REALIZING EFFECTIVENESS ACROSS CONTINENTS WITH HYDROXYUREA (REACH): A PHASE I/II PILOT STUDY OF HYDROXYUREA FOR CHILDREN WITH SICKLE CELL ANEMIA
Phase: PHASE1
Conditions: Sickle Cell Disease
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 
 
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REALIZING EFFECTIVENESS ACROSS CONTINENTS WITH 
HYDROXYUREA (REACH):  A PHASE I/II PILOT STUDY OF 
HYDROXYUREA FOR CHILDREN WITH SICKLE CELL ANEMIA 
 
 
Principal Investigator: 
Russell E. Ware, MD, PhD 
 
 
 
 
Marjory Johnson Chair of Hematology Translational Research 
 
 
 
 
Professor of Pediatrics 
 
 
 
 
Director, Division of Hematology 
 
 
 
 
Associate Director, Global Health Center 
 
 
 
 
Cincinnati Children’s Hospital Medical Center 
 
 
 
 
Cincinnati, Ohio, USA 
 
 
Co-Investigators: 
 
Banu Aygun, MD 
(alphabetical order)  
Director, Pediatric Sickle Cell Program 
 
 
 
 
Division of Pediatric Hematology/Oncology 
Associate Professor of Pediatrics 
 
 
 
 
Cohen Medical Center, New York, NY 
 
Patrick T. McGann, MD 
 
 
 
 
Assistant Professor of Pediatrics 
Division of Hematology 
Cincinnati Children’s Hospital Medical Center 
Cincinnati, Ohio, USA 
 
Peter Olupot-Olupot, MB ChB, MPH 
Scientist, Mbale Regional Referral Hospital 
Busitema University Faculty of Health Sciences 
Mbale, Uganda 
 
Brigida Santos, MD 
Specialist in Pediatrics 
Director, Sickle Cell Clinic 
Hospital Pediátrico David Bernardino 
 
 
 
 
 
Leon Tshilolo, MD PhD 
 
 
 
 
Director, Pediatric Sickle Cell Program 
Centre Hospitalier Monkole 
Kinshasa, Democratic Republic of Congo (DR Congo, DRC) 
 
 
George Tomlinson, MSc, PhD  
Scientist, Department of Medicine 
 
 
 
 
Associate Professor of Biostatistics 
Institute of Health Policy, Management, and Evaluation 
Dalla Lana School of Public Health 
 
 
 
 
University of Toronto, Toronto Ontario, Canada 
 

 
 
 
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Thomas N. Williams, MBBS DCH DTM&H MRCP PhD 
Professor of Heamoglobinopathy Research, Imperial College 
London 
Honorary Consultant Paediatrician, Imperial College London 
and KEMRI/Wellcome Trust Research Programme 
Kilifi, Kenya 
 
 
Clinical Sites: 
1. 
Luanda, Angola 
Hospital Pediátrico David Bernardino 
 
 
 
 
 
2. 
Kilifi, Kenya 
Kilifi District Hospital, KEMRI 
 
 
 
 
 
3. 
Kinshasa, Democratic Republic of Congo (DRC) 
Centre Hospitalier Monkole (Monkole Hospital) 
 
 
 
 
 
4. 
Mbale, Uganda 
 
 
 
 
 
Mbale Regional Referral Hospital 
 
Medical Coordinating Center: 
Cincinnati Children’s Hospital Medical Center 
 
Cincinnati Ohio, USA 
 
Data Management Center:  
Cincinnati Children’s Hospital Medical Center,   
 
 
 
 
 
Cincinnati, Ohio, USA 
 
Central Pharmacy Support: 
Cincinnati Children’s Hospital Medical Center 
 
 
 
 
 
Cincinnati Ohio, USA 
 
Study Consultants:  
 
Banu Aygun, MD (Hydroxyurea) 
(co-Investigators) 
 
 
George Tomlinson, MSc PhD (Biostatistics) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
 
                                           
 
SYNOPSIS......................................………………………………...…  5 
 
 
 1.0    INTRODUCTION.................................………………………………..  6 
 
1.1 
Background and Rationale.......................…….……………..  6 
1.2   Hydroxyurea Therapy for SCA……………………………….  7 
1.3   
Hydroxyurea in Developing Countries:  The Knowledge Gap...  7 
1.4 
Potential Clinical Sites…………………………………………….  8 
1.5 
Study Design..............................................……………………  9 
 
 2.0 
STUDY OBJECTIVES................................………………………….. 10 
 
 
 3.0 
PATIENT SELECTION AND ENROLLMENT............................…… 10 
 
3.1 
Inclusion Criteria..........................……………………………… 10 
 
3.2 
Exclusion Criteria..........................................………………… 11 
 
3.3 
Enrollment Procedures.......................................……………. 11 
 
 4.0 
STUDY TREATMENT................................………………………….. 12 
 
4.1 
Dosing Regimens.........................………………………......... 12 
 
4.2 
Drug Regimens, Formulation and Administration.................. 14 
4.3 
Toxicity Management ……….………………………………….   14 
 
4.4 
Procedures for Treatment Discontinuation…………………… 15 
 
4.5 
Adverse Experience Reporting Requirements................…… 15 
 
4.6 
Concurrent Medications.................................….…………..… 18 
 
4.7 
Investigational Agents......................................………………. 19 
 
 
 
 5.0 
CLINICAL AND LABORATORY EVALUATIONS............................. 19 
 
5.1   Pre-treatment Evaluations..............................……………..… 19 
 
5.2   Hydroxyurea Initiation, Month 0................................……….. 20 
 
5.3   Study Months 1-48…....................................……….………... 20 
 
5.4   Pharmacokinetics, Pharmacodynamics, Pharmacogenomics 28 
5.5 
Discontinuation of Study Drug..............................…………… 29 
 
5.6 
Lower of Drug Dose due to Excess Toxicities……………….. 29 
 
5.7 
Data Management Issues……………………………………… 30 
 
6.0 
EVALUATION OF EFFECTS...................................………………… 31 
 
6.1   Safety Endpoints………........................………………………. 31 
 
6.2   Feasibility Endpoints……………..............……….……………. 31 
 
6.3 
Efficacy Endpoints………………………………………………. 31 
 
 7.0 
STATISTICAL CONSIDERATIONS.....................................……….. 32 
 
7.1 
Sample Size…..................................…………………………. 32 
 
7.2 
Patient Recruitment and Retention…………………………… 34 
 
7.3 
Expected Drop-out Rate.....………………………………...….. 35 
 
7.4 
Planned Statistical Analyses…………………………………… 35 
 
 
 
 
 
 
                                          
 8.0 
HUMAN SUBJECTS.........................................…..…………………. 35 

 
 
 
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8.1 
Institutional Review Board (IRB) and Informed Consent ....... 35 
 
8.2 
Confidentiality.....................................…………………………. 35 
      
8.3 
Study Discontinuation.......................................………………. 36 
 
 9.0 
DATA AND SAFETY MONITORING BOARD……………………….. 36 
 
9.1 
Rationale…………………………………………………………. 36 
 
9.2 
Composition……………………………………………………… 36 
 
10.0 ORGANIZATIONAL STRUCTURE…………………………………….. 36 
 
11.0 PUBLICATION OF RESEARCH FINDINGS......................………….. 39 
 
12.0 REFERENCES................................………………………………….... 40 
 
 
APPENDICES 
I. 
WHO WEIGHT-FOR-HEIGHT GROWTH CURVES……………. 43 
II. 
SCHEDULE OF EVALUATIONS …………………………………. 49 

 
 
 
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REALIZING EFFECTIVENESS ACROSS CONTINENTS WITH 
HYDROXYUREA (REACH):  A PHASE I/II PILOT STUDY OF 
HYDROXYUREA FOR CHILDREN WITH SICKLE CELL ANEMIA 
 
OBJECTIVES: 
 
 To assess the feasibility of conducting a prospective research study using 
hydroxyurea therapy for SCA in sub-Saharan Africa (including adherence to monthly 
clinic visits and laboratory assessments, and medication compliance). 
 
 To monitor the safety of hydroxyurea therapy, specifically documenting 
hematological toxicities (cytopenias) and serious infections (bacterial and malarial) 
 
 To evaluate the benefits of hydroxyurea therapy, using both laboratory (e.g., fetal 
hemoglobin, hemoglobin, white blood cell count) and clinical parameters (e.g., pain, 
hospitalization, growth). 
 
 To explore the pharmacokinetic and genetic basis for any observed inter-patient 
variability in the clinical or laboratory response to hydroxyurea. 
 
 To evaluate the economic cost of providing hydroxyurea therapy in the REACH 
study sites. 
 
 
To investigate the effects of hydroxyurea dose escalation on laboratory and clinical 
parameters  
 
 
DESIGN: 
Prospective phase I/II open-label dose escalation pilot trial of oral 
hydroxyurea for pediatric patients with sickle cell anemia (SCA) 
 
POPULATION: 
Children with confirmed SCA between 1.0 and 10.0 years of age at 
the time of enrollment 
 
SAMPLE SIZE:  
Approximately 150 per study site 
4 clinical sites 
 
TREATMENT: 
After patient enrollment, a two-month pre-hydroxyurea evaluation 
phase will be used to perform baseline evaluations including 
nutritional and infectious assessments, and to provide supplements 
or treatments as deemed necessary.  After the pre-hydroxyurea 
evaluation and supplementation phase, hydroxyurea dosing will be 
administered as a single daily dose, using capsules provided as a 
monthly supply in 200mg, 300mg, 400mg, or 500mg sizes. 
 
DURATION: 
Six months of hydroxyurea treatment will be given at a fixed dose of 
15-20 (17.5 ± 2.5) mg/kg/day, followed by another six months of 
treatment with dose escalation as tolerated to 20-30 mg/kg/day to 
establish a maximum tolerated dose (MTD).  After twelve months of 
hydroxyurea treatment, children with an acceptable toxicity profile 
and favorable hematological responses will be given the opportunity 
to continue hydroxyurea therapy, through 18-years-old pending 
biennial review of BMS support. 

 
 
 
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1.0 
INTRODUCTION   
 
 
1.1   Background and Rationale 
 
Sickle cell anemia (SCA) is among the world's most common forms of inherited 
hemolytic anemia, and results in significant morbidity and early mortality.  SCA is most 
prevalent in Africa, with as many as 300,000 babies born annually, representing up to 
2% of newborns in some sub-Saharan countries. [1,2]  Assuming most of these 
babies die early in childhood, the World Health Organization (WHO) estimates that 
SCA causes 6-16% of under-five mortality for many African countries, [3] and this 
burden is projected to further increase substantially in the next 40 years. [4] This 
alarmingly high contribution of SCA to under-five mortality makes the recognition and 
management of SCA an important cornerstone of efforts by many African countries 
toward achieving Millennium Development Goal #4, the reduction of child mortality. [5] 
Since deaths due to SCA mostly occur in children under 5 years old, efforts to save 
lives must include early diagnosis and treatment.  In addition to early death, SCA 
also causes profound adverse effects among surviving children on their education 
and future employment with resultant loss of productivity.  As the overall mortality 
declines in the region due to demographic transition, along with the expansion of 
vaccine and malaria control programs, the economic and health burden of non-
communicable diseases such as SCA will undoubtedly increase proportionately 
and consume significant medical and social resources in Africa [2,4]. 
 
In the US and Europe, each of which contributes only about 1% of the global annual 
sickle cell births, SCA is a medical condition with recognized impact upon both the 
quality and length of affected lives.  However, due to effective early identification with 
newborn screening, aggressive early interventions with pneumococcal immunizations 
and prophylactic penicillin, and now with availability of hydroxyurea therapy, the 
morbidity and mortality associated with SCA in developed countries have dramatically 
improved with 95-99% survival to adulthood. [6] This is not the case in the global 
setting, however, where the demand for impactful intervention for individuals with 
SCA is long overdue.  Without any identification by newborn screening or early 
interventions, the vast majority of these children will die from acute anemia or 
infection, especially bacterial sepsis or malaria. [1, 7-12] 
 
WHO has recently recognized SCA as a significant health problem for Africa and 
recommends that sub-Saharan countries develop screening and treatment programs 
for SCA. [3] With the development and implementation of newborn screening and 
treatment programs, the early mortality of SCA is likely to be significantly reduced; 
however, these interventions will not treat or cure the underlying disease.  Increased 
identification of SCA from public awareness and widespread screening efforts are 
likely to increase the perceived morbidity and burden of SCA in these countries, with 
many more children identified by screening, surviving early childhood, and suffering 
from its medical complications.  Accordingly, the introduction of hydroxyurea, as a 
once-daily inexpensive oral medication with a well-established short-term safety 
profile, is an intriguing and potentially ideal option for affected patients with SCA in 
the developing world, since access and safety of other potential therapeutic options, 
primarily transfusions or stem cell transplantation, are currently not realistic options. [13] 

 
 
 
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1.2   Hydroxyurea Therapy for SCA 
 
Hydroxyurea is a cytotoxic, antimetabolic, and antineoplastic agent used for several 
decades to treat a variety of medical disorders, most notably myeloproliferative 
neoplasms, [14] chronic myelogenous leukemia, [15] and HIV. [16] The efficacy of 
hydroxyurea for these varied medical conditions is due to its mechanism of action as 
a potent inhibitor of ribonucleotide reductase, [17] a ubiquitous intracellular enzyme 
that converts ribonucleotides to deoxyribonucleotides, which are required for DNA 
synthesis and repair.   
 
The first clinical application of hydroxyurea for patients with SCA was reported in 1984, 
when Platt and colleagues demonstrated a rapid and dramatic increase in HbF-
containing reticulocytes without significant bone marrow toxicity. [18]  This and other 
'proof-of-principle' experiments led to a critical phase I/II study of adults with SCA 
treated with hydroxyurea at maximum tolerated dose (MTD), which demonstrated 
significant dose-dependent increases in hemoglobin and HbF along with concurrent 
reduction in total white blood cell count, neutrophils, and reticulocytes. [19]  Similar 
results were observed in phase I/II studies involving school-age children, toddlers, and 
infants, all documenting the safety, laboratory benefits, and clinical efficacy of 
hydroxyurea for young patients with SCA. [20,21]   A pivotal Phase III trial of adults 
with SCA, using a randomized, double-blinded, placebo-controlled study design, 
proved the clinical efficacy of hydroxyurea for reduction of vaso-occlusive pain, acute 
chest syndrome, transfusions, and hospitalizations. [22] 
 
The phase III study of hydroxyurea in infants (BABY HUG) has recently been 
completed; although equivocal benefits for organ protection were observed during the 
2-year treatment period, significant laboratory efficacy and clear clinical benefits for 
reducing pain, acute chest syndrome, hospitalizations, and transfusions were 
demonstrated. [23] Three reports have documented the benefits of hydroxyurea on 
reducing mortality in SCA:  two adult trials [24,25] and one pediatric study. [26] 
Taken together, accumulated evidence over 25-30 years documents the short-term 
and long-term safety and efficacy of hydroxyurea for children and adults with SCA. 
 
1.3  
Hydroxyurea in Developing Countries:  The Knowledge Gap 
 
Hydroxyurea is a once-daily oral medication with excellent bioavailability but 
variable pharmacokinetics and pharmacodynamics. [27] Hydroxyurea has a 
cytotoxic and myelosuppressive effect upon the bone marrow due to its mechanism of 
action as a potent inhibitor of the enzyme ribonucleotide reductase, [17] and this effect 
results in mild and predictable cytopenias. [28] These cytopenias are expected 
and can be used to determine the maximum tolerated dose (MTD).  In developed 
countries, these mild reductions are observed primarily in the white blood cell 
(WBC) count, absolute neutrophil count (ANC), absolute reticulocyte count (ARC), 
and platelet count but have not resulted in any significant clinical toxicities. [28,29]  
However, hydroxyurea has not yet been used systematically as a disease-modifying 
therapy in Africa for the treatment of SCA, and it is unknown whether the significant 
infectious and nutritional comorbidities in sub-Saharan African children will 
exacerbate the marrow-toxic effects of hydroxyurea. 

 
 
 
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Currently there is limited and only sporadic use of hydroxyurea for SCA within Africa.  
No treatment consensus guidelines have been established, and no prospective 
clinical trials have been performed.  It is critical to conduct properly designed clinical 
research on this topic, to prevent improper and potentially dangerous use.  The 
REACH protocol was presented in concept at the 1st Global Congress on Sickle Cell 
Disease (Accra, Ghana in June 2010) and more specifically at REDAC consortium 
meetings (Dar es Salaam, Tanzania, June 2012 and Yaounde, Cameroon, June 
2013); the response was extremely positive at all 3 meetings where attendees 
appreciated the importance of conducting clinical trials with hydroxyurea, before its 
use becomes more widespread without appropriate safety and efficacy data.  Even if 
short-term benefits were observed, the safety profile with long-term use throughout 
childhood is critical to investigate and document. 
 
The limited medical capacities of many countries in sub-Saharan Africa, coupled 
with the significant infectious and nutritional comorbidities of these populations will 
undoubtedly present substantial challenges for initiation and maintenance of 
hydroxyurea therapy.  The prohibitive cost of hydroxyurea for most patients also must 
be managed.  But with a carefully planned approach and local medical personnel 
willing to be trained and involved in the care of these children, hydroxyurea can be 
introduced into this highly burdened population via solid North-South research 
partnerships. [1,9]  If proven to have safety and efficacy for children with SCA in 
developing countries, hydroxyurea could realistically emerge as the main disease-
modifying therapeutic intervention to help reduce the global burden of SCA [30]. 
 
1.4   
Potential Clinical Sites 
 
The primary goal of this prospective research trial is to investigate the feasibility, 
safety, and benefits of hydroxyurea for children with SCA in sub-Saharan Africa, 
using a select group of clinical sites and investigators who will conduct high-quality 
research.  Through the Global Sickle Cell Disease Network, clinical programs in 
sub-Saharan Africa were invited in January 2013 to complete a survey requesting 
detailed information about their site, which focused on the issue of readiness to 
conduct high-quality clinical research.  The survey contained questions about the 
size and resources of the program, but also about research support, internet 
capability, investigational pharmacy, and many other research-related topics.  The 
REACH Principal Investigator and selected co-Investigators reviewed these survey 
responses to determine if adequate clinical, laboratory, pharmacy, and data 
management facilities and operations are in place.  
 
Based on 23 completed surveys, 6 sites across sub-Saharan Africa were identified 
with the best likelihood of conducting high-quality research that is required in the 
REACH protocol.  These six sites included the following locations:  Luanda, 
Angola; Dar es Salaam, Tanzania; Kampala, Uganda; Kinshasa, Democratic 
Republic of Congo; Accra, Ghana; and Kilifi, Kenya.  In each setting, the country 
and region has a known substantial burden of SCA, an experienced local clinical 
investigator who could lead the trial, and adequate local resources to conduct the 
trial. 
 

 
 
 
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A 90-minute teleconference was then held with each site leader, to ask specific 
questions about their level of interest and ability to conduct the REACH trial.  
Subsequent communication further documented the ability of individual sites to 
conduct the REACH trial.  Following this screening process, four clinical sites 
within sub-Saharan Africa (Luanda Angola, Kilifi Kenya, Kinshasa Democratic 
Republic of Congo, and Mbale Uganda) were identified as the initial clinical sites 
for the REACH study, based on investigator interest and site qualifications.  Other 
sites may become eligible, but at most 4 sites will be activated for study treatment.   
 
All four clinical sites were provided a draft version of the protocol and encouraged 
to make comments and edits.  Over the period of several months and frequent 
email and teleconference communication, several key changes were made in the 
study design including eligibility criteria, frequency of monitoring visits, and support 
for the participants.  This final protocol version represents a joint writing effort, and 
has been reviewed by all investigative teams and approved by all co-Investigators.  
 
1.5   
Study Design 
 
REACH is a prospective, phase I/II open-label dose escalation pilot trial of 
hydroxyurea for children with confirmed SCA between 12 months and 10 years of 
age.  The short-term goal is to obtain critical pilot data regarding the feasibility, 
safety, and benefits of hydroxyurea for children with SCA in multiple research 
settings in Africa.  Based on that information, the longer-term goal is to develop a 
safety and benefits profile associated with extended hydroxyurea use throughout 
childhood, and to make hydroxyurea more widely available for children with SCA in 
Africa, particularly those identified with SCA through expanded newborn screening 
programs. 
 
After enrollment, a two-month screening phase will be used to perform baseline 
evaluations including nutritional and infectious assessments, along with 
supplements and treatments as deemed necessary by local guidelines (e.g., 
penicillin, pneumococcal immunization, Vitamin A and albendazole/mebendazole 
treatment, malaria prophylaxis, and iron/folate supplementation).  Hydroxyurea 
capsules will then be provided as a monthly supply in 200mg, 300mg, 400mg or 
500mg sizes, to be administered as an open-label single daily dose.  Six months of 
treatment will be given at the fixed dose of 15-20 mg/kg/day, followed by another 
six months with dose escalation (2.5-5.0 mg/kg increments every 8 weeks) as 
tolerated to 20-30 mg/kg/day or MTD.  Interval history, physical examination, and 
blood counts will be conducted every month, until MTD.   
 
After completion of the first 12-months of hydroxyurea treatment, children with an 
acceptable toxicity profile and favorable responses will be given the opportunity to 
continue hydroxyurea therapy until reaching the age of 18 years pending biennial 
review of BMS support.  Data will be analyzed centrally using standardized data 
collection forms and a secure CTSA electronic database provided by Cincinnati 
Children’s Hospital Medical Center in Cincinnati, Ohio.   
 
REACH will be the first prospective study using hydroxyurea for children with SCA 
in Africa.  The importance of gathering critical pilot data regarding the feasibility, 

 
 
 
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safety, and efficacy of hydroxyurea in this setting is enormous; these data could 
lead to transformation of treatment practices for SCA across Africa.  
 
 
2.0 
STUDY OBJECTIVES 
 
2.1  
To assess the feasibility of conducting a prospective research study using 
hydroxyurea therapy for SCA in sub-Saharan Africa (including adherence to 
monthly clinic visits and laboratory assessments, and medication 
compliance). 
 
2.2 
To monitor the safety of hydroxyurea therapy, specifically documenting 
significant hematological toxicities (cytopenias) and infections. 
 
2.3 
To evaluate the benefits of hydroxyurea therapy, using both laboratory (e.g., 
fetal hemoglobin, hemoglobin, white blood cell count) and clinical 
parameters (e.g., pain, hospitalization, growth parameters). 
 
2.5 
To explore the pharmacokinetic and genetic basis for any observed inter-
patient variability in the clinical or laboratory response to hydroxyurea. 
 
2.6 
To evaluate the economic cost of providing hydroxyurea therapy in the 
REACH study sites. 
 
2.4 
To investigate the feasibility of hydroxyurea dose-escalation on laboratory 
and clinical parameters. 
 
 
 3.0 
PATIENT SELECTION AND ENROLLMENT 
 
3.1     Inclusion Criteria 
 
3.1.1 
Pediatric patients with documented sickle cell anemia (typically HbSS 
supported by hemoglobin electrophoresis, complete blood count, and 
peripheral blood smear) 
3.1.2 
Age range of 1.00-9.99 years, inclusive, at the time of enrollment 
3.1.3 
Weight at least 10.0 kg at the time of enrollment 
3.1.4 
Parent or guardian willing and able to provide written informed consent, 
with child's verbal assent as per local IRB/Ethics Board requirements 
3.1.5 
Willingness to comply with all study-related treatments, evaluations, 
and follow-up 
 
 
 

 
 
 
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3.2 
Exclusion Criteria 
3.2.1 
Known medical condition making participation ill-advised, (e.g., acute 
or chronic infectious disease, HIV, or malignancy) 
3.2.2 
Acute or chronic severe malnutrition determined by impaired growth 
parameters as defined by WHO (weight for length/height or height for 
age >3 z-scores below the median WHO growth standards, as 
defined in Appendix I) 
3.2.3 
Pre-existing severe hematological toxicity (temporary exclusions) 
a. 
Anemia:  Hb <4.0 gm/dL 
b. 
Anemia:  Hb <6.0 gm/dL with ARC <100 x 109/L 
c. 
Reticulocytopenia:  ARC <80 x 109/L with Hb <7.0 gm/dL 
d. 
Thrombocytopenia:  Platelets <80 x 109/L 
e. 
Neutropenia:  ANC <1.0 x 109/L 
3.2.4 
Blood transfusion within 60 days before enrollment (temporary 
exclusion) 
3.2.5 
Hydroxyurea use within 6 months before enrollment (temporary 
exclusion) 
 
3.3 
Enrollment Procedures 
 
3.3.1 
Patients will be recruited from the existing sickle cell populations at 
each clinical site. 
3.3.2 
Clinical staff will identify eligible participants and discuss the study 
with the patient and family.  
3.3.3 
The parent or legal guardian will provide written informed consent at 
the time of patient enrollment. 
3.3.4 
Enrolled patients will begin a 2-month evaluation phase with 
screening studies, before commencing hydroxyurea treatment; 
treatment will have a fixed dose phase (6-months), an escalation 
phase (6-months), and maintenance phase (until the participant 
reaches 18-years-old pending biennial review of BMS support). 
3.3.5 
Participants who do not complete the initial screening phase will not 
begin hydroxyurea, and will be exited from the study and replaced 
with new patients.   
3.3.6 
Participants who start hydroxyurea but do not complete the initial 3-
months of hydroxyurea treatment will be censored at the time of 
study exit, and then replaced with new patients, unless they already 
reached the primary safety endpoint.  These censored data will still 
be used for the primary safety analysis. 

 
 
 
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3.3.7 
Participants who complete at least 3-months of hydroxyurea 
treatment will not be replaced.  
3.3.8 
To ensure that at least 53 children have completed three months of 
hydroxyurea therapy for the first phase safety analysis, enrollment 
will be temporarily suspended after the first 60 participants are 
enrolled at each site, allowing for up to 12% participant drop-out or 
discontinuation of medication before restarting enrollment to the full 
150 patients.  
3.3.9 
Patient enrollment is expected to be completed within 24 months 
after initiation at each clinical site.  All participants will remain on 
study until reaching18-years-old pending biennial review of BMS 
support. 
 
4.0 
STUDY TREATMENT 
 
4.1 
Dosing Regimens  
 
Overview of Dosing and Duration of Treatment.  Eligibility Screening (ES) will 
occur at Month -2 and Month -1, followed by Baseline Evaluation (BE) and 
hydroxyurea initiation that occur together at Month 0.  Hydroxyurea treatment will 
commence at 15-20 mg/kg PO daily and continue at this fixed dose for 6 months (24 
weeks), with appropriate adjustments as needed for hematological toxicities as 
outlined below.  Participants will have clinic visits and laboratory assessments 
(according to Appendix II) every month (4 ± 1 weeks).  Six months of treatment will 
be given at the fixed dose of 15-20 mg/kg/day, followed by another six months with 
dose escalation (2.5-5.0 mg/kg increments every 8 weeks) as tolerated to 20-30 
mg/kg/day or MTD.  Interval history, physical examination, and blood counts will be 
conducted every month. 
 
Study treatment with hydroxyurea will continue in a dose escalation phase through 
the 12-month (Week 48) evaluation, after which hydroxyurea will continue in a 
maintenance phase until the end of study participation.  Whenever possible, an 
equivalent daily dose will be prescribed (i.e., the same mg of hydroxyurea will be given 
each day, rather than a variable daily dose throughout the week to give an average 
daily dose) using the hydroxyurea dosing calculator. 
 
Dose Initiation Plan for Study Months 0-6.  Using the participant’s weight at 
Month 0, the daily dose will be calculated using available capsule sizes and a goal of 
15-20 (17.5 ± 2.5) mg/kg/day using dosing calculator based on weight.  At each 4-
week interval visit, laboratory studies (Appendix II) will be used to assess treatment 
toxicity, typically anemia or neutropenia, but possibly also reticulocytopenia or 
thrombocytopenia.  The daily dose will be held or lowered as per treatment toxicity 
guidelines outlined below.  The daily dose will not be escalated until Month 6, thus 
representing 6 months of fixed dosage.  
 
Dose Escalation Plan to MTD for Study Months 6-12.  After 6 months of 
treatment, hydroxyurea will be titrated according to myelosuppression, and will be 

 
 
 
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increased to 20-30 mg/kg/day or the maximum tolerated dose (MTD) as defined by 
hematological toxicity, even if the participant has clinical improvement on lower doses. 
The target ANC on hydroxyurea therapy will be 2.0 - 4.0 x 109/L, which is similar to the 
goals of hydroxyurea in previous clinical trials, [23,24] but MTD may be based on the 
reticulocyte count.  Hydroxyurea dose escalation will occur in 5.0 ± 2.5 mg/kg/day 
increments, adjusting every 2 months unless hematological toxicity occurs.  Safety is 
paramount and so both toxicity and dose escalation thresholds have been established 
for REACH, based on previous clinical trials and experience using hydroxyurea.   
 
Dose-limiting hematological toxicity and dose escalation criteria are summarized in 
Table 1. For on-study hematological toxicity criteria, any single parameter qualifies as a 
toxicity threshold; these criteria constitute the primary safety endpoint.  For dose 
escalation criteria, all laboratory parameters should be within the ranges listed to allow 
hydroxyurea dose escalation.  Minor adjustments to the dosing schedule may be 
recommended based on an individual participant's clinical course or laboratory 
trends. 
 
 
 
Table 1.  Dose-Limiting Laboratory Toxicity Thresholds 
 
Toxicity 
Parameter 
Escalation 
Criteria 
Toxicity Criteria 
Neutropenia 
ANC* (x 109/L) 
>4.0 
<1.0 x 109/L 
Anemia 
Hb* (gm/dL) 
>6.5  
Hb < 4.0 gm/dL OR 
Hb <6.0 gm/dL unless 
ARC >100 x 109/L 
Reticulocytopenia 
ARC* (x 109/L) 
>150 
ARC <80 x 109/L 
unless Hb >7.0 gm/dL 
Thrombocytopenia 
Platelets (x 109/L) 
>150 
<80 x 109/L 
 
Table 1.  Laboratory toxicity thresholds and hydroxyurea dose escalation criteria for 
hemoglobin, reticulocytes, neutrophils, and platelets.  *ANC – absolute neutrophil 
count; Hb – Hemoglobin; ARC – Absolute reticulocyte count.  Hydroxyurea dose 
escalation criteria are relevant only to Months 6-12. 
 
Based on previous experience and published data from the US, [20,21,23,27-29,31] 
most pediatric patients require hydroxyurea doses of 20-30 mg/kg/day to reach the 
target myelosuppression.  After reaching MTD, minor dose adjustments will be made 
as necessary based on weight changes and blood counts, to maintain the desired 
laboratory effects.  Effects of hydroxyurea therapy (excessive myelosuppression; 
reticulocytopenia, severe anemia; thrombocytopenia; or drug noncompliance) will be 
collected at each visit.  Medication adherence will be stressed at each visit and 
attempts will be made to collect treatment compliance data. 

 
 
 
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Dose Maintenance Plan for Study Months 12 through End of Study.  After 
12 months of treatment, hydroxyurea will be offered in a maintenance phase to 
compliant participants at MTD. Children will be escalated during Month 6-12 to 
establish the MTD, but may require further adjustments after Month 12, based on 
weight and blood counts, to maintain dosing at the MTD.  Interval visits and 
laboratory monitoring will continue but at a less frequent interval, as outlined in the 
Schedule of Evaluations (Appendix II). 
  
 
4.2 
Drug Regimens, Formulation and Administration 
 
Packaging, Administration and Storage of Hydroxyurea.  Hydroxyurea will be 
provided by Bristol Myers Squibb (BMS) as capsules (200 mg, 300 mg, 400 mg, or 
500 mg).  The medication is stable at room temperature (20-30C) and does not 
require refrigeration.  These capsules have been demonstrated to be stable with 
mixing or crushing, with dissolution in a wide array of liquids for immediate use.  For 
example, for children incapable of swallowing capsules, the capsules can be opened 
daily and mixed with water or juice.  Medication will be stored in local pharmacy 
space and a 30-day supply of capsules will be dispensed to study participants with 
each monthly clinic visit until reaching MTD, and a 90-day supply will be dispensed 
after that time.  If a follow-up appointment needs to be scheduled more than 30 or 
60 days from the previous visit (for example, due to clinic closings for a public 
holiday or other scheduling limitations), an adequate amount of hydroxyurea 
should be dispensed to last until the next scheduled visit.  In these instances, up to 
an additional seven day supply can be dispensed.  Study drug will be handled in 
accordance with guidelines set forth in the consent form and the REACH Manual of 
Operations, which will reflect language in the drug Package Insert and guidance from 
current US-based clinical trials that use hydroxyurea for children with SCA. 
 
4.3 
Toxicity Management and Dose Modification or Discontinuation 
 
Dose Modification/Suspension Plan.  Laboratory toxicities from hydroxyurea will 
manifest primarily as reversible and transient myelosuppression, especially of 
granulocytes.  Myelosuppression with modest neutropenia and reticulocytopenia 
is a therapeutic goal of hydroxyurea therapy, however.  Careful monitoring of CBC’s 
will be performed every 4 weeks (± 1 week) since several studies have documented 
that monthly monitoring is acceptable. [23,29]  If a hematological toxicity occurs during 
the dose escalation phase or the maintenance phase (e.g., the ANC falls <1.0 x 109/L), 
hydroxyurea will be withheld and weekly blood counts performed.  Upon recovery, 
the hydroxyurea dosing will depend on the recovery:  if the toxicity has resolved 
within 1 week, then the hydroxyurea dose can resume at the same previous dose, 
but if it persists for > 1 week or occurs twice within a 3-month period, the 
hydroxyurea dose can be reduced by 2.5-5.0 mg/kg/day.  
 
A similar algorithm will be used for platelet toxicity, with thrombocytopenia defined as 
<80 x 109/L. For anemia, the thresholds will be any of the following: if the Hb 
concentration falls to <4.0 gm/dL; or Hb <6.0 gm/dL with the ARC <100 x 109/L; or for 
reticulocytopenia (ARC <80 x 109/L with Hb <7.0 gm/dL), hydroxyurea should be 
withheld until weekly counts document recovery.  If the toxicity occurs during the dose 

 
 
 
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escalation phase, upon recovery the hydroxyurea dose will be restarted at a dose that 
has been reduced by 2.5-5 mg/kg/day.  During the maintenance phase, if the toxicity 
resolves in 1 week, hydroxyurea should be resumed at the previous dose.  If recovery 
takes longer than 1 week or occurs twice within a 3-month period, the dose can be 
reduced by 2.5 mg/kg/day. 
 
These algorithms will serve as the general guidelines for the study.  Individual 
toxicities will be evaluated by the MCC and recommendations may be made on an 
individual basis to ensure patient safety.  Drug will be held during acute anemic 
events (e.g., malaria, parvovirus) and during acute renal toxicity (creatinine doubled 
from the baseline value and ≥1.0 mg/dL). 
 
If the statistical analysis of safety data for the initial cohort of children demonstrates 
that the starting dose of 15-20 mg/kg/day has too many dose-limiting hematological 
toxicities, then subsequent dosing will begin at 10-15 mg/kg/day with a similar dose 
escalation regimen and statistical analysis. 
 
4.4     Procedures for Treatment Discontinuation 
 
 
Participants can be discontinued from the study for any of the following reasons: 
 
 Participants missing two consecutive monthly clinic visits or three clinic 
visits during any 12-month period; 
 
 Severe allergic reaction or life-threatening drug-related toxicity; 
 
 Request of the study sponsor, parent, legal guardian, or investigator. 
 
 Should a female participant become pregnant, she will be required to 
stop study treatment. 
 
Final decisions about study discontinuation remain with the clinical site, but the 
Medical Coordinating Center (MCC) should be contacted prior to any participant's 
permanent discontinuation of study treatment so that data can be gathered prior to 
the study exit.  Reasons for withdrawal should be fully documented in the data 
collection forms.   
 
 
4.5 
Adverse Event Reporting Requirements 
 
Following the family’s written consent to participate in the study, all adverse events 
(AE) and serious adverse events (SAE) will be collected and reported to the MCC 
and Data Management Center (DMC) using the correct data collection forms. AE 
reporting will utilize the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0, where all AE are categorized by organ system and graded 
by severity.  A list of expected and potentially serious AE, as well as exceptions to 
the CTCAE, is included in Tables 2, 3, and 4 below. 
 
 
 
 

 
 
 
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Table 2.  Sickle Cell Disease Symptoms and Associated Conditions 
 
Acute chest syndrome 
Empyema  
Pain, long bone  
Adenotonsillar disease 
Hand-foot 
syndrome/dactylitis 
Pain, severe abdominal  
Albuminuria 
Headache 
Pain, sternal or rib  
Amenorrhea 
Hematuria  
Priapism  
Anemia (severe) 
Hemiplegia  
Proteinuria  
Aplastic crisis 
Hemolysis  
Pneumonia  
Arthralgia 
Hepatic sequestration  
Pulmonary embolism  
Avascular necrosis of 
hip/shoulder 
Hepatomegaly  
Pulmonary hypertension  
Bacteremia 
Hospitalization >24 
hours  
Pulmonary infiltrate on 
chest x-ray  
Bone infarction 
Hyperbilirubinemia  
Pyelonephritis  
Cardiac arrythmia 
Hypersplenism  
Renal failure  
Cardiomegaly 
Hypertension  
Renal insufficiency  
Cerebrovascular 
accident 
Hypocalcemia  
Renal papillary necrosis  
Cholecystitis 
Hyposthenuria  
Reticulocytopenia  
Cholelithiasis 
Hypotension  
Reticulocytosis 
Cognitive dysfunction 
Hypoxemia (PO2 < 
65mm Hg) 
Retinopathy  
Constipation 
Ileus  
Retinal hemorrhage  
Cranial nerve palsy 
Infection, bacterial  
Rhabdomyolysis  
Death 
Infection, 
pneumococcal  
Seizure  
Decreased renal 
function 
Infection, line  
Septicemia  
Decreased lung function 
Infection, viral  
Silent organ infarction 
Delayed growth/puberty 
Jaundice  
Skin ulcer  
Depression 
Leukocytosis  
Splenic sequestration  
Dizziness 
Meningitis  
Splenomegaly  
Electrolyte imbalance 
Nephropathy  
Stroke 
Elevated urinary 
urobilinogen 
Osteomyelitis  
Transient Ischemic Attack 
(TIA) 
Elevated serum 
transaminases 
Pain, back  
Tonsillar enlargement or 
infection 
Elevated TCD velocities 
Pain, chest  
Transfusion, unanticipated 
Fever  
Pain, joint  
Vaso-occlusive pain 
 
Table 2.  List of REACH expected and potentially serious adverse events associated 
with sickle cell anemia. Table 2 may not be all-inclusive and should not be 
considered the total universe of possibilities since some events may have been left 
off the list inadvertently.  The Lead Investigator should use clinical judgment along 
with consensus knowledge about SCD in determining event expectedness.  

 
 
 
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Table 3.  Hydroxyurea-Related Adverse Events 
 
Allergic reaction 
Increased creatinine 
Reticulocytopenia 
Anemia 
Increased ALT 
Skin ulcers/gangrene 
Anorexia 
Leukopenia 
Splenomegaly 
Constipation 
Nail/skin 
hyperpigmentation 
Thrombocytopenia 
Diarrhea 
Nausea 
Vomiting 
Gastritis 
Neutropenia 
Increase in the following 
laboratory parameters: 
MCV, MCH, MCHC, 
Nucleated RBC, %HbF) 
Hair loss 
Pancytopenia 
Decrease in the following 
laboratory parameters: 
Reticulocytes, RBC, WBC, 
ANC, Platelets, Hematocrit, 
%HbS, Total Bilirubin, 
LDH, and Ferritin. 
Hypersplenism 
Rash 
Skin ulcers 
 
Table 3.  List of REACH expected and potentially serious adverse events associated 
with hydroxyurea treatment of sickle cell anemia. Table 3 may not be all-inclusive 
and should not be considered the total universe of possibilities since some events 
may have been left off the list inadvertently.  The Lead Investigator should use 
clinical judgment along with consensus knowledge about hydroxyurea in determining 
event expectedness.  

 
 
 
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Table 4.  Laboratory Exceptions to the CTCAE List 
 
Parameter 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin (gm/dL) 
5.0 – 6.0 
4.0 – 4.9 
< 4.0 
Total WBC (x 109/L) 
1.0 – 1.999 
0.5 – 0.999 
< 0.5 
ANC (x 109/L) 
0.5 – 0.999 
0.2 – 0.499 
< 0.2 
Platelets (x 109/L) 
50 – 79 
20  –  49 
< 20 
Total Bilirubin (mg/dL) 
5.0 – 10.0 
10.1 – 20.0 
> 20.0 
AST (IU/L) 
150 – 300 
301 – 1000 
> 1000 
ALT (IU/L) 
150 - 300 
301 – 1000 
> 1000 
Creatinine (mg/dL) 
doubling of baseline 
serum creatinine and 
value ≥1.0 mg/dL 
1.6 – 2.0 
> 2.0 
ARC (x 109/L) and  
Hb < 7.0 gm/dL 
50-80 
10-49 
< 10 
 
Table 4.  List of Laboratory Exceptions to the CTCAE, version 4.0, Guidelines  
 
4.5 Serious Adverse Event Reporting Requirements  
SAE reporting will use commonly accepted definitions (typically any life-threatening 
illness or condition) with the exception of hospitalization, which is common in 
children with SCA.  Accordingly, all hospital stays more than 7 days must be 
scored as SAEs in REACH.  Drug-related and unexpected SAE are of particular 
concern, however all SAEs including death require prompt reporting by the local 
site, using email communication or telephone to the MCC and Medical Monitor.   
BMS Worldwide Safety (worldwide.safety@bms.com) will be notified within 24 
hours of the MCC becoming aware of the SAE, and then to the IRB of record within 
the required timeframe. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational 
product, a follow-up SAE report should be sent to the MCC and DMC.  All SAEs 
should be followed until resolution or stabilization. 
 
Pregnancy 
If it is discovered that a study participant is pregnant or may have been pregnant at 
the time of exposure to the BMS product associated with this study, the pregnancy, 
AEs associated with maternal exposure and pregnancy outcomes must be recorded 
on the Pregnancy Form and reported following SAE guidelines.  If only limited 
information is initially available, follow-up reports may be required.  Follow-up 

 
 
 
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information should be obtained on pregnancy outcomes for one year following the 
birth of the offspring.  The investigational product will be permanently discontinued in 
an appropriate manner.  Protocol-required procedures for study discontinuation and 
follow-up must be performed on the participant.  Follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome and, where 
applicable, offspring information must be reported on the Pregnancy Form.   
 
Any pregnancy that occurs in a female partner of a male study participant should 
also be reported.  Information on this pregnancy will be collected on the Pregnancy 
Form.  Any pregnancy that occurs in a female partner of a male study participant 
should be reported.  Information on this pregnancy will be collected on the 
Pregnancy Form.  In order for Sponsor or designee to collect any pregnancy 
surveillance information from the female partner, the female partner must sign an 
informed consent form for disclosure of this information.  
 
 
4.6 
Concomitant Medications 
 
 
 
4.6.1 All concomitant medications should be recorded on the appropriate 
data collection form, including name and dose of the medication, along 
with the medication start and end dates.  This includes malaria 
prophylaxis, if appropriate, as well as malaria treatment. 
 
 
4.6.2   No known or suspected SCA disease-modifying therapy, whether 
registered or approved for therapeutic use, should be administered 
during the hydroxyurea treatment period.  Herbs or other alternative 
medications that might be used to treat the signs and symptoms of 
SCA will be discouraged, and their concomitant use will be recorded. 
 
 
 
4.6.3 Use of blood products (e.g., erythrocyte transfusion) is permitted but 
should be captured, first on paper and then entered into the electronic 
data capture system. 
 
4.7 
Investigational Agents 
 
 
4.7.1  Hydroxyurea is the study treatment but may also be an investigational 
agent, depending on local national standards.  Site investigators are 
responsible for ensuring compliance with local country regulatory for 
importation and use of hydroxyurea.  BMS may provide guidance as 
feasible. 
 
 
4.7.2  Supply, Distribution and Storage – all hydroxyurea capsules will be 
stored locally at room temperature in secure pharmacy storage space, 
under the supervision of local investigational pharmacy staff.  
 
 
4.7.3 Study drug accountability - the local Study Coordinators will maintain a 
complete record of all study drugs, reagents and supplies.  The 
Principal Investigators and their designees will work closely with local 
site co-Investigators to ensure that study drug will be dispensed only 
to patients enrolled on the study. 
 

 
 
 
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5.0 
CLINICAL AND LABORATORY EVALUATIONS (SEE APPENDIX II - 
SCHEDULE OF EVALUATIONS) 
 
Eligible patients will be enrolled in the study upon signing the informed consent 
document.  Pre-treatment screening assessments can commence immediately, but 
should be completed within 8 weeks of initiation.  All evaluations should occur on 
the study month indicated in Appendix II.  Every effort should be made to ensure 
that all evaluations and supplementations occur around the time of the scheduled 
appointment. 
 
 
5.1 
Pre-treatment Evaluations (required) 
 
 
 
5.1.1 Screening Month -2 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
assessment of growth parameters to identify severe malnutrition 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, HIV testing by 
local standards, malaria assessment by local standards, serum (stored 
at -20C or -80C for future studies), and blood for serum and genomic 
DNA stored at -20C or -80C. 
 
 Measles and PCV-13 (if not yet completed); PPV-23 (if over age 2 years) 
 
 Nutritional supplementation as needed, based on dietary history and 
growth parameters 
 
 Folate and iron supplementation, based on local guidelines 
 
 Malaria protection, either insecticide-treated bednets or 
chemoprophylaxis, as per local standards 
 
 
5.1.2 Screening, Month -1 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
growth assessments 
 
 CBC with white blood cell differential, reticulocyte count 
 
 If not collected during Screening Month -2, serum chemistries 
(creatinine, AST, ALT, bilirubin), %HbF level, HIV testing by local 
standards, malaria assessment by local standards, serum (stored at -
20C for future studies), and blood for genomic DNA stored at -20C. 
 

 
 
 
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 Treatment for possible helminth infection with either albendazole or 
mebendazole, as per local guidelines 
 
 For children <5 years of age, vitamin A supplementation with 200,000 
units orally, if not already received and documented within the past six 
months 
 
5.2 
Hydroxyurea Initiation, Month 0 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
assessment of growth parameters 
   
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment 
 
 Hydroxyurea (15-20 mg/kg/day) as a daily oral dose 
 
 
5.3 
Study Month 1 through End of Study 
 
5.3.1 Study month 1 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea (15-20 mg/kg/day) 
 
 
5.3.2 Study month 2 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea (15-20 mg/kg/day) 
 
 
5.3.3 Study month 3 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 

 
 
 
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 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment 
 
 Hydroxyurea (15-20 mg/kg/day) 
 
5.3.4 Study month 4 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea (15-20 mg/kg/day) 
 
 
5.3.5 Study month 5 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea (15-20 mg/kg/day) 
 
 
 
5.3.6 Study month 6  
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment 
 
 Hydroxyurea dose escalation by 5 ± 2.5 mg/kg/day every 2 months (8 
weeks) as tolerated to MTD 
 
 Treatment for helminth infection with either albendazole or mebendazole 
 
 
5.3.7 Study month 7 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 

 
 
 
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 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea at 15-25 mg/kg/day 
 
 
5.3.8 Study month 8 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea dose escalation by 5 ± 2.5 mg/kg/day every 2 months (8 
weeks) as tolerated or MTD 
 
 
5.3.9 Study month 9  
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment 
 
 Hydroxyurea at 15-30 mg/kg/day or MTD 
 
 
5.3.10 Study month 10 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Hydroxyurea dose escalation by 5 ± 2.5 mg/kg/day every 2 months (8 
weeks) as tolerated or MTD 
 
 
5.3.11 Study month 11 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), HbF level, malaria 
assessment. 
 

 
 
 
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 Hydroxyurea dose at 15-30 mg/kg/day or MTD 
 
 
5.3.12 Study month 12  
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment, saved serum and blood for DNA 
 
 Hydroxyurea dose at 15-30 mg/kg/day or MTD 
 
 Treatment for helminth infection with either albendazole or mebendazole 
 
 PPV-23 booster at age 5 years and 12 years 
 
 For children <5 years of age, vitamin A supplementation with 200,000 
units orally, if not already received and documented within the past six 
months 
 
5.3.13 Quarterly (Tri-Monthly) Visits after Reaching MTD until End of Study 
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
medication adherence assessment 
 
 CBC with white blood cell differential, reticulocyte count 
 
 Urine pregnancy test for girls who have reached menarche 
 
 Tanner Staging for growth and development, menarche query 
 
 Hydroxyurea dose at MTD  
 
 PK Study Sample to be collected after MTD is officially established but 
only once after reaching MTD. 
 
 
 
5.3.14 Annual Visits after Reaching MTD until End of Study 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, saved serum, 
blood cells, urine, and blood for DNA 
 
 Treatment for helminth infection with either albendazole or mebendazole 
 

 
 
 
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 Urinalysis and urine for albuminuria 
 
 Transcranial Doppler (TCD) Examination 
 
 For children <5 years of age, vitamin A supplementation with 200,000 
units orally, if not already received and documented within the past six 
months 
 
 PPV-23 booster at age 5 years and age 12 years 
 
 
5.4 
Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics 
 
To explore the genetic basis for any observed inter-patient variability in the 
clinical and laboratory responses to hydroxyurea, a formal analysis of drug 
pharmacokinetics (PK) will be performed on children after achieving 
hydroxyurea MTD, followed by associations with drug pharmacodynamics 
(PD) and then pharmacogenomics (PG). 
 
 Hydroxyurea PK studies will be performed as described, using a sparse 
sampling schedule of 4 time-points: a single collection before and 3 
collections at about 15-20 minutes, 60 minutes, and 180 minutes after 
administering the hydroxyurea dose. [31] The whole blood specimens 
will be collected using Mitra® microsampling devices, with a total blood 
volume of <1mL for the PK studies. 
 
 The samples will be stored at -20C or -80C until transport to Cincinnati 
Children’s Hospital for quantitative analysis using either HPLC or LC-
MS/MS analytic techniques.  The PK analysis will be performed using a 
pharmacometrics strategy as described, [31] to calculate the 
hydroxyurea Tmax, Cmax, t1/2, and other critical pharmacokinetic 
parameters 
 
 PD variables will include Hb, MCV, HbF, ANC, hematological toxicities, 
and MTD dose, among others. Demographic variables and PK 
parameters will be correlated with these PD parameters, in an attempt to 
identify statistical associations and predictors of toxicities and response. 
 
 Genomic DNA will be isolated from FTA cards or other storage devices 
and used to identify genetic variants that influence either the PK or PD 
parameters. Such PG analysis will require transport of the biological 
specimens to Cincinnati Children’s Hospital for candidate gene analysis 
and unbiased whole exome/genome sequencing.    
 

 
 
 
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5.5 
Discontinuation of Study Drug  
 
 Medical history, physical exam, length or height (cm) and weight (kg), 
assessment of nutritional parameters, medication adherence 
assessment 
 
 CBC with white blood cell differential, reticulocyte count, serum 
chemistries (creatinine, AST, ALT, bilirubin), %HbF level, malaria 
assessment, and serum, blood, urine, and DNA for future studies. 
 
 Urinalysis and urine for albuminuria 
 
 Tanner Staging for growth and development, menarche query 
 
 Serum, blood and urine for future analysis as well as blood for genomic 
DNA purification and analysis, all stored at -20C or -80C. 
 
 Transcranial Doppler (TCD) Examination 
 
5.6 
Lowering of Drug Dose due to Excess Toxicities 
 
After the initial cohort of children is enrolled, toxicities will be closely 
monitored and analyzed.  If the number of dose-limiting hematological 
toxicities is below the number allowed in the statistical analysis plan, 
enrollment will continue at the starting dose of 15-20 mg/kg/day.  But if the 
number of dose-limiting toxicities is excessive, then the starting dose will be 
lowered by 5 mg/kg/day to 10-15 mg/kg/day and the first phase of statistical 
analysis will be repeated. 
 
5.7 
Data Management Issues  
 
5.7.1 Research Electronic Data Capture (REDCap™) system 
 
Study data will be collected and managed using REDCap electronic 
data capture tools. [33]  REDCap is a secure, web-based application 
designed to support data capture for research studies, providing: 1) 
an intuitive interface for validated data entry; 2) audit trails for 
tracking data manipulation and export procedures; 3) automated 
export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from 
external sources.  
 
The REDCap system is available for use through institutions 
participating in the REDCap consortium.  As of January 2013, this 
consortium is composed of 533 active partners in 49 countries.  
Cincinnati Children’s Hospital Medical Center is serving as the home 
institution to allow the REDCap system for data collection in the 

 
 
 
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REACH study.  The consortium supports a secure web application 
designed exclusively to support data capture for research studies, 
with a secure internet-based connection that uses low band-width, 
suitable for research in low-income countries. 
 
5.7.2 Forms Management 
 
Data will be entered into the electronic data record directly from each 
clinical site.  Each enrolled patient will be given a study ID number, 
which will allow de-identified information to be collected without the 
child’s name.  All electronic data collection forms will be reviewed for 
accuracy and completion by the local Study Coordinator or Data 
Manager, as well as by the local study PI.  
 
5.7.3 Database 
 
An electronic database developed and managed by Cincinnati 
Children’s Hospital Medical Center will accommodate data entry and 
management of the study’s data. 
 
A file for each study form will be created.  The files will be templates 
of the data collection forms. A Data Entry Technician will access the 
database file templates to enter data from the study data collection 
forms. 
 
5.7.4 Database Management 
 
Programs will be created to run logical and missing value error 
checks on the data files.  Edit reports will result from these programs 
and will be used to clean the data. 
 
Quality control analyses are performed on the data at standard time 
intervals.  Outliers are reviewed, resolved and the database is 
updated, as necessary. 
 
Standard database reports will be generated monthly.  These reports 
will include enrollment, withdrawal, endpoints, cumulative toxicities, 
and adverse events. 
 
6.0 
EVALUATION OF EFFECTS 
6.1 
Safety Endpoints 
 
 The percent of participants and number of participants with pre-defined dose-
limiting hematological laboratory toxicities; also the type and severity of the 
hematological toxicities. 
 

 
 
 
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 
Number and type of serious infections, both bacterial and malarial 
 
6.2 
Feasibility Endpoints 
 
 The percentage adherence to monthly clinic visits will be calculated between 
Month -2 and Month 12 
 
 The percentage of laboratory assessments that were successfully obtained 
between Month -2 and Month 12 
 
 The percentage of medication taken per pill counts (along with the Modified 
Morisky adherence score, described below) between Month 0 and 12 
 
 
6.3 
Efficacy Endpoints 
 
 Change in laboratory measures of efficacy from baseline (e.g., fetal 
hemoglobin, hemoglobin, ARC, WBC, ANC, and bilirubin).   
 
 Clinical complications will be captured, including pain, hospitalizations, and 
other sickle-related events.   
 
 These on-study data will be compared to historical data for each patient 
gathered at study entry. 
 
Correlate the PK parameters with PD variables, including hematological toxicities 
and treatment responses and identify genetic variants that affect both PK and PD 
parameters using a pharmacogenomics approach. 
 
 
 7.0 
STATISTICAL CONSIDERATIONS   
  
7.1 
Sample Size  
 
The enrollment goal for REACH is to recruit and treat a large cohort of 
children with SCA, up to 600 total participants at up to 4 different clinical 
sites.  Because each local population of SCA will be different, based on a 
variety of criteria such as tribal ethnicity, genetics, income and nutritional 
status, each clinical site is considered independently for sample size 
calculations.  
 
To achieve 90% power to detect significant differences in the primary safety 
outcomes described below, a sample size of 133 is required per site.  
Because of the possibility of excess drop-out during the initial 3 months of 
treatment, we will therefore aim for about 150 patients to be enrolled at 
each site (to ensure that 133 receive the entire initial 12-month treatment 
period), for a maximum total of 600 patients across 4 sites. 

 
 
 
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7.1.1 Safety endpoint – hematological toxicities 
 
The specific safety hypotheses are as follows: 
H0: AE rate > Unacceptable value [unsafe] 
Ha: AE rate < Unacceptable value [safe] 
The investigators would like to reject H0 and declare the medication safe.  
Low observed numbers of AEs will favor the alternative hypothesis.  With 
this approach, early analysis will search for evidence that the drug is unsafe.   
Hematological toxicities and occasional dose adjustments or medication holds 
are expected with hydroxyurea therapy.  Some of these adjustments will be 
due to drug-related toxicity while others will be sporadic.  The recently 
completed BABY-HUG study reported toxicities of severe neutropenia (5%), 
severe anemia (1%), and thrombocytopenia (11%), but hematological toxicities 
were also noted in the placebo-treated arm. [19] The earlier HUSOFT study 
reported severe neutropenia (21% of patients) and severe anemia (25%), but 
that study had a much smaller cohort than BABY HUG, was open-label without 
a control arm, and had slightly different toxicity thresholds. [25] Based on these 
data, we estimate a dose-limiting hematological toxicity event rate of 20% for 
our sample size calculations, meaning 20% of the participants will have at least 
one hematological toxicity during the first 3-months of study treatment.  
However, given the potential for non-medication-related cytopenic events, an 
acceptable toxicity event rate of 30% will be the primary safety outcome 
measure. 
 
Simon’s two-stage procedure was used to calculate sample size and assess 
safety.  An “expected” toxicity rate of 20% and “acceptable” toxicity rate of 30% 
were used for statistical calculations.  Using this model, the first stage of 
analysis occurs after 53 participants at each site have completed 3 months of 
hydroxyurea therapy, but will also include participants who experience a dose-
limiting hematological toxicity and withdraw from the study during the first 3 
months of enrollment.  To ensure that we have 53 children in this first phase, 
we will halt enrollment after 60 children have enrolled, allowing for up to 
12% participant drop-out or discontinuation of medication. If ≤15 participants 
have hematologic toxicity as defined in Table 1, there is no early evidence 
against safety, and thus enrollment continues to the full 150 participants.  If ≥15 
of the initial participants experience hematologic toxicity, however, this is early 
evidence against safety.  Future participants will begin at a lower dose of 
hydroxyurea (10 ± 2.5 mg/kg) and the study will in effect be restarted, with 
another 60 participants recruited for the same safety analysis at this lower dose.  
Upon final analysis of 133 participants at the same starting dose, safety for 
fixed-dose hydroxyurea can be concluded with 90% power if ≤33 participants 
experience hematologic toxicity.  The main advantage of this two-stage 
design is the ability to identify that the drug is unsafe at an early part of the 
study, thus allowing dose modification to determine a safe hydroxyurea 
dose. 
 

 
 
 
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Serious infections, both bacterial and malarial, will be recorded descriptively 
and compared to pre-enrollment rates. 
 
7.1.2 Feasibility endpoint – adherence to visits 
 
Monthly clinic visits with laboratory testing are required in REACH, since this 
frequency of monitoring is the current standard or care in the United States, 
and also necessary to ensure safety while assessing efficacy.  The feasibility 
of this monitoring schedule is relevant, since hydroxyurea cannot be safely 
administered with infrequent monitoring.  Hydroxyurea treatment will be 
dispensed only 30 or 60 days at a time as outlined in Section 4.2, requiring a clinic 
visit every 4 ± 1 or 8 ± 2 weeks.  Medication adherence and the ability for families 
to adhere to monthly clinic visits are important feasibility outcomes.  
 
Families will be asked to bring their medication each month and pill counts will 
serve as one measure of medication compliance.  Adherence will be scored 
categorically as follows:  ≥80% adherence (Excellent), 60-79% adherence 
(Good), 40-59% (Moderate) and <40% (Poor). 
 
Secondarily, the Modified Morisky Scale [34,35] will be administered verbally by 
nursing or medical staff.  The adapted scale includes these four questions:  
 
(1) Do you ever forget to give your child the hydroxyurea medication? 
 
(2)  Are you careless at times about giving your child the hydroxyurea 
medication? 
 
(3) When your child feels better, do you sometimes stop giving your child 
the hydroxyurea? 
 
(4) Sometimes, if your child feels worse when taking the hydroxyurea, do 
you stop giving them? 
 
A simple yes/no will be used to assess adherence. Each "yes" answer is 1 
point, and each "no" is 0 points.  The answers are summed to give a score 
(range, 0-3).  Adherence will be scored as follows:  0 (Excellent), 1 (Good); 2 
(Moderate); 3 (Poor).  Statistical analysis of the Feasibility Endpoint will be 
descriptive. 
 
7.1.3 Efficacy endpoint – laboratory measures 
 
The benefits of hydroxyurea will be primarily assessed through fetal 
hemoglobin (HbF), comparing treatment with baseline values.  Additional 
measures of laboratory efficacy will include changes in Hb, MCV, WBC, 
ANC, ARC, and bilirubin.  Clinical events such as vaso-occlusive pain will 
be captured as secondary outcomes. 
 
 
 

 
 
 
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7.2 
Patient Recruitment and Retention 
 
The clinics at the proposed clinical sites have large populations of children 
with SCA, with most seeing hundreds or even thousands of new patients 
annually.  All patients will be recruited from these existing centers.  Most 
patients live locally and travel to clinic by foot or local bus/taxi.  Accordingly, 
physical distance to the clinic is not likely to affect recruitment and retention 
of our study population living in the urban centers where these clinics reside.   
 
Recruited patients will be informed of study procedures and expected monthly 
follow-up schedule.  Patients will be enrolled based upon the family's ability to 
maintain such a follow-up schedule.  Patients will be enrolled after written, 
informed consent has been obtained from the parent or surrogate, according to 
the guidelines of the main IRB and the local Ethics Committees.  Given the 
burden of traveling to the clinic each month, remuneration per visit will be 
provided for families, to help defray the costs of travel, meals and lost wages.  
The amount of this remuneration will be determined locally by the clinical site 
Investigator. 
 
Given the early mortality of SCA in these countries, enrollment will primarily 
target young patients.  With a goal of 150 participants per site, in each location 
we aim to enroll about 100 participants who are between twelve months and five 
years of age, about 50 participants between five and ten years of age.  We 
have chosen twelve months of age as the minimum age, based on published 
experience from the Phase III infant hydroxyurea (BABY HUG) clinical trial. 
[19]  We will also enroll some older children as available, because they will 
also receive clinical benefits from hydroxyurea therapy and data from these 
children are necessary to establish evidence-based guidelines for children with 
SCA of all ages.  We will not address the treatment of adults. 
 
Participants of reproductive age should not become pregnant, and should 
either practice abstinence or use medically-approved contraceptive measures 
since hydroxyurea has teratogenic potential.  There are no adequate and 
well-controlled studies in pregnant women, so precautions will be taken in the 
REACH trial to recommend against pregnancy and to regularly monitor 
menstruating female participants for pregnancy.  Male participants also will be 
counseled about the need to avoid fathering a child while taking hydroxyurea 
treatment.  Should a female participant become pregnant, she will be asked 
to stop study treatment. 
 
 
7.3 
Expected Drop-Out Rate 
 
Based on data from the US in clinical trials and discussion with the local site 
investigators, we estimate ≤ 25% dropout rate over the 12-month treatment 
period.  Participants who drop-out during the screening phase, before receiving 
hydroxyurea treatment, will be replaced by new recruitments.  Data from 
participants who dropout during the first 3-months of the treatment period will be 
censored but still included in the analysis, using data available from 

 
 
 
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successfully attended clinic visits.  These participants will be replaced to 
provide sufficient data for analysis of safety.  For the possibility that the drop-
out rate exceeds 25%, some additional patients will be enrolled (150 per 
clinical site). 
 
 
7.4 
Planned Statistical Analyses 
 
Formal statistical analyses will be developed after additional support and 
funding are secured.  Initial goals will be descriptive summaries of enrollment, 
toxicities, and effects based on participant age, gender, and clinical location. 
 
 
 8.0 
HUMAN SUBJECTS 
 
 
 
8.1 
Institutional Review Board (IRB) and Informed Consent 
 
This protocol, the informed consent document, patient recruitment brochures, 
and any subsequent modifications will be reviewed and approved by the IRB 
at Cincinnati Children’s Hospital (MCC and DMC) and the IRB or Ethics 
Committees at each participating institution.  Compliance with GCP guidelines 
for the conduct and monitoring of this clinical trial will occur through 
observation of the ethical and regulatory requirements presented in ICH E6, 
Good Clinical Practice: Consolidated Guideline.  The Investigators will comply 
with all clinical trial disclosure and registration regulations.  Approval of the 
local IRB or Ethics Committee will be received prior to initiation of the study, 
along with external IRB approval at the institutions of record for both the MCC 
and DMC.  Written informed consent will be obtained from the parent or legal 
guardian of patients, all of whom are below age 10 years so cannot consent 
for themselves (e.g., those below the local legal age).  If required by the local 
IRB or Ethics Committee, the patient's assent will be obtained regarding the 
nature, significance and risks associated with the study.  A notation that 
written informed consent was obtained will be made on the participant's case 
report form.  The signed informed consent forms will be retained at the study 
site; a copy will be put in the participant's records.  A copy of the consent form 
will also be provided to the parent or legal guardian (and to the patient when 
applicable). 
 
 
 
8.2 
Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will 
be identified by a coded number only to maintain patient confidentiality.  All 
records will be kept in a locked file cabinet.  All computer entry and 
networking programs will be completed with coded numbers only.  Clinical 
information will not be released by the REACH MCC or DMC without written 
permission of the patient/parent/guardian, except as necessary for 

 
 
 
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monitoring.  Clinical information can be shared by the site investigators and 
staff for patient care reasons, e.g., local consultations. 
 
 
 
 
 
8.3 
Study Discontinuation 
 
Data from this study will be reviewed in real-time by the Principal 
Investigator and Co-Investigator team members. Data will be reviewed 
periodically with an external DSMB assembled by the MCC team.  The 
study will be discontinued if at any time the study team feels that it is in the 
best interests of study participants to do so.  
 
 
  
9.0 
DATA AND SAFETY MONITORING BOARD (DSMB) 
 
 
9.1 
Rationale 
 
Since REACH is a Phase I/II pilot trial in a potentially vulnerable patient 
population, it is important that an independent group have access to the 
feasibility, safety, and efficacy data.  Periodic review by the DSMB will be 
critical to ensure that the participants are protected from harm, while also 
ensuring that the study integrity is not compromised. 
 
9.2 
Composition 
 
A group of international investigators will be invited to join the REACH trial 
and serve as an independent DSMB.  Among these projected 5-7 persons, 
there will be experience and expertise in international clinical trials, pediatric 
hematology, malaria, and the use of hydroxyurea in sickle cell disease, as 
well as representation from biostatistics, ethics, and patient advocacy. 
 
 
10.0 ORGANIZATIONAL STRUCTURE 
 
The REACH trial will be guided by both a Medical Coordinating Center (MCC) 
located at Cincinnati Children’s Hospital Medical Center and a Data Management 
Center (DMC) through the CTSA located at Cincinnati Children’s Hospital Medical 
Center.  The MCC will be led by Dr. Russell Ware, who will serve as overall 
Principal Investigator (PI) for the study, and Dr. Patrick McGann (co-Investigator) 
who will be the primary Clinical Coordinator to assist the sites with clinical 
questions, adverse events, and other questions related to interpretation of the 
protocol.  The DMC is led by Dr. Russell Ware and assisted by a team of 
experienced CTSA personnel who have substantial REDCap expertise in 
multicenter clinical trials.  The DSMB and a special African Advisory Board will 
provide input to the Steering Committee.  
 

 
 
 
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Each REACH clinical site (Angola, DRC, Kenya, and Uganda) will be led by a co-
Investigator who will serve as site Lead Investigator, along with a team of local co-
investigators.  The MCC will be assisted by the REACH Hydroxyurea Consultant 
who will provide specific expertise for hydroxyurea dosing and toxicities, and 
adverse events that might be drug-related.  The REACH Investigational 
Pharmacist will assist the MCC and clinical sites, to ensure the hydroxyurea is 
stored, managed, and dispensed properly. 
 
 
A monthly REACH Steering Committee call will include representatives of the 
MCC, DMC, and Lead Investigators from all local sites.  Operations Committee 
calls will occur every 2-4 weeks throughout the study.  An illustration of the 
organizational structure for the REACH trial is shown on the following page. 
 
 

 
 
 
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Figure 1.  Organizational Structure for the REACH clinical trial 
 
 
Data Management Center (DMC) 
Cincinnati Children’s Hospital 
Cincinnati, Ohio 
 
Russell E. Ware, MD, PhD (PI) 
DMC Project Team 
REACH Operations Committee 
Principal Investigator 
MCC Representative(s) 
DMC Representative(s) 
Lead Investigators 
Site Personnel (rotating) 
Investigational Pharmacist 
Medical Monitor 
 
Biostatistics 
University of Toronto 
Toronto, Ontario, Canada 
 
George Tomlinson, PhD (Co-Inv) 
REACH Steering Committee 
 
Russell E. Ware, MD, PhD (PI) 
Patrick McGann (Clinical Coordinator) 
Leon Tshilolo (DRC Lead Investigator) 
Brigida Santos (Angola Lead Investigator) 
Thomas Williams (Kenya Lead Investigator) 
Peter Olupot-Olupot (Uganda Lead 
Investigator) 
 
Medical Coordinating 
Center (MCC) 
Cincinnati Children’s 
Hospital 
Cincinnati, Ohio 
 
Russell E. Ware, MD, PhD (PI) 
Patrick T. McGann, MD (Co-Inv) 
MCC Project Team 
Consultants  
 
Banu Aygun, MD (Hydroxyurea)  
Investigational Pharmacist 
 
Data and Safety 
Monitoring Board 
(proposed membership) 
 
Pediatric Hematologists (2) 
Statistician 
Infectious Diseases 
Patient Advocate 
Clinical Trials Specialist 
Study Coordinators 
Committee 
Clinical Sites 
 
HPDB, Luanda, Angola 
Monkole, Kinshasa, DRC 
KEMRI, Kilifi, Kenya 
Mbale Regional, Mbale, Uganda 
African Advisory Board 
(proposed membership) 
 
Public Health Expert 
Clinical Trials Expert 
Sickle Cell Disease Expert 

 
 
 
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11.0 PUBLICATION OF RESEARCH FINDINGS  
 
The results from this clinical trial have the potential for immediate public health 
applicability for the sickle cell community around the world.  The target audience 
will be reached through publications, oral presentations, and seminars.  Data 
analysis and manuscript preparation will occur during the last 6-12 months of this 
proposed trial.  At the end of the trial, the main outcome paper will be submitted to 
a prestigious journal, such as the New England Journal of Medicine, Journal of the 
American Medical Association, or Blood.  The trial results will be presented at the 
annual meetings of the American Society of Hematology (ASH) and regional 
meetings in Africa (REDAC).  Any presentation, abstract, or manuscript will be 
made available to all study team members for review prior to submission. 
 
Other results generated from the trial that are not published in the main outcome 
manuscript will be submitted for publication in prestigious medical journals and 
presented at scientific meetings listed above.  All plans for dissemination of study 
results will be discussed with the investigators and the DSMB before 
implementation.  BMS will have the ability to review draft publications 
approximately 30 days prior to submission, but will not have access to the primary 
data, authority to edit the results, or influence any presentations or publications. 
 
 
 
 

 
 
 
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12. 
REFERENCES  
 
1. Weatherall D, Hofman K, Rogers G, Ruffin J, Hrynkow S. A case for developing 
North-South partnerships for research in sickle cell disease. Blood 2005; 
105(3):921-923. 
 
2. World Health Organization: Regional Office for Africa. Sickle-cell disease: A 
strategy for the WHO African Region. June 2010. 
 
3. 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(7):e1001484.doi, Epub 2013 July 16. 
 
4. UN Millennium Goals: http://www.un.org/millenniumgoals/childhealth.shtml. 
 
5. Piel RB, Patil AP, Howes RE, et al.  Global epidemiology of sickle haemoglobin in 
neonates:  a contemporary geostatistical model-based map and population 
estimates.  Lancet 2013;381(9681):142-151. 
 
6. Quinn CT, Rogers ZR, McCavitt TL, Buchanan GR. Improved survival of children 
and adolescents with sickle cell disease. Blood 2010; 115:3447-3452. 
 
7. Weatherall DJ and Clegg JB. Inherited haemoglobin disorders: an increasing 
global health problem. Bull. World Health Organization 2001; 79(8). 
 
8. Williams TN, Uyoga S, Macharia A, et al.  Bacteraemia in Kenyan children with 
sickle-cell anaemia:  a retrospective cohort and case-control study.  Lancet 
2009;374(9698):1364-1370. 
 
9. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell 
disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med 
2010; 41(6 Suppl 4): S398-405. 
 
10. Odame I. Developing a Global Agenda for Sickle Cell Disease: Report of an 
International Symposium and Workshop in Cotonou, Republic of Benin. Am J Prev 
Med 2010; 38(4):S571-S575. 
 
11. Makani J, Komba AN, Cox SE, et al.  Malaria in patients with sickle cell anemia:  
burden, risk factors, and outcome at the outpatient clinic and during 
hospitalization.  Blood 2010;115(2):215-220. 
 
12. Williams TN, Obaro SK.  Sickle cell disease and malaria morbidity:  a tale with 
two tails. Trends Parasitol 2011;27(7):315-320. 
 
13. McGann PT, Ware RE. Hydroxyurea for sickle cell anemia; what have we learned 
and what questions still remain. Curr Opinion Hematol 2011; 18:158-165. 
 
14. Lofvenberg E. and Wahlin A. Management of polycythaemia vera, essential 

 
 
 
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thrombocythaemia and myelofibrosis with hydroxyurea. Eur J of Haematol 1988; 
41: 375-381. 
 
15. Kennedy BJ and Yarbro JW. Metabolic and therapeutic effects of hydroxyurea in 
chronic myeloid leukemia. JAMA 1966;195:1038-1043. 
 
16. Lori F, Malykh A, Cara A, Sun D, Weinstein JN, Lisziewicz J, Gallo RC. 
Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. 
Science 1994;266:801-805. 
 
17. Lewis WH and Wright JA. Altered ribonucleotide reductase activity in mammalian 
tissue culture cells resistant to hydroxyurea. Biochem and Biophys Res Comm 
1974; 60:926-933. 
 
18. Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea 
enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 
74:652-656. 
 
19. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea:  effects on hemoglobin F 
production in patients with sickle cell anemia.  Blood 1992; 79:2555-2565 
 
20. 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; 94:1550-1554. 
 
21. Thornburg CD, Dixon N, Burgett S, et al. A pilot study of hydroxyurea to prevent 
chronic organ damage in young children with sickle cell anemia. Pediatr Blood 
Cancer 2009; 52:609-615. 
 
22. Charache S, Terrin ML, Moore RD, et al.  Effect of hydroxyurea on the frequency of 
painful crises in sickle cell anemia.  N Engl J Med 1995; 18(330): 1317-1322. 
 
23. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, 
Thornburg CD, Rogers ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, 
Howard TH, Wynn LW, Kutlar A, Armstrong FD, Files BA, Goldsmith JC, 
Waclawiw MA, Huang X, Thompson BW. Hydroxycarbamide in very young children 
with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). 
Lancet 2011; 377:1663-1672. 
 
24. Steinberg MH, McCarthy WF, Castro O, et al. The risks and benefits of longterm 
use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 
2010; 85:403-408. 
 
25. 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-
2363. 
 
26. Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The 

 
 
 
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effect of hydroxycarbamide therapy on survival of children with sickle cell disease. 
Br J Haematol 2013;161(6):852-860. 
 
27. Ware RE, Despotovic JM, Mortier NA, et al.  Pharmacokinetics, 
pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children 
with sickle cell anemia.  Blood 2011;118(18):4985-4991. 
 
28. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. 
Blood 2010; 115:5300-5311. 
 
29. 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; 103:2039-2045. 
 
30. Ware RE.  Is sickle cell anemia a neglected tropical disease?  PLoS NTD 
2013;7(5):e2120. 
 
31. Dong M, McGann PT, Mizuno T, Ware RE, Vinks AA. Development of a 
pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in 
children with sickle cell anaemia. Br J Clin Pharmacol 2016;81:742-52. 
 
32. 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.  J Pediatr 
2001;139(6):790-796. 
 
33. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG.  Research 
electronic data capture (REDCap) - A metadata-driven methodology and workflow 
process for providing translational research informatics support.  J Biomed Inform 
2009;42(2):377-381. 
 
34. Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication 
adherence measure for hypertension control. J Clin Hypertens 2008; 10:348–354. 
 
35. Thornburg CD, Calatroni A, Telen M, Kemper AR. Adherence to hydroxyurea therapy 
in children with sickle cell anemia. J Pediatr 2010;156(3):415-419. 
  

 
 
 
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APPENDIX I:  WHO WEIGHT-FOR-LENGTH, WEIGHT-FOR-HEIGHT, AND LENGTH/HEIGHT-FOR-AGE GROWTH CURVES 
 

 
 
 
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APPENDIX II: SCHEDULE OF EVALUATIONS 
 
 
1 Study evaluations should be performed + one week of the designated study month for the first 24 weeks\s, then + 2 weeks of the designated study month thereafter 
2 Creatinine, AST, ALT, bilirubin  
3 Saved for future testing such as serum folate, B12, ferritin, retinol; urine for albumin and cystatin C; blood for micronuclei; and genomic DNA analysis 
4 Measles and PCV-13 immunizations if not previously provided; PPV-23 if participant is >2 years of age and not previously provided, then booster at age 5 years and 12 years 
 
Evaluations 
Screening 
Initiation 
Study Month 1 
 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 
Q3 
Annual 
EOS 
Clinical Assessments 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Staging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Medication adherence 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TCD Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Laboratory Assessments 
CBC with WBC differential 
X 
X 
X 
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 
X 
X 
X 
Serum chemistries 2 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
HbF level 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
HIV serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Malaria assessment 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Urine for albuminuria 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Serum and DNA collection 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Hydroxyurea PK Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At a visit after MTD is established 
Treatment 
Hydroxyurea (15-20 mg/kg/d) 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Dose escalation (15-30) 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
MTD maintenance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Treatment for helminths 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Vitamin A 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Measles, PCV-13, PPV-23 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Nutritional supplementation 
As clinically indicated