Conditions: Sickle Cell Anemia
Keywords: Sickle cell Hydroxyurea Infants
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
This is a pilot study, single-blind, randomized, multicenter, therapeutic clinical trial designed to evaluate the feasibility of enrolling infants and toddlers (9 months to 36 months) with sickle cell anemia (SCA; HbSS or HbSβ\^0thalassemia), regardless of disease severity, to a therapeutic trial. A prior clinical trial at St. Jude Children's Research Hospital (SJCRH) (BABYHUG, NCT01783990) demonstrated that a fixed dose (20 mg/kg/day) of hydroxyurea was safe and effective in decreasing SCA-related complications in very young children (9-18 months), and largely due to these findings, hydroxyurea is recommended to be offered to all children (≥9 months old) with SCA, independent of disease severity. Nevertheless, children in the treatment arm of BABYHUG continued to experience vaso-occlusive symptoms and to incur organ damage. In clinical trials of older children with SCA, intensification of hydroxyurea to a maximum tolerated dosage (MTD), defined by mild to moderate myelosuppression, may be associated with improved laboratory parameters compared to fixed lower-dosing, but the clinical benefits gained from dose intensification have not been described. Therefore, in this trial, children in the standard treatment arm will receive a fixed dose of hydroxyurea (20 mg/kg/day), and participants in the experimental arm will receive hydroxyurea intensified to MTD, defined by a goal absolute neutrophil count (ANC) of 1500-3000 cells/µL. This trial aims to establish a multicenter infrastructure that will identify, enroll and randomize very young children (9-36 months) to receive fixed dose versus intensified-dose hydroxyurea in a single blinded manner, and to obtain prospective pilot data comparing the clinical and laboratory outcomes between the treatment arms to facilitate design of a definitive phase III trial.

Detailed description:
All participants will initially receive hydroxyurea at a dose of \~20 mg/kg/day in an open label fashion for eight weeks (± 2 weeks) prior to randomization. Participants will receive monthly medical evaluations (every 4 ± 2 weeks) where they will have height and weight measurements, medical history, physical examination, and medication adherence assessments. During these monthly visits complete blood counts with absolute reticulocyte count will be monitored. Hemoglobin electrophoresis, complete serum chemistries, urinalysis, lactate dehydrogenase and quality of life measurements will be obtained every 20 (±2) weeks. Transcranial Doppler (TCD) ultrasound velocities will be obtained at study entry (in participants ≥2 years of age) and study exit. Participants randomized to receive hydroxyurea at MTD will have their dose increased by 5 mg/kg/day every 8 weeks, in the absence of toxicity, until a goal ANC of 1500-3000 cells/µL is achieved, up to a maximum of 35 mg/kg/day.

Both groups will receive their assigned treatment for 48 weeks (± 3 weeks). Participants will be in the study for a total of 56 weeks (± 3 weeks) and have 14 clinic visits to the St. Jude outpatient Hematology Clinic during that time. After the 56 weeks, participants will be followed for an additional 30 days for side effects and will then be taken off study.

Arms:
arm 1: In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment \[a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea\]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment. arm 2: In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment \[a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea\]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.

Interventions: intervention 1: Hydroxyurea
Intervention descriptions: intervention 1: Given orally once daily.

Protocol document:
Prot_SAP_000.pdf: 
Amendment 2.0 , dated: 03-03-2020 
Protocol document date: 05-29-2019
St. Jude Children's Research Hospital 
HUGKISS CTG# - NCT03020615
Initial version, dated: 06-09-16, (IRB Approved: 09-28-16) (UNR IRB Approved: 10-05-
2016) Activation Date: 00-00-00 
Amendment 1.0, dated: 10-24-16 (IRB Approved: 11-22-2016) Activated: 05-03-2017 
Revision 1.1, dated: 07-21-2017 (IRB Approved: 07-28-2017) Activated: 08-07-2017 
Revision 1.2, dated: 06-01-2018 (IRB Approved: 06-01-2018) Activated: 06-04-2018 
Amendment 2.0, dated: 07-16-18 (IRB Approved: 08-28-2018) Activated: 10-15-2018 
Unnumbered Revision, dated:03-03-20 (IRB Approved: ) 
A PILOT STUDY OF HYDROXYUREA MANAGEMENT IN KIDS: INTENSIVE 
VERSUS STABLE DOSAGE STRATEGIES (HUGKISS)
IND# 132032 
Principal Investigator (Site) 
Jeremie Estepp, MD 
Co-Principal Investigator (Sponsor) 
Jeremie Estepp1,2, MD 
Co-Investigators 
Nicole Dockery1, NP 
Nathan Gray1, PA 
Jane Hankins1, MD, MS 
Guolian Kang3, PhD 
Ulrike Reiss1,2, MD 
Kumar Srivastava3, PhD 
Roynetta Lloyd1, NP 
Christina Wills1, NP 
Parul Rai1, MD
Nidhi Bhatt1, MD
Winfred Wang1, MD (Emeritus) 
Departments of Hematology1, Pathology2, and Biostatistics3  
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105-3678 
Telephone: (901-595-3300) 
Collaborating External Co-Investigators: 
Robert (Clark) Brown, MD, PhD 
Children’s Hospital of Atlanta 
An Pham, MD
University of Texas Southwestern Medical Center 
Melissa McNaull, MD 
University of Mississippi Medical Center 
 Contents of this document may not be extracted without permission from the Principal Investigator.
List of Collaborating Investigators/Institutions 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0 , dated: 03-03-2020 
Protocol document date: 05-29-2019
 
Contact Information  
 
 
 
Robert Clark Brown 
Emory University 
Department of Pediatrics 
2015 Uppergate Drive NE 
Atlanta, GA 30322 
  
 
 
Melissa McNaull 
University of Mississippi Medical Center  
2500 North State Street 
Jackson, MS, 39216 
 
  
 
 
An Pham, MD 
University of Texas Southwestern Medical Center 
5323 Harry Hines Boulevard 
Dallas, TX, 75390 
 
 
 
 
 
 
 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0 , dated: 03-03-2020 
Protocol document date: 05-29-2019
 
Protocol Summary 
 
Protocol MNEMONIC and Title: HUGKISS – A pilot study of hydroxyurea management in 
kids: intensive versus stable dosage strategies 
Sponsor Principal Investigator: Jeremie Estepp, MD 
IND Holder: St. Jude Children's Research Hospital (SJCRH), IND #132032.  
Brief Overview: This is a pilot study, single-blind, randomized, multicenter, therapeutic clinical trial 
designed to evaluate the feasibility of enrolling infants and toddlers (9 months to 36 months) with 
sickle cell anemia (SCA; HbSS or HbSβ0thalassemia), regardless of disease severity, to a therapeutic 
trial. The BABY HUG trial demonstrated that a fixed dose (20 mg/kg/day) of hydroxyurea was safe 
and effective in decreasing SCA-related complications in very young children (9-18 months), and 
largely due to these findings, hydroxyurea is recommended to be offered to all children (≥9 months 
old) with SCA, independent of disease severity. Nevertheless, children in the treatment arm of BABY 
HUG continued to experience vaso-occlusive symptoms and to incur organ damage. In clinical trials 
of older children with SCA, intensification of hydroxyurea to a maximum tolerated dosage (MTD), 
defined by mild to moderate myelosuppression, may be associated with improved laboratory 
parameters compared to fixed lower-dosing, but the clinical benefits gained from dose intensification 
have not been described. Therefore, in the HUGKISS trial, children in the standard treatment arm will 
receive a fixed dose of hydroxyurea (20mg/kg/day), and participants in the experimental arm will 
receive hydroxyurea intensified to MTD, defined by a goal absolute neutrophil count (ANC) of 1500-
3000 cells/µL. This trial aims to establish a multicenter infrastructure that will identify, enroll and 
randomize very young children (9-36 months) to receive fixed dose versus intensified-dose 
hydroxyurea in a single blinded manner, and to obtain prospective pilot data comparing the clinical 
and laboratory outcomes between the treatment arms to facilitate design of a definitive phase III trial. 
Intervention: All participants will receive treatment with hydroxyurea, and they will be randomized 
to a fixed dose (20mg/kg/day) versus intensification to MTD. 
Brief Outline of Treatment Plan: All participants will initiate hydroxyurea at a dose of ~20 
mg/kg/day in an open label fashion for eight weeks (±2 week) prior to randomization. Participants 
will receive monthly medical evaluations (4 ± 2 weeks) where they will have height and weight 
measurements, medical history, physical examination, and medication adherence assessments. During 
these monthly visits complete blood counts with absolute reticulocyte count will be monitored. 
Hemoglobin electrophoresis, complete serum chemistries, urinalysis, lactate dehydrogenase and 
quality of life measurements will be obtained every 20 (±2) weeks. Transcranial Doppler (TCD) 
ultrasound velocities will be obtained at study entry (in participants ≥2 years of age) and exit. 
Participants randomized to receive hydroxyurea at MTD will have their dose increased by 5 
mg/kg/day every 8 weeks, in the absence of toxicity, until a goal ANC of 1500-3000 cells/µL is 
achieved, up to a maximum of 35 mg/kg/day.  
Study Design: Open label, single-blind, multicenter, randomized controlled trial comparing fixed 
dose (20mg/kg/day) to dose-escalation (goal ANC of 1500 – 3000 cells/µL) of hydroxyurea therapy. 
Sample Size: Up to 65 participants  
Data Management: Clinical sites will enter data via a secure, internet-based (electronic data capture) 
remote data capture system. Data management will be provided locally by the Clinical Trials 
Management Team within the Department of Hematology at SJRCH. Statistical analyses will be 
performed with the Departments of Biostatistics and Hematology at SJCRH. 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0 , dated: 03-03-2020 
Protocol document date: 05-29-2019
 
Human Subjects: This pilot trial will involve a vulnerable population of children of any race (9-36 
months) affected with SCA; however, we expect mostly children of African descent to be enrolled 
given the epidemiology of SCA in the United States. No nationality or gender exclusions are included 
in this trial. All participating sites will be following the same criteria for inclusion and exclusion on 
the study. All clinical sites chosen for the pilot trial will first undergo a careful checklist of “research 
readiness” to ensure proper clinical research can be safely conducted, including formal Human 
Protocol MNEMONIC and Title: HUGKISS – A pilot study of hydroxyurea management in 
kids: intensive versus stable dosage strategies 
Subjects Protection training to be completed by Clinical Investigators and staff members at each site. 
The risks to subject will be related to toxicity from hydroxyurea. Expected toxicity includes 
neutropenia, anemia, reticulocytopenia, and thrombocytopenia. The plan for dose reduction and 
toxicity monitoring is based on our safety data from BABY HUG1. Patients will be informed of any 
potential toxicity and other minor side effects during informed consent discussion. Adverse events 
(AEs) will be monitored and reported and treated appropriately. This study will be monitored by an 
independent Data and Safety Monitoring Board (DSMB). 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0, dated: 07-16-2018  IRB Approval date: 09-11-2018
Protocol document date: 09-06-2018
 
TABLE OF CONTENTS 
1.0 
HUGKISS FLOW DIAGRAM ...........................................................................................................5
2.0 
STUDY OBJECTIVES AND PURPOSE ..........................................................................................6
2.1. OVERVIEW...........................................................................................................................................6
2.2. PRIMARY AND SECONDARY OBJECTIVES................................................................................................7
2.2.1. 
 Primary Objective ..............................................................................................................7
2.2.2. 
Secondary Objective(s) ......................................................................................................7
2.3. HYPOTHESIS........................................................................................................................................7
3.0 
BACKGROUND AND RATIONALE.................................................................................................8
3.1. BACKGROUND......................................................................................................................................8
3.1.1. 
Sickle Cell Disease (SCD)..................................................................................................8
3.1.2. 
Hydroxyurea Therapy for Children with SCA......................................................................8
3.1.3. Fixed dose hydroxyurea at 20mg/kg/day did not prevent the development of organ 
dysfunction.........................................................................................................................................11
3.1.4. Children on fixed dose hydroxyurea continue to suffer from acute clinical manifestations. .....11
3.1.5. Higher levels of HbF are associates with fewer SCA related complications in older children 
with SCA treated with hydroxyurea at MTD. ......................................................................................12
3.1.6. 
Hydroxyurea: Pharmacokinetics (PK) and Bioavailability.................................................12
3.1.7. 
Hydroxyurea Escalated to MTD for Young Children with SCA .........................................13
3.2. RATIONALE........................................................................................................................................15
4.0 
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY ENROLLMENT....................16
4.1. INCLUSION CRITERIA ..........................................................................................................................16
4.2. EXCLUSION CRITERIA.........................................................................................................................16
4.3.
RESEARCH PARTICIPANT RECRUITMENT AND SCREENING ..............................................................16
4.4. ENROLLMENT ON STUDY AT SJCRH ...................................................................................................17
4.5. PROCEDURES FOR IDENTIFYING AND RANDOMIZING RESEARCH PARTICIPANTS......................................17
4.6. ENROLLMENT INSTRUCTIONS FOR COLLABORATING SITES....................................................................17
5.0 
TREATMENT PLAN ......................................................................................................................18
5.1. HYDROXYUREA THERAPY ...................................................................................................................18
5.2.
STANDARD TREATMENT ARM (20 MG/KG/DAY)...............................................................................18
5.3. INVESTIGATIONAL ARM (ESCALATION TO MTD)....................................................................................19
5.4. TREATMENT MODIFICATIONS FOR COLLABORATING SITES ....................................................................20
5.5. CONCOMITANT THERAPY....................................................................................................................20
5.6. SUBJECT COMPLIANCE.......................................................................................................................20
5.7.
DURATION OF TREATMENT ...........................................................................................................20
5.8. BLINDING...........................................................................................................................................21
5.8.1. HUGKISS Enabled Local Provider for Evaluating Response (HELPER).................................21
5.8.2. Emergent Unblinding................................................................................................................22
5.8.3. Randomization and Treatment Allocation ................................................................................22
6.0 
DRUG INFORMATION..................................................................................................................23
6.1. SOURCE AND DISTRIBUTION ...............................................................................................................23
6.2. FORMULATION AND STABILITY.............................................................................................................23
6.3. DOSAGE AND ROUTE OF ADMINISTRATION...........................................................................................23
6.4. TOXICITY...........................................................................................................................................24
7.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS .....................................................24
7.1. PRE-STUDY EVALUATIONS .................................................................................................................24
7.2. CLINICAL EVENTS ..............................................................................................................................24
8.0 
EVALUATION CRITERIA ..............................................................................................................27
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0, dated: 07-16-2018  IRB Approval date: 09-11-2018
Protocol document date: 09-06-2018
 
8.1. TOXICITY EVALUATION CRITERIA.........................................................................................................27
9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA ...............27
9.1. OFF-STUDY CRITERIA.........................................................................................................................27
9.2. COLLABORATING SITES NOTIFICATIONS...............................................................................................28
10.0 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS..................................................28
10.1. SICKLE CELL RELATED EVENTS ........................................................................................................28
10.2. REPORTING ADVERSE EXPERIENCES AND DEATHS TO SJCRH INSTITUTIONAL REVIEW BOARD (IRB) ...28
10.3. REPORTING TO THE SPONSOR AND/OR FEDERAL AGENCIES ...............................................................31
10.3.1. Notification of Federal Agencies by Investigator ....................................................................31
10.3.2. Recording AEs and SAEs ......................................................................................................31
10.4. PROCESS FOR REPORTING AES FROM THE SITES TO SJCRH, AND TO THE REST OF THE COLLABORATING 
SITES/AFFILIATES.....................................................................................................................................31
11.0 DATA COLLECTION, .......................................STUDY  MONITORING,  AND CONFIDENTIALITY
32
11.1. DATA COLLECTION...........................................................................................................................32
11.2. DATA COLLECTION INSTRUCTIONS FOR COLLABORATING SITES ..........................................................32
11.3. STUDY MONITORING ........................................................................................................................32
11.3.1. Composition and Responsibilities of the DSMB.....................................................................33
11.4. CONFIDENTIALITY.............................................................................................................................37
12.0 STATISTICAL CONSIDERATIONS....................................................................................................37
12.1. DESIGN AND SAMPLE SIZE JUSTIFICATION .........................................................................................37
12.2. STATISTICAL ANALYSES....................................................................................................................40
12.2.1. Describe reasons provided for agreement or refusal for participation in HUGKISS for each 
family approached..............................................................................................................................40
12.2.2. Develop an infrastructure and clinical monitoring plan that facilitates safe administration of 
hydroxyurea at a low-fixed dose and an intensified dose to MTD in a single-blinded manner to 
children. .............................................................................................................................................40
12.2.3. Obtain pilot data on the laboratory effects, clinical outcomes and toxicities observed with 
fixed versus intensified hydroxyurea dosing. .....................................................................................40
12.2.4. Obtain pilot data on health related quality of life in children with SCA treated with a low-fixed 
dose and at MTD................................................................................................................................40
12.3. ANTICIPATED COMPLETION DATES....................................................................................................41
13.0 OBTAINING INFORMED CONSENT .................................................................................................41
13.1. INFORMED CONSENT PRIOR TO RESEARCH INTERVENTIONS ...............................................................41
13.2. CONSENT AT AGE OF MAJORITY........................................................................................................41
13.3. CONSENT WHEN ENGLISH IS NOT THE PRIMARY LANGUAGE ...............................................................41
14.0 REFERENCES ...................................................................................................................................43
APPENDIX I: SCHEDULE OF EVALUATIONS..........................................................................................46
APPENDIX II: RESEARCH TESTS ............................................................................................................47
APPENDIX III: CLINICAL EVENT DEFINITION .........................................................................................48
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
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Amendment 2.0, dated: 07-16-2018  IRB Approval date: 09-11-2018
Protocol document date: 09-06-2018
 
Acronyms used in the protocol 
ACS: Acute Chest Syndrome 
AEs: Adverse Events 
ALT: Alanine Aminotransferase 
ANC: Absolute Neutrophil Count 
ARC: Absolute Reticulocyte Count 
AUCINF: Area under the concentration versus time curve 
BE: Baseline Evaluation 
BPCA: Best Pharmaceuticals for Children Act 
CBC: Complete Blood Count 
CHOA: Children’s Healthcare of Atlanta 
CL/F/BW: Clearance, normalized for Body Weight 
Cmax: Maximum observed plasma concentration 
CPDMO: Central Protocol and Data Monitoring Office 
CRF: Case Report Form 
CRIS: Current Research Information System 
CSSCD: Clinical Study of Sickle Cell Disease 
CTCAE: Common Terminology Criteria for Adverse Events 
CVA: Cerebrovascular Accident 
DCC: Data Coordinating Center 
DSMB: Data and Safety Monitoring Board 
ES: Eligibility Screening 
FDA: Food & Drug Administration 
HbF: Fetal Hemoglobin 
HbS: Sickle Hemoglobin 
HPFH: Hereditary Persistence of Fetal Hemoglobin 
IDE: Investigational Device Exemption 
IMC: Internal Monitoring Committee 
IND: Investigational New Drug 
MAM: Medication Adherence Measure 
MCC: Medical Coordinating Center 
MCV: Mean Corpuscular Volume 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


Amendment 2.0, dated: 07-16-2018  IRB Approval date: 09-11-2018
Protocol document date: 09-06-2018
 
MPR: Medication Possession Ratio 
MSH: Multicenter Study of Hydroxyurea in Sickle Cell Anemia 
MTD: Maximum Tolerated Dose 
NHLBI: National Heart, Lung, and Blood Institute 
OHRP: Office for Human Research Protections 
PI: Principle Investigator 
PK: Pharmacokinetics 
PM: Project Manager 
QOL: Quality of Life 
RUQ: Right Upper Quadrant 
SAE: Serious Adverse Events 
SCA: Sickle Cell Anemia 
SCD: Sickle Cell Disease 
SJCRH: St. Jude Children’s Research Hospital 
TCD: Transcranial Doppler 
TIA: Transient Ischemic Attack 
Tmax: Time to maximum plasma concentration 
UMMC: University of Mississippi Medical Center 
URI: Upper Respiratory Infections 
UTSW: University of Tennessee Southwestern 
WBC: White Blood Count 
WHO: World Health Organization
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IRB NUMBER: Pro00006450
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1.0 
HUGKISS FLOW DIAGRAM 
 
 
 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


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2.0 
STUDY OBJECTIVES AND PURPOSE 
 
2.1. Overview 
 
Serious morbidity and mortality in sickle cell anemia (SCA) is well-described and 
begins early in life with the onset of the physiologic decline of fetal hemoglobin (HbF). 
The BABY HUG trial showed that 20mg/kg/day of hydroxyurea therapy is safe, blunts 
the decline of HbF, and is clinically beneficial for very young infants and children with 
SCA, and hydroxyurea therapy is now suggested to be offered to all very young children 
with SCA, whether or not they have clinical symptoms. Nevertheless, children treated 
with hydroxyurea continued to develop acute complications and acquired end organ 
damage.  
 
The BABY HUG trial established the safety and efficacy of a fixed dosage of 
hydroxyurea in this very young group of children; however, it is now paramount to 
define the optimal dosing regimen in an attempt to maximize the benefits of therapy. 
Defining the clinical and hematologic impact of intensified dosages versus fixed dosing 
of hydroxyurea in this age group is crucial. The aims of this protocol are (1) to establish 
feasibility of enrolling and randomizing young children (9 to 36 months) with SCA 
(HbSS and HbSβ0-thalassemia) to receive either a fixed or an intensified dose of 
hydroxyurea in a single blind manner, and (2) to obtain prospective pilot data comparing 
the clinical and laboratory efficacy of intensified versus fixed-dose hydroxyurea.  
 
The HUGKISS pilot trial seeks to answer a basic question which remains after the 
publication of the BABY HUG study. That is, does escalation of hydroxyurea dose 
provide a clinical benefit in young children with SCA? Extrapolation from the adult 
literature suggests that escalation is beneficial, but the large reductions in adverse events 
observed in the fixed-dose BABY HUG trial call for this question to be addressed 
through a clinical trial. As such, the HUGKISS trial is the next logical step to potentially 
improve upon outcomes observed in the BABY HUG trial and advance the care of 
young children with SCA. 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


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2.2. Primary and Secondary Objectives  
 
2.2.1. 
 Primary Objective 
  
 
Demonstrate feasibility of enrolling, randomizing and administering young children (9 
to 36 months) with SCA (HbSS and HbSβ0-thalassemia) either a fixed or intensified 
dose of hydroxyurea therapy in a single blinded manner.   
 
 
2.2.2. 
Secondary Objective(s) 
 
1. Describe decision making process; i.e.; reasons for agreement or refusal to participate 
in HUGKISS for each family approached. 
 
2. Develop an infrastructure and clinical monitoring plan that facilitates safe 
administration of hydroxyurea at a fixed dose and an intensified dose to MTD in a 
single-blinded manner in children. 
 
3. Obtain pilot data on the laboratory effects, clinical outcomes and toxicities observed 
with fixed versus intensified hydroxyurea dosing. 
 
4. Obtain pilot data on health related quality of life in children with SCA treated with a 
fixed dose and at MTD. 
 
2.3. Hypothesis 
 
The primary hypothesis is that a consortium of four large pediatric sickle cell centers 
will collaborate and demonstrate the feasibility of enrolling, randomizing and 
administering hydroxyurea for approximately 12 months in a single and blind manner. 
Demonstration of feasibility would support the design and implementation of a 
definitive comparison effectiveness trial (phase III) in this young population with SCA.  
 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00006450
IRB APPROVAL DATE: 03/09/2020


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3.0 
BACKGROUND AND RATIONALE 
 
3.1. Background 
 
3.1.1. 
Sickle Cell Disease (SCD) 
 
SCA is a catastrophic hematologic disease that effects 300,000 newborn children 
worldwide every year2. A classic example of recessive Mendelian inheritance, SCA is 
caused by a mutation in the β globin gene that results in production of a mutant globin 
protein, sickle hemoglobin (HbS). In deoxygenated conditions, HbS polymerizes 
leading to the classic “sickle-shaped” erythrocytes. Clinically, children with SCA 
suffer from a wide spectrum of clinical manifestations including severe pain crises, 
acute chest syndrome, splenic sequestration, cholelithiasis, priapism and stroke with 
symptoms beginning in infancy. Without therapy, individuals with SCA experience 
recurrent acute vaso-occlusive complications and progressive organ damage that 
typically leads to a premature death in young adulthood3.   
 
3.1.2. 
Hydroxyurea Therapy for Children with SCA 
 
In natural history cohorts of adults and children4,5 with SCA, high levels of 
endogenous HbF (α2γ2) correlate strongly with an improvement in clinical severity. 
For example, individuals with HbS mutations and concurrent hereditary persistence of 
fetal hemoglobin (HPFH), express very high HbF (mean 31.3%; SD, ±2.4; range, 
27.1-36%) and exhibit a benign clinical course6.  
 
Hydroxyurea, a ribonucleotide reductase inhibitor1,7, is a potent HbF inducer and 
antisickling agent8 that was demonstrated to safely reduce vaso-occlusive events (pain 
and acute chest syndrome), hospitalizations and transfusion requirements compared to 
placebo in adults with SCA9. Subsequently, hydroxyurea was approved by the FDA in 
1998 for the treatment of adult SCA patients with recurrent and severe crises. 
 
In the 1990s, several small studies reported short-term safety and toxicity profiles for 
hydroxyurea therapy in children10-12, but there was reluctance to use the drug in this 
population due to concerns of potential toxicities. Over the past several decades, a 
number of long-term studies have reported the benefits of hydroxyurea in preventing 
complications and reducing mortality in older children with SCA13-16. The HUG-KIDS 
phase I/II prospective trial was designed to identify the maximum tolerated dose 
(MTD) for hydroxyurea in children and treat them at that dose for one year. Eligible 
children 5 to 15 years old were initiated hydroxyurea at 15 mg/kg/day with escalation 
by 5 mg/kg/day every 8 weeks to MTD, defined as the dose 2.5 mg/kg below which 2 
successive hematologic toxicities occurred or a maximal dose of 30 mg/kg, and was 
sustained without toxicity for 8 weeks. The mean (±SD) MTD observed was 25.6 
(±6.2). Children treated with hydroxyurea at MTD showed significant hematologic 
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responses similar to those observed in adults (Table 1) and treatment was well 
tolerated without clinical AEs17.   
 
Table 1. Phase I/II hematologic values of children and adults being treated with hydroxyurea at 
MTD17,18. 
Pediatric Phase I/II 
Adult Phase I/II 
 
Hematologic value, mean (SD) 
Entry 
(n=84) 
6 months 
(n=78) 
12 months 
(n=77) 
24 months 
(n=35) 
 
(n=32) 
Fetal Hemoglobin (%) 
7.3(4.9) 
14.9(6.4) 
17.8(7.2) 
15.5(7.3) 
15(6) 
Hemoglobin (g/dL) 
7.8(1.0) 
8.8(1.0) 
9.0(1.4) 
9.0(1.1) 
9.7(1.8) 
Mean Corpuscular Volume (fL) 
85.9(6.6) 
99.5(9.0) 101.3(10.2) 
98.9(9.1) 
117 (15) 
Absolute Reticulocyte (x109/L) 
354(144) 
204(204) 
191(100) 
215 (92) 
243 (73) 
White Blood Cell (x109/L) 
13.6(3.9) 
9.3(3.0) 
9.2(3.2) 
9.2(3.0) 
8.4 (1.4) 
Absolute Neutrophil (x109/L) 
7(3.0) 
4.4(2.1) 
4.4(2.2) 
4.6(2.3) 
4.6 (1.1) 
Total Bilirubin (mg/dL) 
3.6(2.6) 
2.9(2.1) 
2.5(2.0) 
2.8(2.5) 
1.9(1.2) 
ALT (IU/L) 
27(14) 
28(20) 
22(22) 
27(12) 
37(29) 
All values at six months are significantly different from baseline (p<0.001). At 12 months MCV, HbF, and F-cells are higher than at 
six months (p <0.05). 
 
The first pilot trial in infants with SCA (HUSOFT) demonstrated that hydroxyurea 
therapy was feasible, well-tolerated, and it had hematologic efficacy19. In 1999, 
following results from HUG-KIDS and based on recommendations of the NHLBI 
Sickle Cell Advisory Committee, the NHLBI released a competitive contract to 
conduct a trial to test whether hydroxyurea administered to infants for 2 years would 
inhibit cumulative organ damage. During planning of the Pediatric Hydroxyurea Phase 
III Trial (BABY HUG; NCT 00006400), many investigators advocated for aggressive 
hydroxyurea intensification, similar to the previous HUG-KIDS trial. However, the 
young age of participants (9-18 months) raised concern for toxicity and a lower fixed 
dose of 20 mg/kg/day was selected20. 
 
Between October, 2003 and September, 2009, BABY HUG1 investigators from thirteen 
medical centers randomized very young (9-18 months) children with SCA to receive 
either placebo or hydroxyurea (20 mg/kg/day) and followed subjects for two years. The 
primary endpoints were splenic function (qualitative uptake of 99mTc spleen scan) and 
renal function (glomerular filtration rate by 99mTc-DTPA clearance). Secondary 
endpoints included hematologic parameters, biomarkers of splenic and renal function, 
transcranial Doppler (TCD) ultrasonography and growth. Of primary importance and 
contrary to some investigators’ concerns21, hydroxyurea was found to be safe in this 
young cohort (Table 2). Expectedly, mild to moderate myelosuppression occurred more 
frequently in those on hydroxyurea, but no episode was associated with an invasive 
bacterial infection. Severe anemia and thrombocytopenia occurred infrequently and 
were not associated with hydroxyurea therapy. No renal or hepatic toxicities were 
observed despite monitoring of bilirubin and creatinine22. Importantly, hydroxyurea did 
not adversely alter growth velocity23. Children treated with hydroxyurea had a normal 
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clinical response to pneumococcal polysaccharide vaccines and a normal immune 
state24. Children did not suffer from an increased frequency or a delayed incidence of 
splenic sequestration, and importantly, hydroxyurea did not appear to be mutagenic25. 
 
Table 2. Laboratory toxicities with 20 mg/kg/day of hydroxyurea versus placebo in the BABY 
HUG trial1 
Hydroxyurea (n=96) 
Placebo (n=97) 
 
Events 
Patients 
Events 
Patients 
Hazard Ratios (95% 
CI) 
p value 
ANC <500/μL3 
5 
5 
2 
2 
2.5 (0.5I)- 12.9) 
0.26 
ANC 500–1250/μL3 
107 
45 
34 
18 
3.0 (1.7-5.1) 
<0.0001 
Thrombocytopenia 
12 
11 
8 
7 
1.6 (0.6-4.1) 
0.32 
Severe Anemia 
1 
1 
2 
2 
0.47 (0.04-5.2) 
0.53 
ANC, absolute neutrophil count; ARC, absolute reticulocyte count; ALT, alanine aminotransferase; thrombocytopenia: platelet 
count <80×103/μL3; severe anemia: Hb <7.0 g/dL plus ARC <80×103/μL3, creatinine elevation:≥2×baseline plus ≥10 mg/L 
The benefits of hydroxyurea therapy at a fixed dose were clear and remarkable. 
Hydroxyurea therapy in infants/young children improved hematologic parameters, 
similar to what was observed in adults and in the HUG-KIDS trial, with elevated 
hemoglobin, mean corpuscular volume (MCV) and HbF and reduced white blood cell, 
neutrophil and reticulocyte counts (Table 3). Acute vaso-occlusive rates for the most 
common complications of SCA were significantly reduced in children treated with 
hydroxyurea versus placebo (Table 4). Pain was twice as frequent, dactylitis five times 
more common, and acute chest syndrome three times more likely to occur in the 
placebo group. Hospitalizations and transfusions were marginally increased in the 
placebo group. 
Table 3. Mean hematologic parameters from BABY HUG trial at study entry and exit1 
Hydroxyurea (n=96) 
Placebo (n=97) 
 
Entry 
Exit 
Entry 
Exit 
White Blood Cells(x103/µL) 
14.4 
10.6 
14.3 
13.9 
Hemoglobin (g/dL) 
8.9 
9.1 
9.2 
8.6 
MCV (fL) 
80.2 
92.2 
80 
86.2 
HbF (%) 
25.6 
22.4 
27.1 
17.1 
ANC (x103/µL) 
4900 
4500 
4200 
5600 
Exit versus entry mean differences all p<0.01 calculated via Student’s t test 
 
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3.1.3. Fixed dose hydroxyurea at 20mg/kg/day did not prevent the 
development of organ dysfunction.  
 
Qualitative spleen scans, measured by uptake of 99Tc, were worse at exit than at entry 
in 19/70 (27%) patients on hydroxyurea and 28/74 (38%) of those receiving placebo 
(p=0.21). Additionally, renal function, measured by 99mTc –DTPA clearance, did not 
differ in the two groups (p=0.84). However, quantitative measures of splenic function 
(red blood cell Howell-Jolly bodies and pit counts) and renal function (urine 
osmolality and specific gravity) suggested possible benefits of hydroxyurea therapy26. 
Also, the increase in time-averaged mean maximum velocity on TCD from baseline to 
exit was blunted in the hydroxyurea group (20 cm/sec versus 32 cm/sec, p=0.0002), 
suggesting reduced vasculopathy within the central nervous system1. 
 
Table 4. Adverse clinical events in BABY HUG trial1 
Hydroxyurea (n=96) 
Placebo (n=97) 
 
Events 
Patients Events 
Patients 
Hazard Ratios 
(95% CI) 
p value 
Pain 
177 
62 
375 
75 
0.59 (0.42-0.83) 
0.002 
Acute Chest Syndrome 
8 
7 
27 
18 
0.36 (0.15-0.87) 
0.02 
Hospitalization (all cause) 
232 
69 
324 
84 
0.73 (0.53-1.0) 
0.05 
Transfusion 
35 
20 
63 
33 
0.55 (0.32-0.96) 
0.03 
Dactylitis 
24 
14 
123 
42 
0.27 (0.15-0.5) 
<0.0001 
Hazard ratio and 95% CIs generated via Cox model. p value calculated from log-rank life test  
3.1.4. Children on fixed dose hydroxyurea continue to suffer from acute 
clinical manifestations.  
 
Although we observed a substantial reduction in acute vaso-occlusive complications, 
children on 20mg/kg/day hydroxyurea continued to suffer from pain, acute chest 
syndrome and were still frequently hospitalized (Table 5). 
 
Table 5: Vaso-occlusive complications observed in hydroxyurea and placebo arms in BABY 
HUG1 
Pain Events n (%) 
Acute Chest Events n (%) 
Hospitalizations n (%) 
None 
1 
≥2 
None 
1 
≥2 
None 
1 
≥2 
Hydroxyurea 
34(35) 
29(30) 
33(35) 
89(93) 
6(6) 
1(1) 
27(28) 22(23) 
47(49) 
Placebo 
22(23) 
15(15) 
60(62) 
79(82) 
10(10) 
8(8) 
13(13) 16(17) 
68(70) 
 
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3.1.5. Higher levels of HbF are associates with fewer SCA related 
complications in older children with SCA treated with hydroxyurea at MTD. 
 
Several studies have shown that increased endogenous HbF (not drug-induced) was 
associated with reduced episodes of severe vaso-occlusive pain in SCA patients27,28. 
However, few (<10%) of the individuals studied had HbF >20%. The mean HbF of 
children randomized to fixed dose hydroxyurea in BABY HUG was 22.4% at study 
exit. The clinical benefit of further elevating HbF above this level is uncertain. To 
address this question, we evaluated 230 children who were enrolled in The 
Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175). These patients 
were older [age 9.6 (±5.0) years] when hydroxyurea was initiated and were intensified 
to an average dose of 26.7 (±4.6) mg/kg/day. In 610 patient-years of follow-up, there 
were 521 hospitalizations resulting in 0.85 hospitalizations per patient-year and a 
median of 1 (range, 0-43; mean 2.4, SD 4.5) hospitalization per child. When HbF 
levels were analyzed as a continuous variable, for every 5% decrease in HbF, the odds 
of being hospitalized during a three month interval were 1.2 (95% CI: 1.1-1.3), i.e., a 
20% increase in the odds for each 5% decline in HbF. When HbF levels were 
categorized into 4 groups (<15%, 15 to ≤20%, >20 to ≤25%, and >25%), it was found 
that the odds of being hospitalized during any interval when HbF levels were ≤20% 
more than doubled (Table 6)29. Thus, our preliminary data suggested that higher HbF 
levels are associated with fewer SCD-related complications and support an intensified 
dosing strategy to maximize HbF levels. However, these results may not be 
generalizable to very young children and their clinical implications must be examined 
prospectively in young children. 
 
Table 
HbF, (%) 
Subjects (n) 
Intervals (n) 
All Hospitalizations OR (95% CI) 
<15 
159 
768 
2.1 (1.3-3.3) 
15 to ≤20 
154 
589 
2.2 (1.3-3.6) 
>20 to ≤25 
131 
509 
1.0 (0.6-1.7) 
>25 
98 
573 
1 
Odds ratios (OR) calculated with GEE model controlling for time. HbF Hemoglobin F, ACS acute chest syndrome 
 
 
3.1.6. 
Hydroxyurea: Pharmacokinetics (PK) and Bioavailability 
 
Despite safety and efficacy data from HUG-KIDS and BABY HUG and the 
NIH/NHLBI recent recommendation, limited data existed on the PK of hydroxyurea 
in children. The FDA offered a written request under the Best Pharmaceuticals for 
Children Act (BPCA) to specifically address this knowledge gap. In response, we 
performed the “Pharmacokinetics and Relative Bioavailability of a Liquid 
Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia” trial 
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(HUB01; NCT01506544). Of relevance to the current proposal, we compared: 1) 
bioavailability of the liquid formulation of hydroxyurea administered in BABY 
HUG to capsules; and 2) hydroxyurea PK profiles in younger and older children. 
Liquid and capsule formulations were bioequivalent; hydroxyurea was rapidly 
absorbed with a mean (±SD) time to maximum plasma concentration (Tmax) of 0.86 
(±0.53) hours and a half-life (t1/2) of 2.3 (±0.5) hours. Younger and older children 
had similar PK profiles for every parameter tested (Table 7)30. 
 
 
Table 7. Pharmacokinetics of hydroxyurea in young and old children 
 
Younger Children (n=17) 
Older Children (n=22) 
Age (y), mean (SD) 
4.5 (1.7) 
12.0 (3.6) 
Cmax (μg/mL) 
33.8 (8.3) 
33.6 (8.2) 
Tmax (hr) 
0.86 (0.53) 
0.97 (0.52) 
AUCINF (μg·hr/mL) 
114.1 (29.4) 
116.3 (30.0) 
t½ (hr) 
2.3 (0.5) 
2.3 (0.5) 
Cmax, Maximum observed plasma concentration; Tmax, Time to maximum plasma concentration; AUCINF, Area under the 
concentration versus time curve calculated using the log-linear trapezoidal method from time 0 extrapolated to time infinity; t½, 
CL/F/BW, Clearance, normalized for Body Weight 
 
 
 
3.1.7. 
Hydroxyurea Escalated to MTD for Young Children with SCA 
 
A review of published literature for older children with SCA suggests that 
hydroxyurea intensified to moderate myelosuppression results in an average HbF of 
~20%, compared to 15% when a lower fixed-dose is utilized31. We reported a cohort 
of children (median age 3.4 years, range, 2.6- 4.4 years) who had previously been 
treated with 20 mg/kg/day hydroxyurea for two years, followed by dose 
intensification, as per the HUG-KIDS protocol, to a mean (±SD) of 30 (±1.2) 
mg/kg/day32. This intensification was well tolerated and resulted in improved 
hematologic parameters (Table 8). 
 
 
Table 8. Effects of hydroxyurea intensification in older children32 
Hydroxyurea Dose 
 
20 mg/kg/d (n=21) 
30 mg/kg/d (n=17) 
White Blood Cells (x103/µL) 
10.1 
10.1 
Hemoglobin (g/dL) 
8.8 
9.1* 
MCV (fL) 
90.0 
95.1 
HbF (%) 
20.3 
23.7 
Reticulocyte Count (%) 
8.6 
8.2 
*p<0.05 
 
 
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One important consideration in the HUGKISS study is that very young children are 
undergoing the physiological γ to β globin switch33,34. In children with SCA, levels of 
HbF at birth (60-90%) decline to a mean of 9% (5th-95th percentile; 3.3-21.9%) by 48-
60 months of age as HbF is replaced by HbS33. This phenomenon may have profound 
implications on the therapeutic benefit of intensified hydroxyurea doses for very 
young children. In BABY HUG, HbF declined by 13% (=(0.256-0.225)/0.256) in 
children randomized to hydroxyurea from entry (HbF, 25.6%) to exit (HbF, 22.4%) 
compared to a decline of 37% (=(0.271-0.171)/0.271) (entry HbF, 27.1%; exit HbF 
17.1%) in those randomized to placebo. We do not know what the effect of 
intensifying hydroxyurea therapy on HbF production would be in a population which, 
on average, has an endogenous starting HbF level of ~25%.  
 
At SJCRH, 23 children (<3 years of age) initiated hydroxyurea, had dose 
intensification with a goal of ANC of 1500-3000 cells/μL and had one year of clinical 
follow up. At the time of hydroxyurea initiation, 7 were infants (younger than 18 
months) (mean 12.1; SD ±3.2 years) and 16 were toddlers (18-36 months) (mean 26.4; 
SD ±2.7 months). Dose escalation was handled similarly between the infant and 
toddler groups and was similar after 18 months of therapy (27.0 mg/kg/day in infants 
versus 27.7 mg/kg/day in toddlers, p=0.84). Mean baseline HbF levels were 19% 
(±9%) in infants and 15% (±7%) in toddlers (p=0.25). After 18 months of 
intensification of hydroxyurea therapy, hematologic parameters improved (Table 8); 
specifically, there was a mean increase of HbF by 5% (±6%) (p=0.008). No 
participants in the infant group developed neutropenia, and only four toddlers 
experienced neutropenia. This preliminary data suggests that intensification of 
hydroxyurea in this very young age group does provide higher HbF levels, similar to 
the hematologic changes seen in older populations, but this relationship must be tested 
prospectively.  
 
Table 9. Hematologic parameters of infants and toddlers at baseline and following 18 months of 
intensification of hydroxyurea therapy
Baseline
18 months
Parameter; mean (SD)
n=22
n=19
Hemoglobin (g/dL)
8.2
(0.9)
9.1
(1.4)*
Mean Corpuscular Volume (fL)
86
(7.1)
100
(7.4)†
Fetal Hemoglobin (%)
16
(8)
24
(8)*
Absolute Reticulocyte (x109/L)
310
(80)
190
(90)†
White Blood Cell (x109/L)
16
(5.8)
10
(3.4)†
Absolute Neutrophil (x109/L)
5300
(2500)
3600
(1500)†
*p<0.01, †p<0.001; significance of difference from baseline.
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3.2. Rationale 
 
Mounting evidence supports the safety and clinical efficacy of hydroxyurea for the 
treatment of all children with SCA, however, the following have not been established: 
(1) the optimal dosage for infants and very young children, (2) whether hydroxyurea 
intensification provides further therapeutic benefit compared to standard low dose. 
 
Therapeutic intervention prior to the onset of the clinical manifestations and 
irreversible organ injury during infancy may provide long-term benefits. In very 
young (9-18 months) children with SCD, daily fixed-dose hydroxyurea (20 
mg/kg/day) safely and effectively raises HbF levels, improves hematological 
parameters and reduces clinical manifestations including pain, dactylitis and acute 
chest syndrome1. Nevertheless, children in the treatment arm of BABY HUG 
continued to experience vaso-occlusive symptoms22 and to incur organ damage1. In 
older children and adults with SCD, dose-intensification of hydroxyurea to mild 
myelosuppression 
(ANC 
1500-3000 
cells/μL) 
may 
improve 
hematologic 
parameters16,32 compared to fixed dosing, but intensification is not accepted as the 
standard of care globally because this approach, while promising, is not proven to 
improve clinical outcomes35-38. 
 
Our preliminary data demonstrate that the pharmacokinetic parameters of hydroxyurea 
in young children are predictable and similar to that observed in older children and 
adults30, and that very young children exhibit a safe and robust hematologic response 
when hydroxyurea is intensified (unpublished). Together, these findings support our 
hypothesis that dose intensification of hydroxyurea in very young children will be 
safe and produce superior results compared to fixed dose hydroxyurea, which 
was utilized in the BABY HUG trial. Addressing this question is crucial for 
optimizing hydroxyurea therapy in young patients with SCA and represents the natural 
therapeutic extension to improve upon the BABY HUG study results. 
 
A multicenter clinical trial is necessary to address our hypothesis. Here we describe 
plans to establish the feasibility and infrastructure for this important study. 
 
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4.0 
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT  
 
4.1. Inclusion Criteria  
 
1)
Children with HbSS or HbS/β0thalassemia 
2)
≥9 to ≤ 36 months of age at study initiation 
3)
Enrollment will occur irrespective of clinical severity 
 
4.2. Exclusion Criteria 
 
Permanent: 
1)
Receiving chronic red blood cell transfusion therapy. 
2)
Condition or chronic illness, which in the opinion of the PI makes participation 
unsafe. 
 
 
Transient (participants may be re-evaluated after ≥14 days): 
1)
Recent (<30 days) participation in another clinical intervention trial utilizing an 
IND/IDE agent. 
2)
Erythrocyte transfusion in the past 2 months. 
3)
Laboratory Assessments: 
a.
Hemoglobin <6.0 gm/dL 
b. Absolute reticulocyte count <80 x 109/L if hemoglobin <9.0 mg/dL 
c.
Absolute neutrophil count <1.5 x 109/L 
d. Platelet count <100 x 109/L 
e.
Serum creatinine > twice the upper limit of normal for age 
f.
ALT > twice the upper limit of normal 
 
 
4.3.
Research Participant Recruitment and Screening 
 
Four institutions will collaborate in the proposed project: St. Jude Children's Research 
Hospital (SJCRH); University of Mississippi Medical Center (UMMC); UT 
Southwestern (UTSW) and Children’s Healthcare of Atlanta (CHOA). Recruitment will 
begin in Year 1 and will be completed by the middle of Year 2 to ensure 52-56 weeks of 
study treatment/evaluations and 4 weeks of off-study follow-up. Universal newborn 
screening data will be utilized by each site to determine the number of potentially 
eligible children. We plan on approaching all available eligible participants until 
enrollment is completed. The study will be discussed with each potentially eligible 
family by the local PI and/or study coordinator in an unbiased basis until enrollment 
goals are met. During this recruitment phase, local sites will assess and document 
whether each eligible family verbally agreed to participate or not and will record the 
reason for the choice. Based on our previous experience in BABY HUG reasons for 
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initial affirmative responses will be coded based on common themes, such as: “perceive 
the child to be ill,” “desire to aid  research,” “desire for closer follow-up,” “hope that the 
child would be randomized to receive higher dose hydroxyurea,” and “other.” 
Conversely, reasons for declining participation will be grouped into the categories: “fear 
of research,” “transportation problems,” “excessive clinic visits and/or lab draws with 
hydroxyurea therapy,” “perception that the child was not ill,” “not willing to initiate 
hydroxyurea therapy due to concerns for toxicity,” and “other.” 
 
4.4. Enrollment on Study at SJCRH 
 
A member of the study team will confirm potential participant eligibility as defined in 
Sections 3.1 and 3.2, and complete the “Participant Eligibility Checklist.” The 
completed checklist will be scanned and emailed to the Central Protocol and Data 
Monitoring Office (CPDMO): EligibilityCoordinators@STJUDE.ORG.Eligibility will 
be reviewed and entered into the PPM system. A research participant-specific consent 
form will be generated when applicable. The protocol and consent document will be 
delivered to the area designated on the checklist. The entire signed informed consent 
must be scanned and emailed to the CPDMO to complete the enrollment process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CT, Monday through Friday. A staff member is 
on call Saturday, Sunday, and holidays from 8:00 am-5:00 pm. Enrollments may be 
requested during weekends or holidays by calling the CPDMO on call cell phone 
 or referencing the “On Call Schedule” on the intranet. 
 
4.5. Procedures for Identifying and Randomizing Research Participants 
 
All children will be initiated on hydroxyurea (100 mg/mL) at a dose of ~20 mg/kg/day in 
an open label fashion for eight weeks (±2 weeks) prior to randomization. Participants 
without toxicity (defined in section 6.4), which requires discontinuation of hydroxyurea 
during those eight weeks (±2 weeks), will be randomized to receive “standard” or 
“intensive” therapy in a 1:1 ratio. Randomization will be stratified by clinical center and 
by baseline age of the participant (9 to <24 months and 24 to 36 months) because of the 
natural physiologic decline of HbF with increasing age. 
 
4.6. Enrollment Instructions for Collaborating Sites  
 
Collaborating Site research participants should be registered at SJCRH within 24 hours 
of enrollment at the site. A Project Manager (PM) will serve as a Medical Coordinating 
Center (MCC) Staff Member. The PM will serve as liaison to all collaborating sites to 
ensure compliance with protocol prescribed interventions and evaluations, answer 
questions and provide clarifications. The PM will maintain regulatory documents from 
all collaborating sites, maintain documentation of training for all site personnel, receive 
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and process all AE's, send reports to PI and governing bodies regarding study as 
indicated. 
 
The completed Eligibility Checklist and entire signed Informed Consent should be 
scanned and emailed to the Central Protocol and Data Monitoring Office (CPDMO): 
EligibilityCoordinators@STJUDE.ORGThe Protocol Eligibility Coordinator will then 
register the research participant in the PPM system and assign a study ID number.   
 
5.0 
TREATMENT PLAN 
 
5.1. Hydroxyurea Therapy 
 
All participants randomized to the standard treatment (20 mg/kg/day) and investigational 
treatment (escalation to MTD) will undergo the same number of study visits and 
laboratory tests, which include monthly visits with clinical evaluations (every 4 ± 2 
weeks), laboratory tests, and experimental evaluations (see Table 10). The frequency of 
toxicity monitoring is based on recent guidelines for the management of SCD39. 
 
For all participants, hydroxyurea will be taken once daily, ideally at a regular dosing 
time either in the morning or before bedtime. The starting dose of hydroxyurea is 20 
mg/kg/day. Given the developmental age of this population, hydroxyurea will be 
provided as a liquid formulation (100 mg/mL). Dosing flexibility of up to +/- 2.5 
mg/kg/day is permitted to allow for rounding to available easily measurable volumes. 
Liquid hydroxyurea will be formulated by KP Pharmaceutical Technology, INC. Using 
IND Number 111866, which is held by Kathleen Neville, a pediatric hematologist at 
Arkansas Children’s Hospital, for the liquid formulation of hydroxyurea used in the 
HUBO1 trial (ClinicalTrials.gov identifier: NCT01506544) and a separate liquid 
formulation which was used by BABYHUG, held by NHLBI, IND number 67,289. 
SJCRH has an IND from the FDA to use hydroxyurea in the HUGKISS trial, IND 
Number 132032. 
5.2.
Standard Treatment Arm (20 mg/kg/day) 
 
The plan for dose reduction and toxicity monitoring for the standard treatment arm is 
based on safety data and toxicity monitoring from BABY HUG1.  
 
The starting dose of hydroxyurea will be 20 (+/- 2.5) mg/kg/day. If toxicity occurs 
(defined in section 6.4), treatment will be paused and blood counts will be checked every 
seven days until they return to non-toxic values. Transient toxicity will not cause a dose 
reduction or termination of therapy, but prolonged (defined as ≥21 days) or repeated 
toxicity will. If a toxicity resolves within 21 days, treatment will be resumed at the 
previous dose. If the toxicity recurs, hydroxyurea will again be held for an additional 7 
days. If toxicity resolves, hydroxyurea will resume at a daily dose 2.5 mg/kg lower than 
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the previous dose. If that dose does not cause toxicity for eight weeks, then the lower 
dose will be assigned as the stable dose. If hematologic toxicities occur while a 
participant is being treated with an established stable dose, treatment will be stopped 
until toxicity resolves and then treatment will resume using the previously established 
stable dose. Repeated toxicity in a 12-week period will reduce the stable dose by 2.5 
mg/kg for the remainder of the study. Based on previously published experience with 
hydroxyurea therapy in young subjects with sickle cell disease40, discontinuation of 
hydroxyurea therapy due to persistent or intolerable myelosuppression is extremely 
unusual. 
 
5.3. Investigational Arm (Escalation to MTD) 
 
The goal of the investigational arm of HUGKISS will be to achieve a neutrophil count of 
1500-3000 cells/μL. Hydroxyurea will be titrated according to myelosuppression, and 
will be increased to the MTD as defined by achieving the goal neutrophil count without 
toxicity. Escalation to MTD of hydroxyurea usually takes 6-9 months. Hydroxyurea 
dosing will commence at 20 (+/- 2.5) mg/kg/day. Hydroxyurea dose escalation will 
occur in 5 mg/kg/day increments, adjusting every 8 weeks unless hematological toxicity 
(defined in section 6.4) is achieved. Most pediatric subjects require hydroxyurea doses 
of 20-30 mg/kg/day to reach the target ANC. After reaching MTD, minor dose 
adjustments will be made as necessary based on weight changes and blood counts, to 
maintain the desired laboratory effects. If the ANC rises above the target range on two 
consecutive interval visits, compliance will be reinforced and the dose may be adjusted 
as needed by 2.5 mg/kg/day at eight week intervals to a maximum of 35 mg/kg/day.  
 
Hydroxyurea will be temporarily discontinued if toxicity occurs (defined in section 6.4), 
treatment will be paused and blood counts will be checked every seven days until they 
return to non-toxic values. Transient toxicity will not cause a dose reduction or 
termination of therapy, but prolonged (defined as ≥21 days) or repeated toxicity will. If a 
toxicity resolves within 21 days, treatment will be resumed at the previous dose. If the 
toxicity recurs, hydroxyurea will again be held for an additional 7 days. If toxicity 
resolves, hydroxyurea resume at a daily dose 2.5 mg/kg lower than the previous dose. If 
that dose does not cause toxicity for eight weeks, then the lower dose will be assigned as 
the stable dose. If hematologic toxicities occur while a participant is being treated with 
an established stable dose, treatment will be stopped until toxicity resolves and then 
treatment will resume using the previously established stable dose. Repeated toxicity in 
a 12-week period will reduce the stable dose by 2.5 mg/kg for the remainder of the 
study.  
 
Complications of hydroxyurea therapy (excessive myelosuppression, severe anemia or 
thrombocytopenia, or drug non-compliance) will be collected at each interval visit on the 
interval visit case report form (CRF) and as part of AE reporting. 
 
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5.4. Treatment Modifications for Collaborating Sites  
 
All collaborating sites will follow the study design as written in the protocol. 
 
5.5. Concomitant Therapy 
 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. In the interests of subject safety and acceptable 
standards of medical care the Investigator will be permitted to prescribe treatment(s) at 
his/her discretion. Almost all concomitant medications will be allowed, such as 
antibiotics, anticonvulsants, and asthma therapy. For all enrolled subjects, all 
administered concomitant medications from signing the informed consent until 30 days 
after the subject’s last dose of study drug, will be recorded in the subjects’ CRF 
(medication, dose, treatment duration and indication). All reported prior and 
concomitant medications will be coded using the current version of the World Health 
Organization (WHO) Drug Dictionary.  
 
No subject can be currently participating in other therapeutic clinical trials or taking 
other agents for SCD, such as hydroxyurea, arginine, decitabine, magnesium, nitric 
oxide, etc. Eligible subjects taking any therapeutic agent for SCD will require a washout 
period of at least three months prior to study enrollment.  
 
Clinically-indicated erythrocyte transfusions may need to be given during the study if 
complications from SCA arise, such as a severe episode of acute chest syndrome or 
splenic sequestration.  
 
5.6. Subject Compliance 
 
Interval visit CRFs and study medication logs will be completed by the site study 
personnel at each interval visit to capture medication adherence with hydroxyurea. Study 
visits are scheduled every 4 (± 2) weeks, allowing flexibility for family or center 
scheduling needs. Subjects should bring the previously dispensed medication bottles 
each interval visit for review with study personnel. In addition, the Medication 
Adherence Measure (MAM) will be administered at each interval visit. 
 
5.7.
Duration of Treatment 
 
Subjects in both treatment arms will be followed for a maximum of 56 weeks regardless 
of the actual number of study visits. Upon completion of the 56 weeks, patients will be 
followed for an additional 30 days for toxicities and will then be taken off study. 
 
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5.8. Blinding 
 
All participants enrolled in HUGKISS will be treated with hydroxyurea. A double-blind 
would be logistically challenging and could result in a significant safety risk to 
participants. The population eligible for enrollment will require liquid formulation and 
randomization will dictate a dosage of ~20 mg/kg/day or escalation to ~25-35 
mg/kg/day. 
 
A double-blind design would require either higher concentrations of hydroxyurea 
suspension for participants undergoing dose escalation or for participants to ingest two 
aliquots of study drug or study drug/placebo combinations. Currently, the standard 
formulation of hydroxyurea is 100 mg/mL, and obtaining antimicrobial stability testing 
for other concentrations would incur significant expense and added burden to the local 
pharmacies; furthermore, these formulations would not provide meaningful clinical 
benefit in the future. Requiring participants and/or care givers to administer two aliquots 
of study drug (hydroxyurea + hydroxyurea, or hydroxyurea + placebo) would place a 
burden on participants, likely reduce medication adherence, and be a potential source for 
medication error. 
 
Although both of the double-blind designs were contemplated, they would place 
significant burden on families and/or pharmacies, and it was felt that the objectives of 
HUGKISS could be safely and more efficiently obtained with a single-blind design, in 
which primary investigators and medical providers would remain blinded, and patients 
would have their volume of medication assigned. 
 
5.8.1. HUGKISS Enabled Local Provider for Evaluating Response 
(HELPER) 
 
For clinical decisions regarding dose escalation, drug toxicity and/or management of 
clinical illness, there will be a local clinical provider, not affiliated with HUGKISS, 
who will provide interpretation of laboratory data. 
 
The integrity of the HUGKISS trial will depend upon providing study treatment that is 
blinded to investigators by randomization and delivery of unbiased clinical care for the 
duration of the trial. The MCC will maintain records of each patient’s drug assignment 
and current dosage. The staff of the MCC will have access to individual patient 
treatment assignment codes and current dose on a “need to know” basis. The Clinical 
Center PIs must agree to avoid seeking information that may unblind them to an 
individual participant’s treatment assignment. This requires an “honor system” 
approach, which was successful in the BABY HUG trial. However, as the HUGKISS 
study requires dose intensification of hydroxyurea based on an ANC goal of 15003000 
cells/μL, real-time knowledge of local CBC results is essential for Clinical Center 
study staff. As such, a HELPER will be utilized. The HELPER will be an unblinded 
local medical provider, unaffiliated with the steering committee or data analysis, who 
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is knowledgeable about SCA. These individuals will be charged with transmitting 
endpoint data and monitoring toxicities and adherence in real time with the goal of 
optimizing clinical care of study patients. The HELPER (unblinded) study member 
will perform these clinical responsibilities and that the site PI will attest that they will 
avoid clinical duties that may unblind them to participant treatment status. This will be 
similar to the infrastructure of the BABY HUG trial.  
 
5.8.2. Emergent Unblinding 
 
Every family will be given an identification card describing the child’s participation in 
the HUGKISS study, listing emergency study telephone numbers (e.g., the Clinical 
Center Principal Investigator’s (PI) telephone number and the Central Study 
Emergency Contact’s telephone number). The Central Study Emergency Contact’s 
number will be answered by a pediatric SCA consultant to the MCC at all times.  
 
If HUGKISS children become ill, treating physicians will be urged to call the Clinical 
Center PI before altering the child's study regimen. In an emergency, family members 
will be instructed to call a telephone number that will be manned by a pediatric 
hematologist 24 hours a day. Arrangements will be made so that the child’s 
medication can be disclosed to the Clinical Center PI after consultation between the 
Clinical Center PI and the pediatric SCA consultant to the MCC. 
 
Reasons for unblinding are limited and are based on clinical grounds. Unblinding must 
be initiated by the Clinical Center PI. Reasons for unblinding include overdose of the 
study medication, accidental ingestion of the study medication by another person, 
development of infection or bleeding that could be due to reduced white blood cell or 
platelet counts and for which management might be changed if the nature of the study 
drug were known. Examples of clinical situations when information on study 
treatment could be useful include severe thrombocytopenia calling for a decision to 
use prednisone versus platelet transfusion or severe neutropenia calling for a decision 
on choice of antibiotics. If a child's therapy is unblinded, the Clinical Center PI or staff 
member who unblinded the treatment must send a report to the MCC. 
5.8.3. Randomization and Treatment Allocation 
 
Children who meet all criteria for enrollment will be randomized to single-blind 
treatment at week 8. Randomization will be stratified by baseline age obtained during 
the baseline evaluation obtained on week 0 and Clinical Center. Assignment to 
treatment groups will be determined by a computer-generated random sequence 
housed within the Department of Biostatistics. Treatment allocation will then be 
communicated to the local unblinded study personnel (HELPER and pharmacy) via 
encrypted email regarding treatment allocation.   
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6.0 
DRUG INFORMATION  
 
6.1. Source and Distribution 
 
One form of hydroxyurea will be used in this study, a standardized liquid formulation 
containing 100 mg/mL hydroxyurea will be prepared using a commercial source of 
hydroxyurea, USP and Syrpalta® (without color), USP.  Hydroxyurea will be purchased 
from Spectrum Pharmacy Products to be used as the source drug substance for the liquid 
formulation of hydroxyurea. The Syrpalta® (without color), USP will be purchased from 
Humco Compounding to be used as a suspension for hydroxyurea. Hydroxyurea, USP 
will be hand filled into 4 ounce amber bottles with 11g ± 5% (10.45-11.55g) by KP 
Pharmaceutical Technology (KPPT), INC. Sharp Packaging Services will provide 24 
hour monitored storage of the bottles and shipment to study sites.  
 
6.2. Formulation and Stability 
 
Because of the limited stability of the liquid formulation of hydroxyurea, hydroxyurea 
will be formulated into liquid at 100 mg/ml with assistance of local pharmacies. Purified 
water (60 mL) will be added to a bottle pre-filled hydroxyurea, USP (11 gm/bottle). 
Syrpalta® (without color) will be added to the hydroxyurea-water suspension in a 
sufficient quantity to achieve a final volume of 110 mL.  The final concentration of the 
hydroxyurea solution is 100 mg/mL. The whole bottle will be dispensed to a participant.  
Release testing and specifications for hydroxyurea will include appearance, assay, 
related substance and microbial limits. Release testing results and Certificates of 
Analysis for Hydroxyurea, USP bottle will be performed by KPPT and submitted to the 
FDA prior to shipping of drug to any clinical sites.     
 
Stability and microbial limit testing of this liquid formulation has already been 
performed during the previous “Pharmacokinetics and Relative Bioavailability of a 
Liquid Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia” trial 
and submitted to the FDA (see attached Letter of Cross Reference for IND). The 
stability of the liquid formulation of hydroxyurea has been demonstrated for up to 6 
months41. 
 
 
6.3. Dosage and Route of Administration 
 
Hydroxyurea (100 mg/mL) will be administered orally at a dose of 20 mg/kg/day for 
eight weeks (±2 week) prior to randomization. Participants randomized for dose 
intensification will receive hydroxyurea escalated to 25-35 mg/kg/day.  
 
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6.4. Toxicity 
 
1)
Neutropenia: absolute neutrophil count of less than 1.0 x 109/L or 
2)
Anemia: Hemoglobin less than 6.0 g/dL that occurs in the clinical setting of an 
absolute reticulocyte count of less than 80 x 109/L. or 
3)
Reticulocytopenia: absolute reticulocyte count less than 80 x 109/L, associated with 
a hemoglobin level of less than 9.0 g/dL. or 
4)
Thrombocytopenia: Platelet count less than 80 x 109/L 
7.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
7.1. Pre-Study Evaluations 
 
Eligibility screening (ES) and baseline evaluations should be performed prior to 
initiation of hydroxyurea.  Eligibility screening may be performed the same time as 
baseline evaluations.  A new hemoglobin identification only needs to be performed at 
eligibility screening if a previous result is not already available in the subject’s medical 
record. 
 
7.2. Clinical Events 
 
All patients will be monitored for the occurrence and severity of clinical events. These 
will be identified through the use of standardized history questions administered at each 
clinical encounter. At each visit, parents will be asked to describe any illnesses 
experienced since the last visit. If illness is reported, a directed history will be obtained 
to allow its characterization. All events will be reported utilizing standardized definitions 
(See Appendix III) on an Events Form. 
 
Documentation (discharge summaries, clinic/emergency department records, local 
laboratory values or radiology reports) for all fatal or life threatening events will be 
collected by Clinical Center staff for review. Events of interest include bacteremia with 
known pathogens, meningitis, splenic sequestration, acute chest syndrome, stroke or 
transient ischemic attacks, osteomyelitis, all hospital admissions and any event for which 
the patient receives a transfusion.  
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Table 10. Schedule of HUGKISS Evaluations*  
ES1 
BE 
Weeks 
Exit 
Evaluation 
-4 to 0 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52-56 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, Height & Vital Signs 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History, Physical Exam 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant Medications 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events/Study Endpoints 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hydroxyurea Initiation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with WBC Count 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte Count 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP5 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Lactate Dehydrogenase 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Hemoglobin Identification 
X2 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Urinalysis 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
TCD Examination3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Quality of Life Assessment4  
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MAM6 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Accountability 
 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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*Ideal visits are every 4 weeks +2 weeks, except for ES,BE, and the Exit visit. ES, eligibility screening; BE, baseline evaluation, which should be 
performed prior to initiation of hydroxyurea. 1Eligibility screening may be performed the same time as baseline evaluations. 2A new hemoglobin 
identification only needs to be performed at eligibility screening if a previous result is not already available in the subject’s medical record. 3To be 
performed on participants >2 years of age. 4Age appropriate screening tool. 5CMP, Comprehensive Metabolic Panel, Chemistries include: Sodium, 
Potassium, Chloride, CO2, Glucose, BUN, Creatinine, Calcium, Albumin, Bilirubin Total, Alk, Phos, ALT, AST, Protein Total. 6MAM, Medication 
Adherence Measurement. 
 
 
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8.0 
EVALUATION CRITERIA 
 
8.1. Toxicity Evaluation Criteria 
 
The plan for dose reduction and toxicity monitoring is based on our safety data from 
BABY HUG1. The starting dose of hydroxyurea will be 20 mg/kg. If toxicity occurs 
(defined in section 6.4), treatment will be stopped and blood counts will be checked 
every seven days until they return to non-toxic values. Transient toxicity will not cause a 
dose reduction or termination of therapy, but prolonged or repeated toxicity will. If a 
hematologic toxicity is identified, therapy will be discontinued for seven days. If counts 
recover, treatment will be resumed at the previous dose. If the toxicity persists, 
treatment will continue to be held for an additional 7 days and treatment will resume at a 
daily dose 2.5 mg/kg lower than the previous dose once the toxicity is resolved. If that 
dose does not cause toxicity for eight weeks, then the lower dose will be assigned as the 
stable dose. If hematologic toxicities occur while a participant is being treated with an 
established stable dose, treatment will be stopped until toxicity resolves and then 
treatment will resume using the previously established stable dose. Repeated toxicity in 
a 12-week period will reduce the stable dose by 2.5 mg/kg for the remainder of the 
study. 
 
9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF-STUDY CRITERIA 
 
9.1. Off-study Criteria 
 
1) Initiation of chronic blood transfusion therapy 
2) Stroke 
3) Death 
4) Lost to follow-up 
5) Request of the Patient/Parent 
6) Discretion of the Study PI, such as the following  
a. The researcher decides that continuing in the study would be harmful  
b. A treatment is needed that is not allowed on this study 
c. The participant misses so many appointments that the data cannot be used in the 
study 
d. New information is learned that a better treatment is available, or that the study is 
not in the participant’s best interest 
e. Study evaluations are complete 
 
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9.2. Collaborating Sites Notifications 
 
Collaborating sites will be required to notify the PM with any participant information 
that will affect treatment criteria on this protocol. The PM will send reports to PI and 
governing bodies regarding the study. 
 
10.0 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
10.1. Sickle Cell Related Events 
 
In HUGKISS, clinical event definitions will be applied for consistency with other 
important NHLBI-sponsored clinical studies of sickle cell anemia such as the Clinical 
Study of Sickle Cell Disease (CSSCD), the Multicenter Study of Hydroxyurea in Sickle 
Cell Anemia (MSH), and BABY HUG. 
 
These clinical events are defined in Appendix III. 
 
10.2. Reporting Adverse Experiences and Deaths to SJCRH Institutional 
Review Board (IRB) 
 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4 will be used 
to grade adverse events. Only “unanticipated problems involving risks to participants or 
others” referred to hereafter as “unanticipated problems” are required to be reported to 
the SJCRH IRB promptly, but in no event later than 10 working days after the 
investigator first learns of the unanticipated problem. Regardless of whether the event is 
internal or external (for example, an IND safety report by the sponsor pursuant to 21 
CFR 312.32), only AEs that constitute unanticipated problems are reportable to the 
SJCRH IRB. As further described in the definition of unanticipated problem, this 
includes any event that in the PI’s opinion was: 
 
•
Unexpected (in terms of nature, severity, or frequency) given (1) the research 
procedures that are described in the protocol-related documents, such as the IRB 
approved research protocol and informed consent document, as well as other 
relevant information available about the research; (2) the observed rate of occurrence 
(compared to a credible baseline for comparison); and (3) the characteristics of the 
subject population being studied; and 
•
Related or possibly related to participation in the research; and 
•
Serious; or if not serious suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.  
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Unrelated, expected deaths do not require reporting to the IRB. Though death is 
“serious,” the event must meet the other two requirements of “related or possibly 
related” and “unexpected/unanticipated” to be considered reportable. 
 
Deaths meeting reporting requirements are to be reported immediately to the local IRB 
and sponsor (SJCRH), but in no event later than 48 hours after the investigator first 
learns of the death.  
 
The following definitions apply with respect to reporting adverse experiences:  
Serious Adverse Event (SAE): Any AE temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
 
•
Results in death; 
•
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
•
Requires inpatient hospitalization or prolongation of existing hospitalization; 
•
Results in a persistent or significant disability/incapacity; 
•
Results in a congenital anomaly/birth defect; or 
•
Any other AE that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition (examples of such events include: any 
substantial disruption of the ability to conduct normal life functions, allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse), a congenital anomaly/birth defect, 
secondary or concurrent cancer, medication overdose, or is any medical event which 
requires treatment to prevent any of the medical outcomes previously listed. 
 
Unexpected AE:  
   
•
Any AE for which the specificity or severity is not consistent with the protocol 
related documents, including the applicable investigator brochure, IRB approved 
consent form, IND or Investigational Device Exemption (IDE) application, or other 
relevant sources of information, such as product labeling and package inserts; or if it 
does appear in such documents, an event in which the specificity, severity or 
duration is not consistent with the risk information included therein; or  
•
The observed rate of occurrence is a clinically significant increase in the expected 
rate (based on a credible baseline rate for comparison); or  
•
The occurrence is not consistent with the expected natural progression of any 
underlying disease, disorder, or condition of the subject(s) experiencing the AE and 
the subject’s predisposing risk factor profile for the AE.  
 
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Internal Events: Events experienced by a research participant enrolled at a site under 
the jurisdiction of SJCRH IRB for either multicenter or single-center research projects. 
 
External Events: Events experienced by participants enrolled at a site external to the 
jurisdiction of the SJCRH IRB or in a study for which SJCRH is not the coordinating 
center or the IRB of record. 
 
Unanticipated Problem Involving Risks to Subjects or Others: An unanticipated 
problem involving risks to subjects or others is an event which was not expected to 
occur and which increases the degree of risk posed to research participants. Such events, 
in general, meet all of the following criteria:  
 
•
Unexpected;  
•
Related or possibly related to participation in the research; and  
•
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. An unanticipated problem involving risk to subjects or others 
may exist even when actual harm does not occur to any participant.  
 
Consistent with FDA and OHRP guidance on reporting unanticipated problems and AEs 
to IRBs, the SJCRH IRB does not require the submission of external events, for example 
IND safety reports, nor is a summary of such events/reports required; however, if an 
event giving rise to an IND safety or other external event report constitutes an 
“unanticipated problem involving risks to subjects or others” it must be reported in 
accordance with this policy. In general, to be reportable external events need to have 
implications for the conduct of the study (for example, requiring a significant and 
usually safety-related change in the protocol and/or informed consent form). 
 
Although some AEs will qualify as unanticipated problems involving risks to subjects or 
others, some will not; and there may be other unanticipated problems that go beyond the 
definitions of serious and/or unexpected AEs. Examples of unanticipated problems 
involving risks to subjects or others include: 
 
•
The theft of a research computer containing confidential subject information (breach 
of confidentiality); and  
•
The contamination of a study drug. Unanticipated problems generally will warrant 
consideration of substantive changes in the research protocol or informed consent 
process/document or other corrective actions in order to protect the safety, welfare, 
or rights of subjects or others.  
 
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10.3. Reporting to the Sponsor and/or Federal Agencies 
 
10.3.1. Notification of Federal Agencies by Investigator  
 
Study coordinator will assist PI with protocol submissions for review by federal or 
institutional committees as applicable. 
 
10.3.2. Recording AEs and SAEs 
 
The HUGKISS trial will use a Data Safety and Monitoring Board (DSMB) comprised 
of 5-6 persons with expertise in clinical trials who are not directly involved in the 
study or based at a participating site. These members will include a hematologist with 
sickle cell research experience, pharmacist, statistician, bioethicist, and patient 
advocate/representative. The DSMB will be appointed by the SJCRH and will receive 
regular reports of SAEs and study data 
 
10.4. Process for Reporting AEs from the sites to SJCRH, and to the rest of 
the Collaborating Sites/Affiliates  
 
For the purposes of this protocol, hospitalizations due to expected sickle cell related 
complications (Appendix III) will not be counted as AEs but will be captured as study 
related endpoints.  
 
AEs will be reported to the local IRB by the respective clinical center's PI and study 
staff. In addition, each clinical center will be responsible for reporting AEs to the DCC 
via electronic data entry. The DCC will be responsible for submitting AE reports to the 
DSMB. All serious, unexpected events will be reported within 24 hours to the DSMB. 
SJCRH will assume responsibility for ensuring that AEs are reported to the FDA within 
the appropriate time period, and that DSMB summary reports are distributed to study 
investigators for submission to their local IRBs. 
 
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11.0 DATA COLLECTION, STUDY 
MONITORING, AND 
CONFIDENTIALITY 
 
11.1. Data Collection  
 
Data will be captured during the study visits in a timely manner, as specified in 
Appendix I. The Departments of Biostatistics and Hematology at SJCRH has experience 
in designing and implementing secure databases for multisite clinical trials involving 
SCA in children. Data monitoring of the study will be performed by the CPDMO office 
at SJCRH. 
 
For HUGKISS, a secure Current Research Information System (CRIS) database will be 
established that will facilitate remote data entry with electronic data transfer. All data 
entered into CRIS must have verifiable source documents in the patient chart and should 
be reproducible at site monitoring and audit visits. The sites will complete the data entry 
as it is outlined in the protocol and Manual of Operations. Data entered in the CRIS 
database will be monitored and queried by the protocol coordinator for protocol and 
regulatory compliance. 
 
11.2. Data Collection Instructions for Collaborating Sites  
 
All data will be collected by the participating sites and sent via electronic data capture to 
the study database.  
11.3. Study Monitoring 
 
All Clinical Centers will submit the HUGKISS Protocol and the Informed Consent Form 
as modified for their local IRB for initial review before any patient can be screened for 
eligibility. Centers will submit to their local IRB updates for annual review, protocol 
amendments, study-wide reports such as DSMB recommendations, and any other 
information that may be requested by the IRB. Clinical Centers will comply with local 
IRB requirements regarding reporting serious AEs, whether or not related to study 
treatment. Clinical Centers will provide the MCC with documentation of approval from 
the IRB. The approved local consent form will be submitted to the DSMB Chair for 
review to assure that it conforms to the requirements for protection of human subjects. 
 
Monitoring of this protocol is considered to be in the high-risk 3 category. Protocol and 
regulatory compliance will be assessed as well as the accuracy and completeness of all 
data points for 100% of study enrollees semiannually.   Accrual will be tracked 
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continuously, and the appropriateness of SAE reporting will be assessed on all 
participants. 
 
The study team will meet at appropriate intervals to review case histories or quality 
summaries on participants. 
 
The Eligibility Coordinators will verify 100% of the informed consent documentation on 
all participants and verify 100% of St. Jude participants’ eligibility status within 5 
working days of the completion of enrollment. 
 
The Clinical Research Monitor will track accrual continuously and verify 100% of all 
data points on all study participants semiannually to assess overall study conduct, 
Human Subjects Protections, and the accuracy of database entries.  Essential regulatory 
documents and all study documents including medical records, electronic media 
database entries, study worksheets, and case report forms will be reviewed for recording 
and reporting of Adverse Events/Serious Adverse Events (SAEs) to include type, grade, 
attribution, duration, timeliness and appropriateness. Study documents are also reviewed 
for participant status, eligibility, the informed consent process, demographics, staging, 
study objectives, subgroup assignment, treatments, evaluations, responses, participant 
protocol status, off-study and off-therapy criteria, and for all other specifics as detailed 
in the protocol. The Monitor will generate a formal report which is shared with the 
Principal Investigator (PI), study team and the Internal Monitoring Committee (IMC). 
This will include verification of appropriate documentation of consent. Monitoring of 
timeliness of serious adverse event reporting will be done as events are reported in 
TRACKS.  
 
St. Jude affiliates and domestic collaborating study sites will be monitored on-site by a 
representative of St. Jude at intervals specified in the Data and Safety Monitoring Plan. 
Monitoring may be conducted more frequently if deemed necessary by the CPDMO or 
the IMC. 
 
11.3.1. Composition and Responsibilities of the DSMB 
 
The HUGKISS pilot trial will use a DSMB comprised of 5-6 independent experts, 
including 
a 
hematologist, 
pharmacist, 
statistician, 
bioethicist 
and 
patient 
advocate/representative. The DSMB will be responsible for monitoring the clinical 
centers individually and in the aggregate for unexplained lag in recruitment, missed 
visits, missed specimen collection, missed scheduled procedures, missing expected 
forms, agreement between treatment dose recommended and dose dispensed, study 
treatment not accounted for, medical events required to be reported, and routine AEs. 
Weekly lists of expected visits, blood specimens, and scheduled procedures will be 
generated and reviewed by the Data Coordinating Center (DCC; chaired by Guolian 
Kang) at SJCRH. The DSMB will meet regularly to review cumulative study data. In 
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addition to the routine performance reports, they will review data according to the 
assigned groups. Forms and procedures expected, but not reported within five days 
will be queried in a weekly cumulative delinquency report, and all cases of AEs and 
laboratory alert values will be reviewed in detail. The DSMB will make 
recommendations to the SJCRH regarding recruitment goals, study performance, and 
patient safety. Specific topics for data monitoring are discussed below: 
 
11.3.1.1. Eligibility 
  
Status regarding eligibility criteria will be entered into the database for all 
consented patients. Aggregate reports will be generated weekly throughout 
recruitment showing, according to Clinical Center, the numbers of patients who are 
eligible, those disqualified and reasons for such, those qualified, those randomized 
and enrolled, and those in follow-up. Steering Committee members will monitor 
these accrual reports and make recommendations to improve performance or 
change procedures.  
 
11.3.1.2. Follow-Up Clinic Visits  
 
At every follow-up visit, a standardized data capture form regarding specific events 
and any unusual conditions or occurrences will be collected. The site PIs will be 
required to review this and provide an assessment of whether an AE has occurred. 
Since this is an IND monitored study, the usual definitions of AE may be 
implemented, such as the occurrence of death or a life-threatening condition or an 
event that causes or prolongs hospitalization. For the purposes of this protocol, 
hospitalizations due to expected sickle cell related complications will not be 
counted as AEs but will be captured as study-related endpoints. 
 
11.3.1.3. Study Treatments  
 
Study forms will require complete accounting of study treatments to verify that each 
patient received his/her correct bottle with the correct dose, and that treatment was 
administered daily. Local laboratory results must be entered into the study database 
for the study participant to continue taking prescribed study treatment. If laboratory 
results obtained to monitor for myelosuppressive toxicities are not entered into the 
database within five days, then an immediate stop-treatment order will be issued 
automatically. At every visit, unused study drug is expected to be returned, and 
participants will be assessed for compliance by measurement of residual drug 
returned. Treatment errors will be reported to the Study Chairman immediately and 
will be counted cumulatively. If these errors represent significant protocol 
violations, then study policies regarding remedial action for repeated treatment 
regimen violations will be implemented. 
 
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11.3.1.4. Data Entry and Database Quality Assurance  
 
Because most data entry will be performed at remote Clinical Center sites, data 
quality assurance will be evaluated and maintained through site visits that will 
include complete audits of the local data against the center’s medical records. 
Periodically, copies of original forms may be requested from Clinical Centers for 
independent data entry and review in the MCC and DCC to verify the accuracy of 
the local center data entry. 
 
Given the multisite design (Figure 1.) of HUGKISS, oversight of all study related 
activities will be crucial. Specific topics regarding assuring data quality are 
discussed below: 
 
1. Clinical Centers will be visited and audited during the study to assure quality 
of data collection. The MCC will generate computer printouts of remotely 
entered data for comparison to actual patient charts. If significant discrepancies 
are noted, the Study Chairman, and the MCC staff will visit the Clinical Center 
and provide a site visit report to the DSMB for recommendation on corrective 
action. Treatments dispensed by the Clinical Center (Investigational) 
Pharmacies will be checked for agreement with the treatment kit number 
assigned to the child, as well as the recommended prescription. The Clinical 
Center PI will be notified immediately of any discrepancies. Confirmed 
discrepancies will be tallied cumulatively. Pharmacies accruing unacceptable 
numbers of discrepancies also will be reported to the Study Chairman for 
immediate action.  
 
2. At the DCC, the randomization schedule will assure the appropriate blocking 
and balance of treatment groups for clinically important patient characteristics 
within each Clinical Center. The final schedule will be reviewed to assure that 
randomization is balanced by age and Clinical Center. 
 
3. Within the MCC, laboratory results, treatment assignments, and study drug 
records will be monitored. Local laboratory parameters will be monitored by 
the HELPER, which will allow for real-time assessment of values. All 
laboratory results will be entered into the HUGKISS database within 5 days, 
which will facilitate a second safety evaluation of individuals across the entire 
study. Laboratory value outliers will trigger safety alerts, will be verified, and 
will be reviewed by the Study Chairman. Extreme values that constitute an AE 
will be managed according to specified procedures. Abnormal values that do 
not exceed levels will be used in formulating treatment recommendations. The 
HUGKISS study team will follow standard dose adjustments for hydroxyurea 
therapy and these recommendations and records of treatment will be reviewed 
along with the laboratory results by the designated medical staff at the MCC. 
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Confirmed treatment recommendations will be forwarded to the Clinical 
Center electronically. All misreported laboratory results will be cumulated and 
reported, as well as all alert values, and routine dose changes. MCC staff will 
review reported toxicities and their resolution and consequent dose adjustments 
to see if the frequency of adjustments is reasonable or if patients are being 
stopped too frequently. Tabulations of the time patients are not maintained on 
assigned treatment will also be reviewed.  
  
11.3.1.5. Safety and Patient Monitoring 
 
For the purposes of this protocol, hospitalizations due to expected sickle cell related 
complications (Appendix III) will not be counted as AEs but will be captured as 
study-related endpoints.  
 
All AEs, regardless of attribution to study treatment or SCD will be reported to the 
MCC. Any event meeting the definition of a serious AE will be reported to the 
DSMB Chair, Executive Secretary of DSMB, and the FDA. The Clinical Centers 
will report all serious AEs at their institution according to their local IRB 
requirements. In the event of an emergency in which the Clinical Center PI or local 
treating physician requires knowledge of the patient’s HUGKISS treatment 
assignment is necessary for determining patient management, the PI or treating 
physician will telephone the HUGKISS Study Chairman, or the SJCRH site PI in 
the event the Study Chairman is unavailable, to discuss the need for unblinding. An 
automated system will be available to obtain unblinding information 24 hours/day 
as deemed necessary.  
 
The staff of Clinical Centers and Core Laboratories, the Endpoint Evaluation 
Committee members, and the MCC personnel share in responsibility for patient 
safety and the scientific integrity of HUGKISS. With the assistance of oversight 
provided by the DSMB and the local IRBs, all matters of protocol implementation 
and data reporting will be subject to review. Procedures for monitoring of scientific 
integrity and quality assurance in multicenter trials have been promulgated by the 
Society for Clinical Trials42. Violations of the protocol will be investigated 
promptly to maintain patient safety.  
 
In order to prevent Major Protocol Violations or reporting of incorrect data, we will 
utilize training and certification, site visits, audits, statistical checks, edit checks, 
and careful follow-up of any abnormalities that could result in study-wide 
suspension of randomization or treatment stoppage. Specifically, we will ensure the 
following:  
 
1. Data collection by non-certified personnel will be prevented by training and 
certification (including education that misuse of certification number is a 
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scientific integrity issue) and by review of study forms all of which require 
signature, certification number and date. If this occurs, it will trigger a clinic 
wide audit, deletion of erroneous data, and a corrective action plan from the 
Clinical Center PI to keep the problem(s) from recurring.  
 
2. Requesting enrollment (randomization) for a child who does not meet 
eligibility criteria will be prevented by training and certification, detected by 
review of eligibility data collection forms, and acted upon with suspension of 
randomization.  
 
3. Requesting enrollment (randomization) for a child for whom informed consent 
has not been obtained, or whose family has been noted by the Patient/Family 
advocate to have reservations will be prevented by training and certification, 
detected on site visit, and acted upon with suspension of randomized study 
treatment and randomization.  
 
4. Failure to act to implement a treatment stop order within 72 hours will be 
prevented by training and certification, detected by review of study treatment 
data collection forms and Patient/Family advocate follow-up and acted upon 
with suspension of randomized study treatment and randomization. 
 
5. Failure to report a serious AE within 24 hours of learning of the event will be 
prevented by training and certification, detected on review of study treatment 
data collection forms, and acted upon with suspension of randomized study 
treatment and randomization.  
 
11.4. Confidentiality 
 
All clinical information will be collected by the participating sites and sent via electronic 
data capture to the study database. Data will be encrypted during the internet transfer 
process in order to protect against loss of confidentiality. Access to the HUGKISS 
database will be restricted to the DCC staff and will be password-protected. Each study 
subject will have a study identification number to protect patient identity. Each site will 
maintain a list to allow linkage to subject identity; this list will be kept locally at each 
site and its access will be restricted to local site personnel, and to entities that may need 
access to verify accuracy and completeness of data, including the NHLBI, the 
HUGKISS DCC, and the DSMB. 
12.0 STATISTICAL CONSIDERATIONS 
 
12.1. Design and Sample Size Justification 
 
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HUGKISS is a prospective, randomized, multi-site, single-blinded, therapeutic, pilot 
trial aimed at demonstrating the feasibility of enrolling and randomizing young children 
(9 to 36 months) with SCA (HbSS and HbSβ0-thalassemia) to receive either fixed or 
intensified dose of hydroxyurea therapy in a single blinded manner and at collecting 
pilot clinical and laboratory efficacy data (i.e., estimates of the effect size and variability 
for future studies) to design a future phase III trial. The study is planned to enroll 65 
children with SCA to get 50 randomized in a 27-month period. All eligible participants 
who   consent will be enrolled on the study. The duration of the study is based on 
sample size of 50 patients randomized and/or 27-month period, whichever comes first. If 
we randomize 50 eligible individuals within 27 months of study initiation, we will halt 
enrollment of new participants. If we are unable to randomize 50 patients in a 27 month 
period, then we will conclude that this pilot study is not feasible in terms of the 
feasibility definition below. The patients who are randomized will be evaluable to assess 
the feasibility below. The analysis will be limited to the patients who meet the feasibility 
criteria 2) below.    
 
Given previous experience of the BABY HUG trial, we anticipate a 20% dropout rate 
(which includes removal for noncompliance). Feasibility of the overall study will be 
determined by two points, 1) in terms of enrollment and randomization, that we are able 
to randomize 50 eligible individuals in the 27-month duration; and 2) in terms of the 
feasibility of conducting a randomized trial, that is, after randomization, per each arm, 
80% (40 individuals in total) of randomized individuals will have ≥ 80% chronic 
medication compliance, and will have the %HbF collected at baseline and at study exit. 
Chronic medication compliance is defined based on medication possession ratio (MPR), 
a measure of the percentage of time that a patient has access to medication. Each 
participant MPR is calculated as [(days medication in family’s possession/days 
prescribed medication)×100]. The design of this study will conclude that this pilot 
HUGKISS trial is feasible if both of the feasibility criteria in terms of the enrollment 
and randomization and of conducting a randomized trial are satisfied, that is, for both 
arms, ≥ 40 out of 50 randomized patients in the 27-months and have ≥ 80% chronic 
medication compliance and have the total HbF collected at baseline and at study exit 
after randomization to design a future phase III trial.     
 
This is a pilot study and no formal sample size justification needed. A sample size of 50 
(randomized patients) is based on our enrollment capacity (see next paragraph). 
However, based on our definite phase III trial, we will expect both a significant decrease 
in the rate of hospitalization and a significance increase in %HbF. The two component 
(hospitalization and %HbF) hypotheses and the overall composite hypotheses to be 
tested are expressed as follows: Let μA and μC denote the mean %HbF at study exit for 
the alternative (intensified dose) and standard treatment (fixed dose) arms, respectively. 
The null and alternative hypotheses for the total HbF component of the primary 
endpoint are Hh0: μA - μC = 0 ↔ Hh1: μA - μC > 0. The mean %HbF (SD) at study 
exit (two years) in the standard treatment arm is assumed to be 22.4% (8.7%) based on 
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the results from BABY HUG. Using design parameters and 20 individuals per each arm, 
μA-μC = 5% (based on data from HUSOFT and the SJRCH internal data on infants), the 
power will be 0.56 and 0.70 based on a one-sided t test statistic at a significance level of 
α = 0.05 and 0.1, respectively. Denote pA and pC as the true proportions of individuals 
with hospitalization events during the two year study period in the alternative and 
standard treatment arms, respectively. The null and alternative hypotheses for the 
clinical hospitalization component of the primary endpoint are Hc0: pA = pC ↔ Hc1: 
pA < pC. Based on data from BABY HUG, 69 out of 96 participants experienced at 
least one hospitalization within a two year therapy period (pC = 0.72). Using design 
parameters and 20 individuals per each treatment arm, pA = 0.52, the power will be 0.32 
and 0.45 based on a one-sided exact test at a significance level of α = 0.05 and 0.1, 
respectively. This power calculation is only for illustrative purposes due to the nature of 
the pilot study. 
 
We estimate we will need to approach approximately 125 eligible participants to enroll 
65 patients to get at least 50 randomized. Only the patients who sign the consent and 
enroll on the study but go off study before randomization will be replaced. Once the 
patient is randomized, the patient will be evaluable to assess the feasibility criteria 2) 
above. At St. Jude, we will have approximately 30 children who meet eligibility criteria 
of this study per year; we anticipate that the other three sites will identify about 130 of 
eligible patients per year. Among these eligible patients, we estimate that there are 
approximately half of patients with age 9 to <24 months and half of patients with age 24 
to 36 months. This supports the expectation of an 27-month duration to complete 
enrollment.  
 
In addition to monitor the trial for feasibility, we will closely monitor the excess toxicity 
in terms of invasive infection. If the alternative treatment arm has 3 or more patients 
experienced invasive infection that occurs during excessive myelosuppression from 
hydroxyurea, we will stop the trial for excess invasive infection in the alternative 
treatment arm.  
 
Randomization: 
Eligible patients will be consented  and will be initiated on HU (100 mg/mL) at a dose 
of ~20 mg/kg/day in an open label fashion for eight weeks (±2 weeks) prior to 
randomization. Participants without toxicity (defined in section 6.4), or with toxicity 
which requires discontinuation of HU but resolved and participant continues HU during 
those eight weeks (±2 weeks), will be randomized to receive “standard” or “intensive” 
therapy based on a block randomization. Randomization will be stratified by clinical 
center (four centers: St. Jude, UMMC, UT Southwestern, and Children’s Health Care of 
Atlanta) and by baseline age of the participant (9 to <24 months and 24 to 36 months) 
because of the natural physiologic decline of HbF with increasing age. Block 
randomization with a block size of 4 will be used in each stratum.  Randomization will 
be performed in DCC based on the registration identifiers, using the randomization 
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program developed by the Department of Biostatistics. Once a patient is randomized, all 
related randomization information will be frozen in the Biostatistics randomization 
database and cannot be changed.  
This study is a single blinded randomization study and will need unblinding in some 
emergent cases (Section 5.8.2). The DCC and MCC will document and track 
participants who are unblinded either in an emergent or incidental fashion. The rate of 
unblinding of participants will be described by the percentage of overall participants and 
the percentage of study related visits. 
12.2. Statistical Analyses  
 
12.2.1. Describe reasons provided for agreement or refusal for participation 
in HUGKISS for each family approached.  
 
Descriptive statistics will be provided including the number and frequency.  
 
12.2.2. Develop an infrastructure and clinical monitoring plan that facilitates 
safe administration of hydroxyurea at a low-fixed dose and an intensified 
dose to MTD in a single-blinded manner to children. 
 
No analytical plan is needed for this objective. 
 
12.2.3. Obtain pilot data on the laboratory effects, clinical outcomes and 
toxicities observed with fixed versus intensified hydroxyurea dosing. 
 
Upon the completion of the study, summary statistics including mean, SD, median and 
range for continuous variables and frequency for categorical variables for each 
treatment arm will be provided and will be compared between two treatment arms 
using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality 
of the data tested by the Shapiro-Wilk test. The comparison of time to first event 
defined below will also be compared between two treatment arms using the 
Kalbfleisch-Prentice method43. Death is the competing risk event. The analysis will be 
implemented using SAS macro (bmacro252-Excel2007\cin) available in the St. Jude 
Department of Biostatistics. Longitudinal analysis based on Generalized Estimating 
Equation44 will also be assessed, but it is exploratory analysis due to the small sample 
size. The laboratory effects of hydroxyurea will be characterized by description of 
white blood cell counts, hemoglobin, hematocrit, mean corpuscular volume, platelet 
count, absolute neutrophil count, absolute reticulocyte count, and fetal hemoglobin 
concentrations. The clinical complications observed in participants will be 
characterized by description of sickle cell related events as described in Appendix III. 
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12.2.4. Obtain pilot data on health related quality of life in children with 
SCA treated with a low-fixed dose and at MTD. 
 
For quality of life (QOL), the measurements will be scored on a 0–100 nominal scale, 
with 0 the worst and 100 the best composite outcome score. Changes in QOL scores 
from baseline to study exit will be summarized for each treatment arm using 
descriptive statistics including mean, SD, median and range and will be compared 
between two treatment groups by the exact Wilcoxon -Mann–Whitney test. The 
subscores for each domain, including physical, emotional, social and school 
functioning will be analyzed as well using the same methods. Because PedsQL 4.0, the 
instrument for QOL assessment, contains two components of child self-report and 
parent proxy-report, it is expected that for young patients who cannot fill their self-
report, we will have the parent proxy-report data only. The analyses for the two 
components will be separated using the same methods.  
 
12.3. Anticipated Completion Dates 
 
Anticipated Primary Completion Date: Aug 31, 2020 
Anticipated Study Completion Date: Aug 31, 2021
 
13.0 OBTAINING INFORMED CONSENT 
 
13.1. Informed Consent Prior to Research Interventions  
 
This trial will be designed and implemented with great concern for the welfare of 
subjects. Subjects will be recruited from all participating centers by local clinical staff. 
Because this study will involve the participation of minors, the child's guardian will be 
approached during regular clinic visits and invited to have his/her child participate in the 
HUGKISS pilot study. Approach during hospitalization will be avoided due to the 
vulnerability and stress associated with hospital admissions. If a child is eligible, the 
family will be informed about the study, and detailed information about the trial will be 
given, including the risks and benefits of study participation. An informed consent 
session will take place in which patients and guardians will have the opportunity to ask 
questions regarding participation in the study, and to learn the risks and benefits of 
participation. After detailed discussion of the protocol, they will be given a copy of the 
informed consent document for review. Participation will be completely voluntary and 
parents may withdraw their child from the study at any time. Families will receive no 
payment for participation in the study other than the costs of medical care performed as 
part of the study and modest reimbursement for parking, food, and travel, so there will 
be no undue financial incentive for participation. Subjects and families will be informed 
of any information that becomes available during the trial that might impact their 
continued participation. 
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13.2. Consent at Age of Majority 
 
Not applicable due to study participant’s age and the planned duration of the study. 
 
13.3. Consent When English is Not the Primary Language 
 
When English is not the patient, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter. This 
information will be documented in the participant’s medical record. Either a certified 
interpreter or the telephone interpreter’s service will be used to translate the consent 
information. The process for obtaining an interpreter and for the appropriate use of an 
interpreter is outlined on the Interpreter Services, OHSP, and CPDMO websites. 
 
13.4. Collection of Collaborating Institution Consent Forms 
 Signed collaborating institution’s consent forms will be scanned and emailed to the 
Central 
Protocol 
And 
Data 
Monitoring 
Office 
(CPDMO): 
Eligibilitycoordinators@stjude.org
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sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 
2011;377:1663-72. 
2.
Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell 
anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, 
and interventions. PLoS medicine 2013;10:e1001484. 
3.
Serjeant GR. The natural history of sickle cell disease. Cold Spring Harbor perspectives 
in medicine 2013;3:a011783. 
4.
Odenheimer DJ, Whitten CF, Rucknagel DL, Sarnaik SA, Sing CF. Heterogeneity of 
sickle-cell anemia based on a profile of hematological variables. American journal of human 
genetics 1983;35:1224-40. 
5.
Stevens MC, Hayes RJ, Vaidya S, Serjeant GR. Fetal hemoglobin and clinical severity of 
homozygous sickle cell disease in early childhood. The Journal of pediatrics 1981;98:37-41. 
6.
Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W. Mortality in children and 
adolescents with sickle cell disease. Cooperative Study of Sickle Cell Disease. Pediatrics 
1989;84:500-8. 
7.
Sunshine HR, Hofrichter J, Eaton WA. Gelation of sickle cell hemoglobin in mixtures 
with normal adult and fetal hemoglobins. Journal of molecular biology 1979;133:435-67. 
8.
Elford HL. Effect of hydroxyurea on ribonucleotide reductase. Biochemical and 
biophysical research communications 1968;33:129-35. 
9.
Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea 
enhances fetal hemoglobin production in sickle cell anemia. The Journal of clinical investigation 
1984;74:652-6. 
10.
Ferster A, Vermylen C, Cornu G, et al. Hydroxyurea for treatment of severe sickle cell 
anemia: a pediatric clinical trial. Blood 1996;88:1960-4. 
11.
Jayabose S, Tugal O, Sandoval C, et al. Clinical and hematologic effects of hydroxyurea 
in children with sickle cell anemia. The Journal of pediatrics 1996;129:55965. 
12.
Scott JP, Hillery CA, Brown ER, Misiewicz V, Labotka RJ. Hydroxyurea therapy in 
children severely affected with sickle cell disease. The Journal of pediatrics 1996;128:820-8. 
13.
Ferster A, Tahriri P, Vermylen C, et al. Five years of experience with hydroxyurea in 
children and young adults with sickle cell disease. Blood 2001;97:3628-32. 
14.
Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of 
hydroxcarbamide therapy on survival of children with sickle cell disease. British journal of 
haematology 2013;161:852-60. 
15.
Voskaridou E, Christoulas D, Bilalis A, et al. The effect of prolonged administration of 
hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 
17-year, single-center trial (LaSHS). Blood 2010;115:2354-63. 
16.
Zimmerman SA, Schultz WH, Davis JS, et al. Sustained long-term hematologic efficacy 
of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 
2004;103:2039-45. 
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17.
Kinney TR, Helms RW, O'Branski EE, et al. Safety of hydroxyurea in children with 
sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea 
Group. Blood 1999;94:1550-4. 
18.
Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F 
production in patients with sickle cell anemia. Blood 1992;79:2555-65. 
19.
Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, Ware RE. A two-year pilot trial of 
hydroxyurea in very young children with sickle-cell anemia. The Journal of pediatrics 
2001;139:790-6. 
20.
Thompson BW, Miller ST, Rogers ZR, et al. The pediatric hydroxyurea phase III clinical 
trial (BABY HUG): challenges of study design. Pediatric blood & cancer 2010;54:250-5. 
21.
Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell disease: a 
systematic review for efficacy and toxicity in children. Pediatrics 2008;122:1332-42. 
22.
Thornburg CD, Files BA, Luo Z, et al. Impact of hydroxyurea on clinical events in the 
BABY HUG trial. Blood 2012;120:4304-10; quiz 448. 
23.
Rana S, Houston PE, Wang WC, et al. Hydroxyurea and growth in young children with 
sickle cell disease. Pediatrics 2014;134:465-72. 
24.
Lederman HM, Connolly MA, Kalpatthi R, et al. Immunologic effects of hydroxyurea in 
sickle cell anemia. Pediatrics 2014;134:686-95. 
25.
McGann PT, Flanagan JM, Howard TA, et al. Genotoxicity associated with hydroxyurea 
exposure in infants with sickle cell anemia: results from the BABY-HUG Phase III Clinical 
Trial. Pediatric blood & cancer 2012;59:254-7. 
26.
Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function 
parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants 
with sickle cell anemia. Pediatric blood & cancer 2012;59:668-74. 
27.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk 
factors. The New England journal of medicine 1991;325:11-6. 
28.
Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal 
hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984;63:921-6. 
29.
Estepp JH, Smeltzer MP, Kang G, Aygun B, Ware RE, Nottage K. Higher Fetal 
Hemoglobin Following Escalation of Hydroxyurea to Maximum Tolerated Dose Provides 
Clinical Benefit to Children with Sickle Cell Anemia.  56th Annual American Society of 
Hematology Meeting. San Francisco, CA2014. 
30.
Estepp JH, Melloni C, Thornburg CD, et al. Pharmacokinetics and bioequivalence of a 
liquid formulation of hydroxyurea in children with sickle cell anemia. Journal of clinical 
pharmacology 2016;56:298-306. 
31.
Ware RE, Aygun B. Advances in the use of hydroxyurea. Hematology / the Education 
Program of the American Society of Hematology American Society of Hematology Education 
Program 2009:62-9. 
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Hankins JS, Ware RE, Rogers ZR, et al. Long-term hydroxyurea therapy for infants with 
sickle cell anemia: the HUSOFT extension study. Blood 2005;106:2269-75. 
33.
Brown AK, Sleeper LA, Miller ST, Pegelow CH, Gill FM, Waclawiw MA. Reference 
values and hematologic changes from birth to 5 years in patients with sickle cell disease. 
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1994;148:796-804. 
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Ngo DA, Aygun B, Akinsheye I, et al. Fetal haemoglobin levels and haematological 
characteristics of compound heterozygotes for haemoglobin S and deletional hereditary 
persistence of fetal haemoglobin. British journal of haematology 2012;156:259-64. 
35.
Jain DL, Apte M, Colah R, et al. Efficacy of fixed low dose hydroxyurea in Indian 
children with sickle cell anemia: a single centre experience. Indian pediatrics 2013;50:92933. 
36.
Patel DK, Mashon RS, Patel S, Das BS, Purohit P, Bishwal SC. Low dose hydroxyurea is 
effective in reducing the incidence of painful crisis and frequency of blood transfusion in sickle 
cell anemia patients from eastern India. Hemoglobin 2012;36:409-20. 
37.
Strouse JJ. Is low dose hydroxyurea the solution to the global epidemic of sickle cell 
disease? Pediatric blood & cancer 2015;62:929-30. 
38.
Sharef SW, Al-Hajri M, Beshlawi I, et al. Optimizing Hydroxyurea use in children with 
sickle cell disease: low dose regimen is effective. European journal of haematology 
2013;90:519-24. 
39.
Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: 
summary of the 2014 evidence-based report by expert panel members. Jama 2014;312:1033-48. 
40.
Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatric 
clinics of North America 2008;55:483-501, x. 
41.
Heeney MM, Whorton MR, Howard TA, Johnson CA, Ware RE. Chemical and 
functional analysis of hydroxyurea oral solutions. Journal of pediatric hematology/oncology 
2004;26:179-84. 
42.
Knatterud GL, Rockhold FW, George SL, et al. Guidelines for quality assurance in 
multicenter trials: a position paper. Controlled clinical trials 1998;19:477-93. 
43.
Prentice RL, Kalbfleisch JD, Peterson AV, Jr., Flournoy N, Farewell VT, Breslow NE. 
The analysis of failure times in the presence of competing risks. Biometrics 1978;34:541-54. 
44.
Diggle P, Heagerty P, Liang KY, Zeger S. Analysis of Longitudinal Data. Second ed. 
Oxford, United Kingdom: Oxford University Press; 2002. 
 
 
 
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APPENDIX I: SCHEDULE OF EVALUATIONS 
   
ES1 
BE 
Weeks 
Exit 
               Event 
-4 to 0 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52-56 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, height & vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History, physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hydroxyurea initiation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with WBC count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP5 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Lactate Dehydrogenase 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Hemoglobin identification 
X2 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Urinalysis 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
TCD examination3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Quality of life assessment4 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
MAM6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
*Ideal visits are every 4 weeks ±2 weeks except for ES and BE. ES, eligibility screening; BE, baseline evaluation which should be 
performed prior to initiation of hydroxyurea. 1Eligibility screening may be performed the same time as baseline evaluations. 2A new 
hemoglobin identification only needs to be performed at eligibility screening if a previous result is not already available in the subject’s 
medical record. 3To be performed on participants ≥2 years of age. 4Age appropriate screening tool. 5CMP, Comprehensive Metabolic 
Panel, Chemistries include: Sodium, Potassium, Chloride, CO2, Glucose, BUN, Creatinine, Calcium, Albumin, Bilirubin Total, Alk, 
Phos, ALT, AST, Protein Total. 6MAM, Medication Adherence Measurement.
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APPENDIX II: RESEARCH TESTS 
 
Research Test 
Time Points 
Hemoglobin identification 
All 
Quality of life assessment 
All 
MAM 
All 
Study Drug Accountability 
All 
 
 
 
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APPENDIX III: CLINICAL EVENT DEFINITION 
 
Introduction 
In HUG KISS, clinical event definitions will be applied for consistency with other important 
NHLBI-sponsored clinical studies of sickle cell anemia such as the Clinical Study of Sickle Cell 
Disease (CSSCD), the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), and 
BABY HUG. 
 
Definitions 
 
Anemia: A reduction of hemoglobin level by at least 30% from the steady-state level OR a 
reduction by at least 20% accompanied by an acute increase in spleen size. Acute anemic events 
should be classified into one of the following categories. 
 
1. Splenic sequestration crisis: The event is characterized by an increase in spleen size 
and firmness, reduction of hemoglobin level by at least 20% and may include drop in 
platelet or white counts. Splenic sequestration is defined in HUG KISS by the findings 
of a palpable, large spleen with hemoglobin less than 5 gm/dL for nonfatal 
occurrences. 
 
2. Aplastic Crisis: This event is characterized by a substantial decrease in reticulocyte 
count to below 1.5 % before or concurrent with a reduction in hemoglobin level to a 
level greater than 30% below the steady-state level. Characteristically results from 
acute infection with parvovirus B19. Check the patient’s parvovirus IgM titer; usually 
it should be positive. 
 
3. Other anemia: Reduction of hemoglobin because of blood loss, transfusion reaction or 
hyper-hemolysis will be classified as another anemia. A hyper-hemolytic episode is 
characterized by normal or increased reticulocyte counts and nucleated red cell count 
during an episode of falling hemoglobin associated with an increase in indirect 
bilirubin level over the usual value. The latter finding is important to allow 
discrimination from a recovering aplastic crisis. 
 
Aplastic Crisis: See Anemia. 
 
Arthritis (septic): See Infection (other). 
 
Aseptic Necrosis: Presentation in the age range of patients in BABY HUG would be unusual. 
Patients encounter pain in their hip or shoulder, often of a different character than their usual 
crisis pain. The pain persists indefinitely, long after the expected duration of crisis pain. Early 
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radiographic findings are subepiphyseal lucency and widening of the joint space. Late changes 
include flattening of the epiphysis and sclerosis with fragmentation. 
 
Bacteremia: Febrile illness with blood culture positive for bacteria. Organism must be specified. 
 
Cerebrovascular Accident (CVA): Acute neurologic syndrome secondary to occlusion of an 
artery or hemorrhage with resultant ischemic and neurologic symptoms and signs. 
 
1. Stroke, hemorrhagic: Injury to brain tissue resulting from disturbance of blood supply 
to the brain due to hemorrhage. The area of the hemorrhage should also be reported 
(e.g., subarachnoid, subdural, intracerebral, aneurysm). 
2. Stroke, infarctive: Injury to brain tissue consistent with occlusion of vessel(s) by 
thrombus or embolus which results in neurologic abnormalities on physical 
examination that persist beyond 24 hours. 
3. Transient Ischemic Attack (TIA): Temporary interference with blood supply to the 
brain. The symptoms include neurologic signs that clear within 24 hours (48 hours if 
basilar system is involved). After the attack, no evidence of residual neurologic 
damage remains on physical examination. 
 
Chest Syndrome: Also known as acute chest syndrome (ACS). A clinical syndrome that 
includes at least 3 of the following symptoms: chest pain, temperature elevation over 
38.5oC/101.5oF, tachypnea, wheezing or cough. A new pulmonary infiltrate must be present on 
x-ray involving at least one complete lung segment to be consistent with alveolar consolidation 
instead of atelectasis. 
 
Cholangitis: See Right Upper Quadrant Syndrome 
 
Cholecystitis: See Right Upper Quadrant Syndrome 
 
Cholelithiasis: See Right Upper Quadrant Syndrome 
 
Dactylitis: Pain and tenderness with or without swelling in hands and/or feet. Also known as 
Handfoot syndrome. 
 
Fever without Focus: Elevation of temperature greater than 38.5oC/101.5oF (regardless of route, 
oral, axillary or rectal) not associated with a positive culture from any source or with any other 
special event. Will be characterized as an event managed with blood culture (no growth) and 
empiric parenteral antibiotics or by parental history (no blood culture, no empirical parenteral 
antibiotics). 
 
Hematuria: Blood in the urine (greater than 5 red blood cells per high power field), usually 
suggested by history, confirmed by urinalysis. 
 
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Hepatitis: See Right Upper Quadrant Syndrome 
 
Infection (other): Inflammation, caused by a pathogenic agent, which may or may not be 
accompanied by a fever. Sepsis, meningitis, osteomyelitis, hepatitis and urinary tract infections 
are NOT INCLUDED in this category since they are categorized elsewhere. If encountered, the 
type of infection, site, and organism if known should be specified. 
 
1. Abscess/Cellulitis: Infection of skin or deeper tissues. 
2. Gastroenteritis: Inflammation of the stomach and intestinal tract. Signs include 
nausea, vomiting and diarrhea lasting at least 8 hours. 
3. Lymphadenitis/Lymphangitis: Infection in regional lymph nodes or channels 
draining the primary site of infection. 
4. Mastoiditis: Infection of the mastoid bone. 
5. Orbital Cellulitis: Infection of the orbit and tissues posterior to the eye. 
6. Otitis Media: Infection of the middle ear associated with ear pain and erythema of 
eardrum, bulging or decreased mobility of eardrum with loss of landmarks. 
7. Periorbital or Preseptal Cellulitis: Infection of the eyelids causing erythema and 
swelling. 
8. Pharyngitis: Pain in the pharynx associated with redness of pharyngeal and tonsillar 
mucosa with or without exudates. Indicate if streptococcal culture positive. 
9. Septic Arthritis: Bacterial infection of a joint. The causative agent should be listed if 
known. 
10. Upper Respiratory Infections (URI): An imprecise term for almost any kind of 
infectious process involving the nasal passages, pharynx and bronchi. Often called a 
“cold.” 
11. Varicella Infection: Clinical syndrome of skin lesions, fever associated with varicella 
zoster virus infection. 
 
Liver Sequestration: See Right Upper Quadrant Event 5. Liver Sequestration. 
 
Mastoiditis: See Infection (other). 
 
Meningitis: Inflammation of the membranes of the spinal cord or brain usually caused by and 
infectious agent, as demonstrated by lumbar puncture abnormalities and culture. The causative 
agent should be listed if known. 
 
Orbital Cellulitis: See infection (other). 
 
Osteomyelitis: Bacterial infection of bone requiring long-term antibiotics. The causative agent 
should be listed if known. 
 
Other Event Not Specified: Includes any event that is not included in the list of the events 
specified on this form. 
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Painful events: Pain in the extremities, back, abdomen, chest or head for which no other 
explanation can be found and which is not classified as one of the other special events. The pain 
shall have lasted for at least 2 hours and for which medication either narcotic or non-steroidal, 
antiflammatory agent is taken. In a young child, pain or tenderness on palpation will be 
considered appropriate evidence of event. 
 
Pancreatitis: See Right Upper Quadrant Event 6. Pancreatitis. 
 
Pneumonia: See Chest Syndrome. 
 
Priapism: A painful erection of the penis lasting for more than 2 hours. 
 
Proteinuria: Presence of 1+ protein or more on urinalysis. 
 
Renal Complications (not specified): A renal condition not categorized as hematuria, urinary 
tract infection, proteinuria or renal insufficiency. The type of complication should be sought and 
specified. 
 
Renal Insufficiency: At least a two-fold increase in serum creatinine to a level greater than or 
equal to 1.0 mg/dl. 
 
Right Upper Quadrant (RUQ) Event: Defined as any two of the following; pain only in the 
right upper quadrant of the abdomen, twofold increase in total bilirubin over baseline to a level 
exceeding the upper limit of normal, two centimeter increase in liver size over baseline or 
twofold increase in ALT over baseline to a level exceeding the upper limit of normal. 
1. Cholangitis: Inflammation of the bile ducts. Diagnosis is usually made by abdominal 
ultrasound. 
2. Cholecystitis: Inflammatory condition of the gallbladder causing RUQ pain that may 
or may not be associated with gallstones. Diagnosis is usually made by abdominal 
ultrasound. 
3. Cholelithiasis: Formation or presence of calculi or bile stones in the gallbladder or 
common bile duct, with minimal or no symptoms. 
4. Hepatitis: An inflammation of the liver. The causative agent if known, should be 
specified. 
5. Liver Sequestration/Intrahepatic Sequestration: Jaundice and pain in the liver not 
due to gallstones. May include intrahepatic sickling crisis. 
6. Pancreatitis: Inflammation of the pancreas. May be related to medication, infection or 
gallstone blockage of the Ampulla of Vater. 
 
Seizure: A paroxysmal disorder of cerebral function characterized by sudden, transient attack of 
altered consciousness, motor activity or sensory phenomena. The type of seizure (e.g., petit mal, 
psychomotor, grand mal) and etiology if known should be specified. 
 
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Sepsis: Severe febrile illness with unstable vital signs or shock associated with positive blood 
culture. Organism must be specified. Positive blood culture in stable patients reported as 
bacteremia. 
 
Splenic Sequestration: See anemia. 
 
Splenomegaly: without acute sequestration: Spleen is palpable in abdomen with stable 
hemoglobin (within 1 gm/dl of baseline), and platelet counts > 100,000/cu mm. 
 
Surgery: Any operative procedure will be listed. 
 
Transient Ischemic Attack (TIA): See Cerebrovascular Accident (CVA). 
 
Transfusion: The provision of red blood cells to correct anemia. The reason for the transfusion 
should also be specified. Simple or Exchange transfusion should be specified. 
 
Upper Respiratory Infection (URI): See Infection (other). 
 
Urinary Tract Infection: A clinical event which may or may not be associated with fever and 
symptoms which is associated with a positive urine culture. 
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