because there is no hypothesized pattern of interest to be seen in the BABY HUG Follow-up 
Study, a generalized approach will be formulated that will allow the investigators to describe the 
changes that occur.  This means that a large number of analyses will be performed in this study.  
The investigators will limit the number of spurious associations by setting the alpha level for 
determining statistical significance to 0.01 rather than the traditional 0.05 alpha level.  This 
procedure is consistent with the statistical approach used to identify up-regulated genes in micro-
array studies, where one seeks to make it “highly likely” that statistically significant results are real 
by adjusting alpha levels and powers (Benjamini et al., 1995). As an example, among a large group 
of independent statistical assessments for which 25% of the alternative hypotheses are true and 
75% of the null hypotheses are true, setting alpha at 0.01 for each comparison and power to 0.9 for 
each comparison would mean that on average, 96% of the statistically significant hypotheses 
declared in the study would come from the 25% of tests where the alternative hypothesis is true.  
Setting alpha at 0.05 rather than 0.01 would reduce the number of positive predictions to 86%. 
4.4 
STATISTICAL CONSIDERATIONS IN DESIGN AND STUDY SIZE 
4.4.1 Primary Treatment Comparisons 
 
This follow-up study will have one primary endpoint analysis:  comparison of the proportion 
of infants with decreased or absent spleen function. 
 
The primary comparison of this outcome will be done according to the BABY HUG 
Treatment Study treatment assignment.  In effect, this comparison  will be a test of an early (BABY 
HUG subjects randomized to Hydroxyurea) versus late (BABY HUG patients randomized to 
placebo) onset of HU treatment since after the subject exits the BABY HUG Treatment Study, open-
label HU treatment will be offered to all families of BABY HUG participants.  We have presented 
graphical figures of power as a function of study size for the primary endpoint.  There will be no 
interim monitoring plan proposed for the primary endpoint.  The goal is to estimate treatment 
effects.   

 
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An interim monitoring plan will be constructed to monitor the appearance of adverse events 
and potential toxicities.    
4.4.2 Spleen Endpoint 
 
Study size calculations for the analysis involving the spleen endpoint (a proportion) are 
functions of the overall study size, the proportion of infants in each of the comparison groups, and 
the difference between the expected proportions of events in the different groups.  
 
Let p1 be the probability that the spleen is not functional four years after treatment initiation 
for children assigned to receive HU during the BABY HUG Treatment Study (early HU treatment) 
and p2 be the probability that the spleen is not functional four years after treatment initiation for 
children assigned to receive placebo.  The overall alpha level of this comparison will be alpha = 
0.05 (two-tailed).  We will test the hypothesis:  
HO: p2 – p1 = 0 
versus the alternative: 
HA: p2 – p1 ≠0. 
Figure 4.1 shows that the spleen failure rate in the late treatment (BABY HUG placebo 
[PBO]) group will have to be large (greater than 0.6) while the early treatment group event rate 
(BABY HUG HU treatment) is low (0.4) for the proposed study design to show with adequate 
power that early HU treatment is a superior organ-saving treatment.  This is consistent with the 
BABY HUG Treatment Study goal of determining that HU cuts organ failure in half.    

 
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Figure 4.1 
Power as a Function of Study Size and the  
Late (PBO) Event Rate (Rate 2) 
 
                      
 
 
1:1 Allocation 
Alpha = 0.050, Tails = 2, Rate 1 (Early HU) =  0.400 
 
If the number of children enrolled in the follow-up study is unbalanced with respect to the BABY 
HUG treatment assignments for this hypothesis, Figure 4.2 can be used to address the hypothesis 
for the circumstance in which twice as many parents whose infants were treated with HU continue 
in the study as compared to placebo-treated children.  The operating characteristic of the primary 
comparison with unequal allocation is similar to the equal allocation scenario so long as the 
imbalance does not exceed more than a 3 to 1 ratio.   

 
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Figure 4.2 
Power as a Function of Study Size and the  
Late (PBO) Event Rate (Rate 2) 
                    
 
2:1 Allocation  
Alpha = 0.050, Tails = 2, Rate 1 (Early HU) = 0.400 
 
 
4.4.3  Data Analysis 
4.4.3.1 Introduction 
 
Primary analysis for the BABY HUG Follow-up Study will focus on estimating treatment 
effects on the designated endpoint: loss of spleen function.  Assessment of a treatment difference 
will be based on pooling data across all participating Clinical Centers using all children entered.  
Secondary analyses will develop statistical models to determine associations and relationships 
between dependent variables, risk factors and the three treatment variables described earlier in this 
chapter.  
 
Analysis of binary endpoints will be accomplished using contingency table analysis.    
Significance of results will be assessed with the Chi-square test uncorrected for continuity or 
Fisher’s exact test.  If necessary, contingency table analyses will be adjusted for confounding 
variables using logistic regression. 

 
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For continuous variables, comparisons of groups will be accomplished using Student’s t test 
or the Wilcoxon rank sum test depending on the distributional properties of the data.  Stratified 
designs will be analyzed using regression methods with the strata represented as randomized 
blocks for the analysis. 
 
Analysis of continuous and categorical endpoints that are measured repeatedly over time, 
such as weight, height, and CBC measurements will use longitudinal data analysis models (Laird 
and Ware, 1982; Schlucter, 1992; Liang and Zeger, 1986).  Estimation in these models can be in 
terms of point and interval estimates or trends (i.e., slopes of growth curves) over time.  
 
The comparison between two treatments (or exposures) of time-to-event endpoints will be 
evaluated using the log-rank statistic.  We will use the LIFETEST procedure in SAS to perform the 
test.  The cumulative distributions of this outcome will be estimated using the methods of Kaplan 
and Meier (Kaplan and Meier, 1958).  Multivariate adjustments to this comparison will also be made 
using the PHREG procedure for SAS to accomplish Cox proportional hazards models analyses 
(Cox, 1972). 
 
Non-proportionality of the hazards will be investigated by plotting log[-log(S(t))], in which S(t) 
is the survival function, for important stratifying variables such as age and gender.  Should the 
above functions be non-parallel (and/or cross) for any of the specified variables (p < 0.01), the 
subsequent analysis will be stratified by those variables.  Cox proportional hazards models will be 
stratified for variables that demonstrate non-proportional hazards (crossing or non-crossing).  Once 
determined, we will include these variables as stratification variables in the Cox regression.  
Analyses for the regressors will be summarized across the strata.  Children who are lost to follow-
up before the end of the follow-up interval will be censored at the time of their last visit. For events 
that can occur more than once in a child, the counting processes extension of the Cox model in 
SAS will be used to measure the relative impact of treating children with HU on these endpoints 
(Andersen and Gill, 1982).     

 
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4.4.3.2  Regression Analyses and Adjustment 
 
We will adjust study results for potential confounding factors in secondary analyses.  The 
addition of confounding variables generally improves the operating characteristics of analyses of the 
main effect, but given the small study size, the number of confounding variables to be considered  
in any secondary analysis will be small (limited to five or ten).  We will use step-wise regression 
methods to isolate and include the most important confounding variables in the regression model. 
 
Tests of interaction will be part of regression analyses.  Most of these analyses will be 
designed to determine if BABY HUG Treatment Study treatment effects or other HU exposure 
effects are consistently observed across different clinical groups of subjects.  If an interaction test is 
significant (p < 0.01), we will report that treatment effects differed according to the stratification 
dictated by the interaction test.  Interaction tests such as these have low power to detect specified 
alternatives (e.g., half the efficiency of a main effects comparison).  Additional analyses will be 
required to support the discovery of a proposed interaction, as a large number of interaction tests 
will be performed and some, by chance, will be found to be significant.  One important analysis will 
be to incorporate variables that measure the duration of HU open-label treatment over the follow-up 
interval.  This will be done by including variables that measure the duration of use for a cross-
sectional analysis or time-dependent covariates for a longitudinal analysis. 
 
We will use SAS procedures to perform adjusted analyses, PROC GLM to perform 
randomized block analysis of variance, PHGLM to perform stratified and standard Cox proportional  
hazards analyses, PROC GENMOD and MIXED to perform longitudinal data analyses, and PROC 
LOGISTIC to perform unconditional logistic regression.  The standard output from these procedures 
provides point estimates for the regression coefficients, standard error estimates and confidence 
intervals.  The results of these analyses are printed into computer files so that they can be directly 
inserted in progress reports using PROC REPORT.  In some instances, the procedures in SAS will 
not suffice since SAS procedures usually do not include methods to incorporate information about 

 
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missing data, nor do they include complex models specifically designed to relate a biological 
process with the risk of disease progression.  We will use PROC IML and PROC NLIN to program 
the required models if necessary.   
4.4.3.3  Longitudinal Data Analysis 
 
Many of the endpoints that will be collected and analyzed in the BABY HUG Follow-up Study 
will be longitudinal in nature with collection points at entry into the treatment study, two years after 
the child is enrolled into the treatment study (exit), two years after enrollment into the follow-up 
study (active group only), and four years or exit from the follow-up study (whichever comes first).  
Examples of such endpoints are: HJB, pit counts, GFR estimates, liver-spleen scan data, 
anthropometry, and neuropsychology testing.  For each of these endpoints, we will present box 
plots of the measures according to the three different treatment indicators (BABY HUG Treatment 
Study assignment to HU, ever treated with HU (see page 4-1), and a time-dependent indicator of 
HU treatment) at each collection point.  For the longitudinal analysis, we will use the baseline 
collection from the treatment study as an adjustment variable and then test the longitudinal 
trajectory for differences according to the treatment variable being studied and time-by-treatment 
interactions.  Time trajectories will be analyzed using linear, quadratic and cubic terms.  All data will 
be analyzed using generalized estimating equations (GEE) or mixed model analysis of variance; 
binary data will be analyzed in GEE using a logit link function and continuous data will be analyzed 
using the linear link function.   
4.4.3.4   Missing Data Analysis 
 
We will generally use the methods of Rubin (Little and Rubin, 1987) to impute missing data 
from children’s records with complete data to complete the records for children with missing data.  
This method has been accepted by the FDA as a legitimate method for correcting for missing data.  
We will also use analyses involving rank statistics in which children who die or have bad clinical 
events are given the worst rank for other dependent variables.  This technique has been used 

 
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successfully in the Multicenter Study of Hydroxyurea (McMahon et al, 1997).  For categorical data 
or time to event data, the composite endpoint of death or the event (such as occurrence of acute 
chest syndrome) can be used.   
4.4.4 Interim Monitoring 
 
During the course of this study, the BABY HUG OSMB will review interim data analyses to 
monitor for the emergence of adverse treatment effects and the primary endpoint. No alpha will be 
spent on these primary endpoint reviews, i.e., the reviews will not be evaluated for early termination 
of the study.  The interim OSMB analysis reports for the OSMB will include, but are not limited to 
comparisons by treatment group for:  
1. 
Primary endpoint. 
2. 
Child  characteristics at baseline, completion of the BABY HUG Treatment Study,  four 
years after randomization into the BABY HUG Treatment Study (two years on the 
follow-up study), and four years in the follow-up study or study exit.    
        
 
Spleen function 
 
 
 
Spleen size 
 
 
Pit counts 
 
 
HJB quantitation 
 
 
 
Schwartz equation GFR estimates 
 
 
 
Cystatin C GFR estimate 
 
 
 
Urine microalbumin:creatinine ratio 
 
 
 
Neuropsychological Testing Performance 
 
 
Height, weight, head circumference 
 
 
 
TCD measurements 
3. 
Blood count toxicities 
4. 
Dose adjustments 

 
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5. 
Safety assessments and clinical events 
6. 
Serious Adverse Events 
7. 
Distribution of baseline characteristics: 
 
 
 
Gender 
 
 
 
Age at Entry 
 
The OSMB will also review Clinical Center study performance including completeness of 
follow-up, submission of forms and quality of laboratory data submitted, number of children lost to 
follow-up, and protocol violations. 
4.4.5 Safety Related Outcomes  
 
All clinical data will be collected retrospectively every six months.  For children who agree to 
active follow-up, the results of the active assessment studies will be reported as soon as they are 
performed.  Serious adverse event (SAE) reporting for the conditions listed in Table 4.1 will include 
only events that occur during the first five days following performance of the active assessment 
studies.  Otherwise, a structured listing of clinical events will be submitted to the MCC and tabulated 
based on the affected organ system according to standardized monitoring procedures (e.g., 
MedDRA).  These will be tabulated and a systematic review will be made to determine if one 
treatment group (or HU exposure type) has more reports of SAEs than the other treatment group (or 
HU exposure type).  Depending on the evidence accumulated, it will be the responsibility of the 
OSMB Chair, the Executive Secretary of OSMB and the Project Officer to decide whether a full 
meeting of the OSMB is necessary to discuss the results and make recommendations, whether a 
conference call is necessary, or whether the report warrants no further action.  Classification and 
reporting considerations are discussed in Section 9.2.4 of this protocol.   
 
Ninety-five percent confidence intervals for the difference between proportions for the 
different treatment groups will be used to compare the occurrence of SAEs.  If the confidence 
interval for the difference in these proportions does not cover zero, the Project Officer will be 

 
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notified promptly.  The Executive Secretary of the OSMB and the Project Officer in consultation with 
the OSMB Chair will then recommend whether there should be an emergency meeting (or 
conference call of the OSMB) to determine the appropriate actions for this study.   
Table 4.1 
 
Definition of Serious Adverse Events  
A serious adverse event is any one of the following. 
 
1. Death 
 
2. Life-threatening event 
 
3. Prolonged hospitalization (greater than 7 days) 
 
4. Splenic sequestration crisis 
 
5. Stroke, TIA 
 
6. Acute chest syndrome 
 
7. ICU admissions 
 
Serious Adverse Events that are SCD-related have been added to the list, as defined by the 
FDA. Item #3 has been modified from the FDA definition because frequent hospitalizations occur as 
a consequence of having sickle cell anemia without being enrolled in a study. 

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
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CHAPTER 5 
 
OPEN-LABEL TREATMENT WITH HYDROXYUREA  
 
 
5.1  
OVERVIEW 
 
 
Treatment with open-label HU during the follow-up study is at the discretion of the parent or 
guardian after consultation with the child’s primary care physician. Regardless of the follow-up 
group in which the family chooses to have their child participate, all children on open-label HU will 
be followed according to local center hydroxyurea standards to monitor for toxicity.  All blood tests 
performed for this purpose will be collected and processed locally, except for those noted as “core” 
measurements in Appendix A.  For use of open-label HU, the dose, formulation, monitoring 
intervals, and toxicity levels stated below are guidelines only.  Actual treatment is in accordance 
with routine local clinical care.  Cost of treatment and monitoring will be borne by the family and 
their child’s insurer. 
5.2 
DOSE TITRATION OF OPEN- LABEL HYDROXYUREA 
 
 
The use of open-label HU will not be specifically regulated as was done in the BABY HUG 
Treatment Study.  The dose of HU prescribed will be carefully recorded and reported semi-annually.  
Local criteria for dosing, dose escalation, and toxicity values will be used.    The following guidelines 
for local adaptation are suggested: 
 
Children should begin open-label treatment with HU at the same dose as the dose of the 
BABY HUG Treatment Study drug which was 20 mg/kg..  
 
Dose escalation of 5 mg/kg every 6-8 weeks should be strongly considered if there is no 
toxicity to a maximum tolerated dose or 35 mg/kg. 
 
A CBC with differential white blood cell count and reticulocyte count should be 
monitored monthly while on HU. 

 
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 
Predetermined toxicity levels should be utilized to monitor blood counts.  The toxicity 
values should be no lower than an ANC<1250/mm3, platelet count <80,000/ mm3, a 
hemoglobin level below 6 gm/dl or greater than 20% fall in hemoglobin concentration 
from a three-month rolling average.  Local clinical criteria with higher cut off points for 
declaring a toxic value may be used if desired.   
 
Dose should be reduced for severe or recurrent toxicities, with an attempt to re-escalate 
the dose if six months pass without subsequent toxicity. 
5.3 
MONITORING FOR TOXICITY 
 
Children enrolled in the follow-up study within two months after completion of the BABY 
HUG Treatment Study must have all laboratory data from visits during this time reviewed only by 
the Primary Endpoint Person (PEP) and the MCC staff in order to ensure that masking 
accomplished in the treatment study is maintained. The PEP will determine if toxicities are present.  
The MCC staff will also screen local CBC reports for toxicities. If there are toxicities, the PEP will 
report them to the local Clinical Center staff.  The Clinical Center will treat the child in accordance 
with routine local clinical care. Children who are enrolled in the follow-up study more than two 
months after completion of the BABY HUG Treatment Study will not require review of their initial 
laboratory data by the BABY HUG Treatment Study PEP or MCC staff. 
 
All subsequent laboratory data as well as the labs done for each study visit will be reviewed 
and determination of toxicities will be made by the local Clinical Center BABY HUG PI and 
appropriate other clinical staff at each Clinical Center.  The results will be reported retrospectively 
every six months by structured abstraction of the medical record. The PI, nurse coordinator and all 
clinical staff may view all of the laboratory data from each study visit.  

 
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CHAPTER 6 
 
LABORATORY ANALYSES AND SPECIMENS  
6.1  
OVERVIEW  
All clinical hematology specimens will be processed locally. The Hematology Core 
laboratory will process specimens for fetal hemoglobin, creatinine and BUN. The other core or 
central laboratories in the BABY HUG Follow-up Study will evaluate and report the appropriate 
levels: pit count, HJB, VDJ, Microalbumin:creatinine ratio-urine and Cystatin C as described in the 
BABY HUG Treatment Study Protocol and Manual of Operations.  The TCD Core Laboratory will 
review a clinical TCD done about two years after the end of randomized treatment.  The NHLBI 
Specimen Repository will be utilized for processing study specimens.  The amount of blood and 
times of collection are specified in Appendix A. 
6.2  
PITTED CELL CORE LABORATORY  
After four years or exit of follow-up, a pit count will be obtained using one drop of blood 
preserved in gluteraldehyde.  An additional sample will be obtained for children in active follow-up at 
two years.  Specimens will be stored and refrigerated locally, and shipped in batches to the Pitted 
Cell Core Laboratory at UT Southwestern-Children’s Medical Center Dallas Clinical Laboratory.  
The technique for sample collection is described in the MOO for the BABY HUG Treatment Study 
and the BABY HUG Treatment Study Protocol.  
6.3  
CYSTATIN C CORE LABORATORY 
 
Specimens for measurement of Cystatin C will be processed at the St. Jude Clinical 
Laboratory according to Section 9.11 of the BABY HUG Treatment Study Protocol. 
 
6.4  
VDJ/DNA MUTATION CORE LABORATORY 
 
 
DNA will be isolated using a standard commercially available kit (Puregene DNA Isolation 
Kit, Gentra Systems Inc.).  The purified DNA will be quantitated using a spectrophotometer and 

 
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used directly in the VDJ mutation assay.  The overall goal of the VDJ studies is the investigation 
and quantification of the mutagenic and carcinogenic risks of HU therapy for very young children 
with SCD enrolled in the BABY HUG study,  To accomplish this goal, we will analyze peripheral 
blood for the presence of changes in chromosomal integrity that indicate unrepaired genetic 
damage.  The specific aims of the VDJ mutation study are:  to quantitate the frequency of 
“illegitimate” VDJ recombination events that occur between the T cell receptor gamma (TCD-
gamma) and beta (TCR-beta) gene loci located on chromosome 7; and to compare using serial 
measurements the frequency of VDJ mutational events among subjects depending on their time of 
HU exposure (treatment study, follow-up study, never). 
6.5  
HJB CORE LABORATORY 
 
The sample will be collected and processed in the research laboratory of Dr. Russell Ware 
at St. Jude’s Children’s Research Hospital as detailed in section 9.4 of the BABY HUG Treatment 
Study Protocol.  A small aliquot of RBC will be fixed in ice-cold methanol and frozen at -85oC 
according to a previously published protocol.  This sample will be shipped frozen to Litron 
Laboratories, Inc. in Rochester, NY and analyzed by flow cytometry for quantitation of HJB 
(micronuclei) in both immature and mature erythrocytes.  As above, serial measurements of the 
quantitative HJB measurement will be compared amongst subject groups depending on their time of 
HU exposure (treatment study, follow-up study, never). 
6.6 
NHLBI SPECIMEN REPOSITORY  
Five milliliters of blood will be collected for future use by BABY HUG and other sickle cell 
disease investigators.  The sample will be divided into serum, plasma and cell pellet aliquots and 
stored at the Medical College of Georgia.  In addition, this laboratory will conserve residual plasma, 
serum, and cell pellets.  At the end of the BABY HUG Follow-up Study, these specimens will be 
shipped to the NHLBI Specimen Repository (BioLINCC - Biologic Specimen and Data Repository 
Information Coordinating Center) provided informed consent has allowed for their long-term storage 
and use and the submitted application is approved.  At the end of the follow-up study, a public-use 

 
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database will be delivered to the NHLBI that will allow clinical data to be linked to the specimens to 
aid investigators in carrying out future SCA-related studies.  No DNA will be extracted or saved.  
Anonymized specimens will not provide any identifier to the individual from whom the specimen(s) 
was (were) obtained.  
6.6.1 Specimen Storage 
Parents/guardians must provide consent to have their child’s specimens stored in a central 
repository.  The planned specimens and potential future studies are outlined in Appendix A.  
Specimens will be prepared as outlined in the BABY HUG Follow-up Study Manual of Operations.  
Labels, provided by the MCC, will be applied to the specimens that will be stored at -80 and then 
sent to the NHLBI repository.  Labels will be coded so that the specimens can be linked to relevant 
clinical data (e.g. clinical events, liver/spleen scan results, etc) in the future.   
6.6.2 Obtaining Stored Specimens 
The process involved in requesting biospecimens is determined by the “Proprietary Period” 
or “Open Period” status of the study collection.  The “Proprietary Period” lasts until the clinical study 
data are made available for sharing following the NHLBI Limited Access Data Sharing Policy 
timeline.  During the “Proprietary Period” only centers involved in the BABY HUG Follow-up study 
will be permitted access to the specimens.  During the “Open Period” specimens will be available to 
all investigators successfully completing the application process as described below. 
Investigators will need to provide a design of the proposed research and evidence of the 
qualification to perform the research.  In addition, evidence of the availability of funding to perform 
the requested research must also be provided.  Furthermore, investigators wishing to obtain 
specimens must address ethical and legal considerations, including consistency with the terms of 
the informed consent and compliance with human subjects and HIPAA regulations.  Investigators 
requesting biospecimens during the “Proprietary Period” will need permission of the BABY HUG 
Follow-up study Steering Committee prior to obtaining the specimens. 

 
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6.7  
HEMOGLOBIN F, BUN and MICROALBUMIN : CREATININE RATIO CORE 
 
LABORATORY 
 
 
A 0.5 mL blood sample and a 5.0 mL urine sample will be collected at each Clinical Center 
and shipped to the Medical College of Georgia (MCG), a core laboratory.  The MCG will analyze the 
blood samples to provide HbF, creatinine, and BUN measurements.  The MCG will also analyze the 
urine sample to supply the microalbumin : creatinine ratio.  The BUN measurement was added to 
this protocol in August 2009 and is required for each blood draw.  If a blood draw has already been 
performed before August 2009, a small amount of blood from the stored blood samples or the 
remaining blood samples can be used to obtain the BUN measurement. 
 

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
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CHAPTER 7 
 
GUIDELINES FOR STANDARD CLINICAL CARE 
 
 
7.1 
INTRODUCTION 
 
The basic principles of supportive care for infants enrolled in the follow-up study are similar 
to those in the BABY HUG Treatment Study.  The cooperation of all medical staff involved in the 
clinical care of study children will be solicited to enhance child adherence to the follow-up study 
protocol. Parent education and guidelines for the diagnosis and treatment of common clinical events 
are addressed in the BABY HUG Treatment Study Protocol Section 8.4.  At no time should the 
performance of the BABY HUG Follow-up Study protocol be allowed to compromise the elements of 
good clinical care of the children enrolled in the study. 
7.2 
IMMUNIZATIONS 
 
All routine pediatric immunizations should be given as per standard clinical 
recommendations as noted in the BABY HUG Treatment Study Protocol Section 8.2 and in 
accordance with local routine clinical care.  (American Academy of Pediatrics Red Book 2006) 
7.3 
PROPHYLACTIC MEDICATIONS 
 
Twice daily prophylactic penicillin should have already been initiated prior to enrollment in 
the BABY HUG Treatment Study and continued until at least five years of age. The dose, 
formulation and use of an alternative antibiotic are in accordance with routine local clinical care. 
Reminders about the need for this prophylactic agent should be offered at each clinical contact. 
 
  
 

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
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CHAPTER 8 
 
SPECIAL STUDIES AND READING GROUPS  
8.1 
INTRODUCTION  
 
Special studies and event reports that will be centrally evaluated by individuals independent 
of the BABY HUG Clinical Centers include: liver-spleen scans, abdominal ultrasound, pitted cell 
counts, HJB, creatinine clearance, and Cystatin C measurements.  
8.2 
LIVER-SPLEEN SCANS 
 
Tc99m sulfur colloid liver-spleen scans will be performed once, only in children whose 
parents/guardians gave consent to active assessment, at two years into the follow-up study (four 
years after the child’s enrollment in the BABY HUG Treatment Study) according to standard 
techniques.  The results of this scan will be compared to the scans performed at screening and 
completion of treatment in the BABY HUG Treatment Study. Thus, pretreatment, post treatment and 
follow-up scans performed at time zero, two and four years respectively, will be available for review 
and comparison. Results will be assessed by a panel of three pediatric radiologists who are 
unaware of the original treatment assignment of the child.  The reading process has previously 
been described in Section 9.5 of the BABY HUG Treatment Study Protocol. The proportion of 
children in each treatment group over the four years of combined treatment and follow-up will be 
compared according to spleen function (normal, decreased, or absent). In addition, the number of 
times that there is a decline in splenic function from one category to another will be compared in 
each treatment group.  Scans that demonstrate an improvement in uptake will be scored as not 
demonstrating a decline.   
8.3 
PITTED CELL COUNTS (Pit Counts) and HOWELL JOLLY BODIES (HJB) 
 
Pit counts will continue to be done in a single laboratory, the Pitted Cell Core Laboratory.  
Tubes containing the glutaraldehyde buffer and directions for specimen collection will be provided to 

 
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the Clinical Centers by the Pitted Cell Core Laboratory as in the MOO of the treatment study.  HJB 
will be performed in the single laboratory that performed them in the BABY HUG Treatment Study.  
Pitted cell counts and HJB will be performed from specimens collected from all follow-up study 
children once, at four years or exit after the child’s enrollment in the BABY HUG Follow-up Study, 
whichever comes first.  Children whose parents/guardians gave consent for active follow-up will 
have an additional (third) measurement two years after entry into the follow-up study (four years 
after enrollment in the BABY HUG Treatment Study). 
8.4 
CLINICAL EVENTS 
 
Clinical events (hospitalizations and specific other sickle cell related events) will be 
retrospectively abstracted from the medical records of study participants at specified intervals (two 
times per year).  Clinical Centers will be asked to classify the event based upon BABY HUG criteria 
using simple yes/no data forms.  Definitions of clinical events can be found in Appendix F of the 
BABY HUG Treatment Study Protocol except for the post-hoc Steering Committee definition of 
splenic sequestration which is defined as follows: 
Splenic Sequestration:  2 cm or more increase from last visit in palpable spleen size AND a 
decrease in Hb of 2 g/dL or more below the last steady state value as determined by the 
investigator. 
8.5   
CREATININE CLEARANCE AND CYSTATIN C 
 
Creatinine clearance will be estimated from Cystatin C measurements and the Schwartz 
equations as indicated in the BABY HUG Treatment Study MOO. These studies will be done at the 
times indicated in Appendix A. 
8.6 
ABDOMINAL ULTRASOUND 
 
An abdominal ultrasound will be performed by standard clinical techniques to estimate the 
size of the spleen and the presence of gall stones according to the techniques outlined in the MOO 
of the BABY HUG Treatment Study.  This assessment will document if the spleen is enlarged and 
the subject therefore at risk for splenic sequestration or if it has involuted.  The presence or 

 
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absence of gall stones is a secondary endpoint assessment for the degree of hemolysis occurring 
over time. 
8.7 
TRANSCRANIAL DOPPLER (TCD) 
 
Transcranial Doppler studies will be performed as part of routine clinical care.  They will be 
performed by technicians certified by the Medical University of South Carolina (MUSC) and the 
Medical College of Georgia (MCG) for the BABY HUG Treatment Study.  As annual TCD evaluation 
is standard of care in the BABY HUG Follow-up Study age group, it is anticipated that most children 
will have at least one TCD study during the follow-up period.  The study performed for clinical 
indications closest to two years in the follow-up study will be copied and sent for review and 
analysis by the TCD reading committee. 

 
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PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
 FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 9 
 
FOLLOW-UP PROCEDURES  
9.1 
INTRODUCTION  
Children in both the passive and active follow-up groups will have data from clinic visits no 
less than every six months in the first four years of the follow-up study and then not less than once 
per year until the common termination date, December 2011, is reached.   The first child was 
enrolled into the BABY HUG Treatment study in October 2003 and the last child was enrolled in 
September 2007.  Therefore, the total follow-up period including randomized treatment time will 
range from 4 years and 3 months to 8 years and 2 months.  
9.2 
FOLLOW-UP VISITS 
Once informed consent for the follow-up study is obtained, retrospective data abstraction will 
be carried out for all medical visits that occur between the treatment study and enrollment in the 
follow-up study.  The type of data to be collected is shown in Appendix B. 
 
All follow-up visits will be performed at the Sickle Cell Clinic of the local Clinical Center and 
children will be evaluated in accordance with routine local clinical care.  At each visit during this 
period the evaluation for those children on HU will include an interval medical history and 
information regarding adverse events and toxicity.  In addition, height and weight will be recorded. 
Head circumference will also be measured and recorded until the age of five years.  Results of all 
testing obtained for clinical indications, including but not limited to TCDs, neuroimaging, and 
medical consultations, will be collected in a systematic manner in the follow-up study.  
9.2.1 Passive Follow-up Group 
 
All children (active and passive) in the follow-up study will have Cystatin C (if not done at 
exit from the treatment study), BUN, urine microalbumin: creatinine ratio and a stored blood sample 
collected at entry to the follow-up study.  At four years or exit from the follow-up study (whichever 

 
_________________________________________________________________________________________________________ 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 9-2  
 
occurs first), a repeat Cystatin C, creatinine, BUN, VDJ, Pit count, HJB, urine microalbumin: 
creatinine ratio, and a stored blood sample will be collected (see Appendix A).  All other laboratory 
testing will be limited to those tests performed in accordance with routine local clinical care, 
including HU monitoring for those children being treated with HU.  These later tests will be 
performed locally. Study data will be abstracted from the medical record using structured forms 
collected semi-annually. 
9.2.2  Active Follow-up Group 
 
In addition to the collections specified in Section 9.2.1 for the passive follow-up group, active 
follow-up will involve the collection of many of the same primary and secondary endpoint 
measurements as in the BABY HUG Treatment Study.  These will include: Hgb F, pit counts, HJB, 
liver-spleen scan information (quantitative and qualitative), multi-digit serum creatinine, BUN (for the 
calculation of the Schwartz estimates of GFR), Cystatin C, and neuropsychological testing.  The 
schedule of child visits during which specimens will be collected for laboratory testing is shown in 
Appendix A.  Most primary and secondary endpoints will be measured four years after the child’s 
enrollment in the BABY HUG Treatment Study.  The Vineland neuropsychological test will be 
measured four years after the child’s exit from the BABY HUG Treatment Study.  This schedule is 
designed to measure all endpoints along the combined continuum of treatment and follow-up at 
zero, two and four years. 
 
The timing of the active follow-up group special studies will depend upon the subject’s exit 
date from the BABY HUG Treatment Study.  The ideal time window is 24 months (-1 month/+2 
months).  However, some subjects will be entering the Follow-up Study greater than two years after 
they have exited from the BABY HUG Treatment Study.  Therefore, the special studies will need to 
be performed within 3 months of entry. Consequently, the timing of the “24 month” special studies is 
actually staggered across many months contingent upon the subject’s lapse of time from the BABY 
HUG Treatment Study.  For example, if a subject enters the BABY HUG Follow-up Study three (3) 

 
_________________________________________________________________________________________________________ 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 9-3  
 
years after exiting BABY HUG, the subject will have his “24 month” special studies done within 3 
months of entry, which is approximately 36 months post BABY HUG. 
9.2.3  Collection of Laboratory Data 
 
As noted in section 5.3, only the PEP will review the local laboratory results for children 
enrolled in the follow-up study within two months after the completion of the randomized BABY 
HUG Treatment Study.  The PEP will enter these data into the BABY HUG Follow-up Study 
database via the Internet Data Entry System maintained by the MCC within seven days of receiving 
them and keep these in a locked file with no access by BABY HUG Follow-up Study Clinical Center 
staff.  For all study visits after this two-month period, any local Clinical Center staff member may 
collect and enter laboratory data.  
9.2.4 Adverse Event Reporting 
Clinical events reported on the semi-annual follow-up form (Form 10) will be tabulated by the 
MCC based on the affected organ system. If any child dies while on study, efforts will be made to 
obtain complete post-mortem information.  Narratives of fatal events will be sent with study forms to 
the MCC.   
      
The NHLBI OSMB reviews the protocol at six-month intervals. A progress report showing 
results according to the different treatment types (see Chapter 4) will be forwarded by the MCC to 
the OSMB at these times and their recommendations will be expeditiously implemented. The OSMB 
members will also be provided with annual reports documenting each child’s growth, development 
and progress and other analyses as requested. The OSMB may recommend early termination of 
the study for considerations of safety.    

 
_________________________________________________________________________________________________________ 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 10-1  
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
 FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 10 
 
CLOSE-OUT PROCEDURES  
 
10.1 
OVERVIEW  
 
As noted in Section 9.1, the anticipated common termination date for this proposal is 
December 31, 2011, although every attempt will be made to secure follow-up funding for this unique 
group of children beyond this date.  Because the last child recruited into the BABY HUG Treatment 
Study will complete the study by September 2009, it is estimated that the treatment study will be 
completed and results disseminated during the follow-up study.  Whether HU is found to be 
efficacious in the BABY HUG Treatment Study or not, and whether or not toxicities are found in the 
treatment study, the follow-up study will be performed. If interim or final analysis of the BABY HUG 
Treatment Study demonstrates that HU is not safe and/or efficacious, parents/guardians with 
children on the follow-up study will be advised to stop HU treatment if their children are currently 
receiving HU.  Data processing and analysis of final study data will be continued according to the 
original schedule.  As mentioned in Chapter 2, regardless of efficacy outcome it is important to 
determine a complete long-term toxicity profile for the subjects in the BABY HUG Treatment Study.  
If HU treatment is found to be efficacious, it will be essential to determine how long this effect is 
preserved.  
10.2 
DEBRIEFING CONTACT 
 
After final long-term follow-up data have been collected and final reports on the results have 
been prepared for presentation or submitted for publication, each child’s family will be scheduled for 
a debriefing contact. Families will be informed of the results of follow-up study and any 
recommendations of the investigators.   
 
 

 
_________________________________________________________________________________________________________ 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 10-2  
10.3 
FINAL STUDY DATA AND DISSEMINATION OF RESULTS 
Data processing and analysis of final follow-up study data will proceed on a “time-of-the-
essence” basis. Clinical Centers will implement the following procedures for finalization of study 
data.  All queries for data clean-up including resolution of forms/procedures expected but not 
completed, as determined by the MCC, will be addressed within two months of the last follow-up 
visit.  Clinical Centers will be responsible for archiving records that document reported events and 
specified outcomes.  The MCC will archive all electronic study data.  Data from the Core 
Laboratories, Endpoints Evaluation Committees and medical records serve as the definitive sources 
for child outcomes in the study.   
The OSMB will review the final data analyses regarding the main findings of the study, 
including analyses for efficacy and safety, at a planned final meeting. These data analyses will form 
the basis of the final consensus recommendations from the OSMB, Steering Committee and the 
NHLBI.  These consensus recommendations will be shared first with the study children’ families and 
will be made public as soon as possible thereafter.  The final data analysis report will be available 
for submission to the FDA and for archival as will any databank studies.   
 
Archival of central source data, including Core Laboratory results, will be consistent with 
requirements for a study conducted under an Investigational New Drug (IND) Exemption and 
sponsored by the NHLBI and NICHD. Storage of frozen and preserved specimens will be 
maintained according to the requirements of the NHLBI specimen repository as outlined in Chapter 
6, following approval of the application to establish a biorepository.  The MCC will archive study 
data in accordance with FDA guidance and NHLBI requirements.  Public data files will be made 
available according to NHLBI policy.   
 

 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 11-1  
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) 
 FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 
 
CHAPTER 11 
 
ORGANIZATIONAL STRUCTURE AND PARTICIPATING UNITS  
11.1 
INTRODUCTION   
 
The BABY HUG Follow-up Study will be conducted by the same participating units as in the 
BABY HUG Treatment Study except for the Pharmacy Distribution Center and Clinical Center 
Pharmacies which are no longer necessary. All open-label HU will be prepared and distributed by 
the pharmacy at each Clinical Center. Descriptions of the various participating units can be found in 
Chapter 13, Section 2, of the BABY HUG Treatment Study Protocol. 
 
Administration of this study will involve the same structure, personnel, and reporting 
procedures as in the BABY HUG Treatment Study.  Descriptions of these functions can be found in 
Chapter 13, Section 3, of the BABY HUG Treatment Study Protocol.  Exhibit 11.1 details the 
organizational chart for the follow-up study.  A list of participating centers is found in Exhibit 11.2. 
11.2 
CLINICAL CENTER STAFF 
 
The Clinical Center staff will be trained in accordance with the procedures set out in the 
follow-up study protocol, many of which are the same as those in the BABY HUG Treatment Study 
protocol.  The objective is to standardize all study procedures carried out in the Clinical Centers. 
Treatment of study children whether on open-label HU or not, will be in accordance with routine 
local clinical care. 
11.3 
MONITORING AND ENDPOINT EVALUATION 
 
Study monitoring will be carried out by the OSMB, Steering Committee and Operations 
Committee based on this protocol. The Endpoints Evaluation Committees will perform their 
respective functions according to the BABY HUG Treatment Study Protocol. 

 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
 
 
 
 
Page 11-2  
Exhibit 11.1 
Pediatric Hydroxyurea Phase Clinical Trial (BABY HUG) 
Follow-up Observational Study Organizational Chart   
  
NATIONAL INSTITUTE OF 
CHILD HEALTH AND 
HUMAN DEVELOPMENT 
Zhaoxia Ren, M.D., Ph.D., 
Project Officer 
Anne Zajicek, Pharm.D, M.D. 
 
 
 
 
NATIONAL HEART, LUNG,  
AND BLOOD INSTITUTE 
Jonathan Goldsmith, M.D.,  Project Officer 
Myron Waclawiw, Ph.D., Statistician 
Henry Chang, M.D.  Executive Secretary of the 
OSMB 
 
OBSERVATIONAL AND 
SAFETY MONITORING 
BOARD 
Paul Swerdlow, M.D.  (Chair) 
Kenneth Bridges, M.D. 
Gary Cutter, Ph.D. 
Carlton Haywood, M.A. 
Larry Muenz, Ph.D. 
Alexis Thompson, M.D. 
Joann Bodurtha, M.D., M.P.H. 
 
OPERATIONS COMMITTEE  
Winfred Wang, M.D.  (Chair) 
Russell Ware, M.D., Ph.D.  (Vice Chair) 
Zora Rogers, M.D. (Follow-up Study) 
Two Clinical Center PIs 
Coordinator Chair 
Two Clinical Center Coordinators 
Jonathan Goldsmith, M.D. 
Michael Jeng, M.D. 
Bruce Thompson, Ph.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MEDICAL COORDINATING CENTER (MCC) 
Bruce Thompson, Ph.D.,  PI 
 
 
CLINICAL CENTERS 
Exhibit 11.2 
 
 
 
STEERING COMMITTEE  
PI’s of 14 Clinical Centers 
NHLBI Project Officer 
NICHD Project Officer 
MCC PI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
STUDY COORDINATOR 
COMMITTEE 
ENDPOINTS EVALUATION 
COMMITTEES 
Neurological - Rebecca Ichord, M.D. 
Clinical Events 
- Millicent Sutton, M.D. 
- Thomas Kinney, M.D. 
- Howard Pearson, M.D. 
Liver-Spleen 
- Eglal (Gila) Shalaby-Rana, M.D. 
- Michael Gelfand M.D. 
- Barry Shulkin, M.D. 
Abdominal Ultrasound  
Psychometric - Daniel Armstrong, Ph.D. 
 
HEMATOLOGY CORE 
LABORATORY 
 
 
OTHER CORE 
LABORATORIES 
 
 
 
 
 
 
 

 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
Page 11-3  
 
 
 
 
 
Exhibit 11.2  
 
 
 
PARTICIPATING CLINICAL CENTERS 
 
CLINICAL CENTERS 
Children’s Research Institute, Lori Luchtman-Jones, M.D.  - 01 
(Washington, DC) 
Duke University Medical Center, Courtney Thornberg, M.D.  - 02 
(Durham, NC) 
Howard University College of Medicine, Sohail Rana, M.D.  - 03 
(Washington, DC) 
Johns Hopkins University School of Medicine, James F.  Casella, M.D.  - 04 
(Baltimore, MD) 
Medical University of South Carolina, Sherron Jackson, M.D.  - 05 
(Charleston, SC) 
St.  Jude Children’s Research Hospital, Winfred C.  Wang, M.D.  - 06 
(Memphis, TN) 
State University of New York - Brooklyn (SUNY), Scott T.  Miller, M.D.  - 07 
(Brooklyn, NY) 
University of Miami School of Medicine, Ofelia Alvarez, M.D.  - 08 
(Miami, FL) 
University of Mississippi Medical Center, Rathi V. Iyer, M.D.  - 09 
(Jackson, Mississippi) 
University of Texas Southwestern Medical Center, Zora R.  Rogers, M.D.  - 10 
(Dallas, TX)  
University of Alabama, Birmingham, Thomas Howard, M.D.  - 11 
(Birmingham, AL)  
Drexel University, Norma Lerner, M.D.  - 12 
(Philadelphia, PA) 
Emory University School of Medicine, R. Clark Brown, M.D., Ph.D.  - 13 
(Atlanta, GA)  
Wayne State University, Ingrid Sarnaik, M.D.  - 14 
(Detroit, MI) 
 
MEDICAL COORDINATING CENTER 
Clinical Trials & Surveys, Corp.  (Baltimore, MD) 
 
Bruce W.  Thompson, Ph.D., Principal Investigator 
 
 
 
 
PROJECT OFFICE 
Division of Blood Diseases and Resources 
National Heart, Lung, and Blood Institute (Bethesda, MD) 
 
Jonathan Goldsmith, M.D., Project Officer 
 
Myron Waclawiw, Ph.D., Statistician 
 
Henry Chang, M.D., Executive Secretary of the OSMB 

 
 
 
_____________________________________________________________________________________________________ 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
 
References 
 
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D., Kutlar 
A, Nichols FT, Bonds DR, Brambilla D, Woods G, Olivieri N, Driscoll C, Miller S, Wang W, Hurlet 
A, Scher C, Berman B, Carl EM, Jones AM, Roach ES, Wright R, Zimmerman RA, and 
Waclawiw M.  Prevention of a first stroke by transfusions in children with sickle cell anemia and 
abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998; 339:5-11. 
 
Alvarez O, Zilleruelo G, Wright D, Montane B, and Lopez-Mitnik G (2006).  Serum cystatin  C 
levels in children with sickle cell disease.  Pediatr Nephrol. 2006; 21:533-37. 
 
American Academy of Pediatrics.  Active Immunization. In: Pickering LK, Baker CJ, Long SS, 
McMillan JA, eds.  Red Book:  2006 Report of the Committee on Infectious Diseases.  27th Ed. 
Elk Grove Village, IL.  American Academy of Pediatrics; 2006; 9-54, (especially Figure 1.1 page 
26). 
 
Andersen PK and Gill RD  (1982).  Cox’s regression model for counting processes: A large 
sample sized.  Ann Statistics 1982; 10(4):1100-20. 
 
Benjamini Y and Hochberg Y.  Controlling the false discovery rate: A practical and powerful 
approach to multiple testing.  Journal of the Royal Statistical Society.  Series B.  1995; 
57(1):289-300. 
 
Cox DR .  Regression models and life tables.  J R Stat Soc B.  1972; 34:187-220. 
 
Darnidharka VR, Dabbagh S, Atiyeh B, Simpson P, and Sarnaik S. Prevalence of microalbuminuria 
in children with sickle cell disease.  Pediatr Nephrol.  1998; 12:475-8. 
 
Hankins JS, Ware RE, Rogers ZR, Wynn LW, Lane PA, Scott JP, and Wang WC.  Long-term 
hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT Extension Study.  Blood. 
2005; 106:2269-75. 
 
Hoppe C, Vichinsky E, Quirolo K, van Warmerdam J, Allen K, and Styles L. (2000).  Use of 
hydroxyurea in children ages 2 to 5 years with sickle cell disease.  J Pediatr Hematol/Oncol.  2000; 
22:330-34. 
 
Kaplan E and Meier P.  (1958).  Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc.  1958; 53:457-81. 
 
Liang K.Y. and Zeger S.L. Longitudinal data analysis using generalized models.  Biometrika.  1986; 
73:13. 
 
Laird NM and Ware JH. Random-effects models for longitudinal data.  Biometrics.  1982; 
38:963-74. 
 
Manson JE, Hsia J, and Johnson KC.  Estrogen plus progestin and the risk of coronary heart 
disease.  N Engl J Med 2003; 349:523-34.   
 
R-1 

 
 
 
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McMahon RP, Waclawiw MA, Geller NL, Barton FB, Terrin ML, and Bonds DR.  An extension of 
stochastic curtailment for incompletely reported and classified recurrent events:  The Multicenter 
Study of Hydroxyurea in Sickle Cell Anemia (MSH).  Control Clin Trials 1997; 18:420-30. 
 
Miller ST, Sleeper LA,  Pegelow CH,  Enos LE, Wang WC, Weiner SJ, Wethers DL, Smith J, Kinney 
TR.  Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 
342:83-89. 
 
Quinn CT, Rogers ZR, Buchanan GR.  Survival of children with sickle cell disease.  Blood 2004; 
103:4023-27. 
 
Schlucter MD  Methods from the analysis of informatively censored longitudinal data.  Stat in Med.  
1992; 11:1861-70. 
 
1Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New 
equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009; 20(3):629-37 
Steinberg MH,Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, 
Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, 
Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw 
M, Bonds D, Terrin M.  Effect of hydroxyurea on mortality and morbidity in adult sickle cell 
anemia. JAMA 2003: 289:1645-51. 
Wassertheil-Smoller S,Hendrix SL, and Limacher M, Effect of estrogen plus progestin on stroke 
in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA 2003; 
289:2673-84. 
 
Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, and Ware RE.  A two-year pilot trial of 
hydroxyurea in very young children with sickle cell anemia.  J Pediatr. 2001; 139: 790-96. 
 
..   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
A-1 
 
APPENDIX A 
Schedule and Volume of Blood and Urine Collection and Schedule of Special Studies  
BABY HUG Follow-up Observational Study 
 
CLINICAL 
DATA 
REPORTS 
               Blood Sample Collection                                                                                    Other Tests 
                 (All volumes in ml) 
 
Time Point 
 
HbF 
(Core) 
 
HJB 
(Core) 
Pitted 
Cells 
(Core) 
 
STORED 
BLOOD 
SAMPLE 
VDJ 
Cystatin 
C 
(ml)  
(Core)  
Creatinine 
and BUN 
(core) 
Liver 
Spleen 
Scan 
Abdominal 
Ultrasound 
⁯Neuropsych 
(WPPSI) 
Microalbumin/ 
Creatinine Ratio 
           Urine  
           (Core) 
Vineland 
CONSENT (end of 
randomized study) 
  
** 
  
** 
** 
5.0^ 
** 
0.5 
** 
** 
** 
** 
5.0 
 
+6 Months  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 +12 Months 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+18 Months 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+24 MO  
(Active Follow-Up 
Only) 
-1 month/+2 
months 
X (all) 
0.5 
 
0.1 
0.1  
 
  
0.5 
0.5 
Y 
Y 
Y 
 
 
+30 MO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+36 MO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+48 MO  
-1 month/+2 
months 
X 
 
 
0.1 
0.1 
5.0^ 
3.0 
0.5 
0,5 
 
 
 
5.0 
Y (for 
active 
follow-up 
only) 
+60 MO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
+72 MO or Exit 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
 
CBC with diff and reticulocyte count will be done at each clinic visit as a clinical parameter.  All CBCs performed for medical management within two months 
after completion of the BABY HUG Treatment Study should be reviewed only by the PEP. 
** Done on exit from BABY HUG Treatment Study 
 
^ 
The stored blood sample will be collected, separated and aliquots made and stored for future study 
 
The entry visit has a time window of 3 months from consent signing for those who exited the BABY HUG Study > 6 weeks before enrolling in BABY HUG Follow-
up and a time window of 6 weeks for those subjects who are entering the BABY HUG Follow-up Study immediately following the BABY HUG Treatment Study. 
 
The 24 month Active special studies visit has a time window of -1month/+2 months. 
 
The 48 month visit has a time window of -1month/+2 months.

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 1 of 13 
 
 
Appendix B 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY DATA COLLECTION SHEET 
For child visits between the treatment and follow-up studies 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY 
 
CLINICAL DATA REPORT 
 
PART I:  IDENTIFYING INFORMATION 
 
1. 
Patient’s ID Number: 
 
 
 
 
 
2. Current Clinic:  
 
 
 
3. 
Patient’s Letter Code: 
 
 
 
 
 
4. 
Abstraction Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
PART II:  INTERVAL INFORMATION 
 
1.  
Visit: 
 
 
M 
 
2. 
Interval Start Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
3. 
Interval End Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
 
 
 
 
Yes 
No* 
4. 
Any patient contact during this interval? 
(1 ) 
(2 ) 
*A.  If no, reason    
  
 
 
*If No, Skip to Part IX. 
 
 
PART III:  HU USE 
 
 
 
Yes** 
No* 
1. 
Was the patient prescribed HU at any time during this interval? 
(1 ) 
(2 ) 
 
*If No, Skip to Part IV. 
 
 
**A.  If yes, what was the: 
 
 
1.  Dose at the first time it was prescribed this interval: 
 
 
 
. 
 
mg/kg 
 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 2 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
 
 
 
2.  Dose form: 
Liquid 
Capsules 
 
 
 
(1 ) 
(2 ) 
 
 
 
Yes* 
No** 
2. 
Was the patient still being prescribed HU at the end of the interval? 
(1 ) 
(2 ) 
 * A.  If Yes, what was the: 
 
 
1.  Dose at the end of the interval: 
 
 
 
. 
 
mg/kg 
 
 
 
 
 2.  Dose form: 
Liquid 
Capsules 
 
 
 
(1 ) 
(2 ) 
 **B. If No, what was the date the patient stopped being prescribed HU? 
 
 
 
 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
Yes* 
(1 ) 
No 
(2 ) 
3. 
Did the patient have HU held because of possible drug toxicity during  
this interval? 
 *A.  If Yes, check all that apply: 
 
 
 
 
 
1. 
Low ANC 
(1 ) 
 
 
 
 
 
 
2. 
Low Hgb 
(1 ) 
 
 
 
 
 
 
3. 
Low PHs 
(1 ) 
 
 
 
 
 
 
4. 
Other bacterial or viral infection 
(1 ) 
 
 
 
 
 
 
5. 
Other  
(1 ) 
 
 
 
 
 
 
 
a.  Specify ______________________ 
 
 
 
4. 
Estimate how many weeks during this interval the patient actually took HU: 
 
 
This is the number of weeks HU was taken minus the number of weeks HU was stopped 
due to toxicity, if applicable.  If there was no toxicity, it is the number of weeks HU was 
taken in this time period. 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 3 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
PART IV:  BLOOD RESULTS 
 
 
 
Yes 
No* 
1. 
Were any blood specimens collected for clinical reasons during this interval? 
(1 ) 
(2 ) 
 
 *If NO, reason: 
 
 
 
If No, Skip to Part V.  
 
2. 
First CBC in interval: 
 
A. 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
B. 
Hemoglobin 
 
 
 
 
 
 
. 
 
gm/dl 
 
 
C. 
MCV 
  
 
 
 
 
. 
 
fL 
 
 
D. 
Reticulocyte (% of RBC) 
  
 
 
 
 
. 
 
% 
(1 ) Not Done 
 
E. 
White Blood Cell Count 
 
 
 
 
 
 
. 
 
K/mm3 
 
 
F. 
Absolute Neutrophil Count 
  
 
 
 
. 
 
 
K/mm3 
(1 ) Not Done 
 
G. 
Platelet Count  
 
 
 
 
 
 
 
 
K/mm3 
 
 
H. 
Red Blood Cell Count 
 
 
 
 
 
. 
 
 
M/mm3 
 
 
3. 
Last CBC in interval: 
 
A. 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
B. 
Hemoglobin 
 
 
 
 
 
 
. 
 
gm/dl 
 
 
C. 
MCV 
  
 
 
 
 
. 
 
fL 
 
 
D. 
Reticulocyte (% of RBC) 
  
 
 
 
 
. 
 
% 
(1 ) Not Done 
 
E. 
White Blood Cell Count 
 
 
 
 
 
 
. 
 
K/mm3 
 
 
F. 
Absolute Neutrophil Count 
  
 
 
 
. 
 
 
K/mm3 
(1 ) Not Done 
 
G. 
Platelet Count   
 
 
 
 
 
 
 
 
K/mm3 
 
 
H. 
Red Blood Cell Count 
 
 
 
 
 
. 
 
 
M/mm3 
 
 
 
Yes 
No* 
  (1 ) Not Done 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 4 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
4. 
Were any of the following laboratory values obtained during this interval? 
(1 ) 
(2 ) 
 
 *A.   
If No, reason:  
 
 
 
Not a part of routine care 
(1 ) 
 
   
Other 
(2 ) 
 
 
a.  If other, Specify: _________________________________________ 
 
 
 
*If No, Skip to Part V.    
 
 
 B. 
Creatinine: 
 
 
 
1.  Date: 
 
 
 
- 
 
 
- 
 
 
 
 
  (1 ) Not Done 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
 
2.  Value: 
 
 
. 
 
 
 
mg/dL 
 
 
 
 
C. 
ALT 
 
 
 
1.  Date: 
 
 
 
- 
 
 
- 
 
 
 
 
  (1 ) Not Done 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
2.  Value: 
 
 
 
 
 
 
IU/L 
 
 
 
 
 
D. 
GGT 
 
 
 
1.  Date: 
 
 
 
- 
 
 
- 
 
 
 
 
  (1 ) Not Done 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
2.  Value: 
 
 
 
 
 
 
u/L 
 
 
 
E.  
Fetal Hemoglobin: 
 
 
 
1.  Date: 
 
 
 
- 
 
 
- 
 
 
 
 
  (1 ) Not Done 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
2.  Value: 
 
 
. 
 
% 
 
 
 
 
 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 5 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP OBSERVATIONAL STUDY PROTOCOL 01/2010 
PART V:  IMAGING RESULTS 
 
 
 
 
 
 
 
 
 
 
Yes 
No* 
1. 
Were any TCD’s performed during this interval? 
 
 
(1 ) 
(2 ) 
 
 
 
*If No, Skip to Part V, 4. 
 
A. 
 
B. 
TCD Date 
 
*Results 
1. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
 
Month 
 
Day 
 
Year 
 
 
2. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
Month 
Day 
 
Year 
 
 
3. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
Month 
Day 
 
Year 
 
 
4. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
Month 
Day 
 
Year 
 
 
5. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
Month 
Day 
 
Year 
 
 
6. 
 
 
 
- 
 
 
- 
 
 
 
 
 
(1 ) 
(2 ) 
(3 ) 
Month 
Day 
 
Year 
 
 
 
 
*Results 
1. 
Normal (all mean velocities less than 170) 
2. 
Conditional (highest mean velocity 170-199) 
3. 
Abnormal (any mean velocity over 200) 
 
 
COMPLETE TRANSMITTAL FORM 105 AND FAX ALONG WITH A COPY 
OF ALL TCD REPORTS TO THE MEDICAL COORDINATING CENTER. 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 6 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
 
 2. 
MRI Date* 
 
 
 
- 
 
 
- 
 
 
 
 
  (1 ) Not Done 
 
 
 
Month 
 
Day 
 
Year 
 
 
 *A. 
If MRI done, result: 
 
 
 
CHECK THE MOST SEVERE RESULT 
 
 
 
Normal 
 (1 ) 
 
 
Silent Infarct(s) (gliosis) 
 (2 ) 
 
 
Stroke (CVA or thrombosis) 
 (3 ) 
 
 
Hemorrhage (subarachnoid or subdural) 
 (4 )   
 
 
Other 
 (5 )^ 
 
  1.   ^If Other, Specify:   
  
 
COMPLETE TRANSMITTAL FORM 105 AND FAX ALONG WITH A COPY 
OF THE REPORT TO THE MEDICAL COORDINATING CENTER. 
 
 
 3. 
MRA Date* 
 
 
 
- 
 
 
- 
 
 
 
 
 (1 )  Not Done 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
Yes 
No 
*A. If MRA done, any result abnormal? 
(1 ) 
(2 ) 
 
COMPLETE TRANSMITTAL FORM 105 AND FAX ALONG WITH A COPY 
OF THE REPORT TO THE MEDICAL COORDINATING CENTER. 
 
 
 4. 
CT Date* 
 
 
 
- 
 
 
- 
 
 
 
 
 (1 )  Not Done 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
Yes 
No 
*A. If CT done, any result abnormal?: 
(1 ) 
(2 ) 
 
COMPLETE TRANSMITTAL FORM 105 AND FAX ALONG WITH A COPY 
OF THE REPORT TO THE MEDICAL COORDINATING CENTER. 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 7 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
PART VI:  OTHER PROCEDURES 
 
 1. 
EEG Date* 
 
 
 
- 
 
 
- 
 
 
 
 
 (1 )  Not Done 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
Yes 
No 
*A. If EEG done, any result abnormal? 
(1 ) 
(2 ) 
 
2. 
PFTs Date* 
 
 
 
- 
 
 
- 
 
 
 
 
 (1 )  Not Done 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
Yes 
No 
*A. If Pulmonary Function Tests done, any result abnormal? 
(1 ) 
(2 ) 
 
3. 
Neuropsych Date* 
 
 
 
- 
 
 
- 
 
 
 
 
 (1 )  Not Done 
 
 
Month 
 
Day 
 
Year 
 
 
 
 
 
Yes^ 
No 
*A. If neuropsychology testing done, any results abnormal? 
(1 ) 
(2 ) 
 
^1. Specify test: _________________________________________ 
 
COMPLETE TRANSMITTAL FORM 105 AND FAX ALONG WITH A COPY 
OF THE REPORT TO THE MEDICAL COORDINATING CENTER. 
 
 
 
 
Yes* 
No 
4. 
Other clinical tests done: 
(1 ) 
(2 ) 
 
*A.  If Yes, specify:  
________________________________________ 
 
 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 8 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
PART VII:  CLINICAL EVENTS 
 
1. 
Clinic Visits 
 
A. 
During this interval how many times was this patient seen in clinic (not 
ER, day unit, or hospital)? 
 
 
 
 
 
 
 
If zero, Skip to Part VII, Item 2. 
 
B. 
Enter the number of visits for which the following were the main reasons 
for each visit in this time period: 
 
 
 
 
1. Routine Clinical Visit (physical examination by sickle cell team) 
 
 
 
 
 
 
 
 
 
2. HU toxicity assessment (blood count check to monitor HU therapy 
and possible side effects) 
 
 
 
 
 
 
 
 
3. Other clinical service (including follow-up of crisis event and general 
pediatrics) 
 
 
 
 
 
 
 
 
4. Other 
 
 
* 
 
 
 *a. 
If other, Specify: ________________________________________________ 
 
2. 
Hospitalization 
 
A. 
How many times was this patient seen in an ER or day hospital during this 
interval (in your facility or another): 
 
 
 
 
 
 
If zero, Skip to Part VII, Item 3. 
 
B. 
Reasons for visits: 
 
Yes 
No 
1. 
Acute splenic sequestration crisis 
(1 ) 
(2 ) 
 
2. 
Acute chest syndrome 
(1 ) 
(2 ) 
 
3. 
Neurologic event (stroke or seizure) 
(1 ) 
(2 ) 
 
4. 
Aplastic Crisis 
(1 ) 
(2 ) 
 
 
 
 
 
 
5. 
Urinary tract infection 
(1 ) 
(2 ) 
 
 
 
 
6. 
Fever or febrile illness including URI/sinusitis/cold/flu 
(1 ) 
(2 ) 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 9 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
7. 
Other acute illness, no fever 
(1 ) 
(2 ) 
 
 
 
 
8. 
Trauma including broken bones and sprains 
(1 ) 
(2 ) 
 
 
 
 
9. 
Sickle Cell Pain Crisis (including dactylitis) 
(1 )  
(2 ) 
 
 
 
 
10. 
Other 
(1 )* 
(2 ) 
 *a. 
If other, specify: ___________________________________________ 
 
3. 
How many times was the patient admitted to the hospital during this 
interval (in your facility or another)? 
 
 
 
 
 
 
 
If zero, Skip to Part VII, Item 4.  
 
A. 
What was the primary discharge diagnosis for each of these admissions?  
 
 
1. 
Neurologic event (stroke or seizure) 
 
 
 
 
 
2. 
Acute splenic sequestration crisis 
 
 
 
 
 
3. 
Acute chest syndrome 
 
 
 
 
 
4. 
Aplastic Crisis 
 
 
 
 
 
 
 
 
 
 
 
5. 
Urinary tract infection 
 
 
 
 
 
 
 
 
 
6. 
Fever or febrile illness including URI/sinusitis/cold/flu 
 
 
 
 
 
 
 
 
 
7. 
Other acute illness, no fever 
 
 
 
 
 
 
 
 
 
8. 
Trauma including broken bones and sprains 
 
 
 
 
 
9. 
Sickle Cell Pain Crisis (including dactylitis) 
 
 
 
 
 
10. 
Surgery (see Part VII, Item 5 below) 
 
 
 
 
 
11. 
Other 
 
 
* 
 
 
 
*a. 
If other, specify: _________________________________________ 
 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 10 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
4. 
Pain 
 
 
 
Yes* 
No 
A. 
Has the child experienced pain (defined as pain lasting four hours or 
more without other obvious cause for which medication such as 
ibuprofen, acetaminophen, or acetaminophen with opioid was taken 
for relief) even if not seen by a medical professional during the 
interval? 
 (1 ) 
(2 ) 
 
 
 
 
 
*1. 
If yes, how many episodes of pain has the patient experienced 
during this interval? 
 
 
 
 
 
 
 
 
5. 
Surgery 
 
 
 
Yes* 
No 
A. 
Did the patient have at least one surgery during this interval? 
(1 ) 
(2 ) 
 
 
*1.   If yes, identify the type of each surgery and give date: 
 
 
 
a. 
Tonsillectomy, Adenoidectomy or both 
(1 ) Not Done 
 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
b. 
Splenectomy (open or laproscopic) 
(1 ) Not Done 
 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
c. 
Cholecystectomy and/or ERCP 
(1 ) Not Done 
 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
d. 
Ear tubes, hernia repair, dental rehabilitation 
(1 ) Not Done 
 
Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
Yes^ 
No 
 e. 
Other 
(1 ) 
(2 ) 
        ^1.  If other,  specify: ______________________________________ 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 11 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
6. 
Transfusion 
 
 
 
Yes* 
No 
A. 
Was the patient on a chronic transfusion program during this interval 
(meaning scheduled transfusions every two-six weeks for three 
months or more)? 
(1 ) 
(2 ) 
 
*1. 
If yes, what was the main reason for the chronic transfusion program: 
 
Stroke (clinical neurologic deficit lasting 24 hours or more) 
(1 ) 
Elevated TCD velocity 
(2 ) 
TIA or other neurologic events 
(3 ) 
Splenic Sequestration 
(4 ) 
Recurrent Acute Chest Syndrome 
(5 ) 
Recurrent Painful Events 
(6 ) 
Other 
(7 )^ 
 ^a.  If other, specify: ______________________________________ 
 
 
 
 
Yes* 
No 
B. 
Did the patient receive an episodic transfusion during this interval 
(meaning a transfusion, scheduled or not that was for a specific 
problem or to prepare them for surgery)? 
(1 ) 
(2 ) 
 
*1. If yes, what was the main reason for the episodic transfusion? 
 
Acute Splenic Sequestration 
(1 ) 
Acute Chest Syndrome 
(2 ) 
Neurologic Event or Stroke 
(3 ) 
Aplastic Crisis 
(4 ) 
Peri Operative Preparation 
(5 ) 
Other 
(6 )^ 
 ^a.  If other, specify: _______________________________________ 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 12 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
 
PART VIII:  PHYSICAL EXAMINATION 
 
If there are more than three sets of collected physical examination data, use the first and last in 
the sequence and select the one closest in days to the midpoint of the interval.  Sickle Cell or 
Hematology clinic examinations are preferred over ER/hospital/general pediatric visits if there is 
a choice.   
 
 
 
Yes 
No 
1. 
Was a physical examination performed during this interval? 
(1 ) 
(2 ) 
 
 
 
 
 If No, Skip to Part IX. 
 
 
2. 
Growth Parameters: 
 
 
A.  First Encounter Date: 
 
 
 
- 
 
 
- 
 
 
 
 
 
 
Month 
 
Day 
 
Year 
 
 
 
1. Height 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 
2. Weight 
 
 
 
 
. 
 
kg 
(1 ) Not Done 
 
3.  Head Circumference 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 
B. Second Encounter 
       midpoint Date:  
 
 
 
- 
 
 
- 
 
 
 
 
 (1 ) Not Done* 
Month 
 
Day 
 
Year 
 
 
 
*If Not Done, Skip to Part VIII, Item 2C. 
 
1. Height 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 
2. Weight 
 
 
 
 
. 
 
kg 
(1 ) Not Done 
 
3.  Head Circumference 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 
C. Last or latest Visit 
     Date:  
 
 
 
- 
 
 
- 
 
 
 
 
 (1 ) Not Done 
Month 
 
Day 
 
Year 
 
 
 
*If Not Done, Skip to Part VIII, Item 3. 
 
1. Height 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 
2. Weight 
 
 
 
 
. 
 
kg 
(1 ) Not Done 
 
3.  Head Circumference 
 
 
 
 
. 
 
cm 
(1 ) Not Done 
 

BABY HUG FUP Form 10 
Rev. 4  05/25/2009 
Page 13 of 13 
 
ID Number 
 
Visit 
 
Seq 
 
 
 
 
 
 
 
 
- 
 
 
 
BABY HUG FOLLOW-UP STUDY PROTOCOL 08/14/2009 
 
 
 
 
 
Yes 
No 
3. 
A. Was the spleen reported to be palpable below the costal margin at any 
time during this interval? 
 
(1 ) 
 
(2 ) 
 
 
 
 
 
 
If No, Skip to Part IX. 
 
 
B. On what date was it the largest (most 
centimeters below costal margin): 
 
 
 
- 
 
 
- 
 
 
 
 
Month 
 
Day 
 
Year 
 
              Write the largest value below: 
 
 
1. Mid-clavicular line: 
 
 
. 
 
cm below costal margin 
 (1 ) Not Done 
2. Anterior anxillary line:  
 
 
 
cm below costal margin 
 (1 ) Not Done 
 
 
Yes 
No 
C. 
Was the child diagnosed with acute splenic sequestration during this 
interval? 
 
(1 ) 
 
(2 ) 
 
 
PART IX:  COORDINATION 
 
1. 
Checked for completeness and accuracy: 
 
A. 
Certification number:  
 
 
- 
 
 
 
 
B. 
Signature:  
 
 
 
C. 
General Comments: