Hydroxyurea Therapy: Optimizing Access in Pediatric Populations Everywhere
Phase: PHASE2
Conditions: Sickle Cell Disease, Thalassemia
Sponsor: St. Jude Children's Research Hospital

Initial version, dated: 06/04/2018 
Protocol document date: 03/14/2019 
St. Jude 
HOPE18 CTG# - NCT03825341
Initial version, dated:  06-04-2018, (IRB Approved: 12-21-2018) Activated: 03/06/2019 
Unnumbered revision 03-14-2019 
Hydroxyurea therapy: Optimizing Access in Pediatric Populations Everywhere 
(HOPE18) 
IND # 141719  
Principal Investigator 
Jeremie Estepp, MD 
Co-Investigators 
Winfred Wang1 (Emeritus), MD 
Jane Hankins1, MD 
Nicole Dockery1, NP 
Nathan Gray1, PA 
Nidal Boulos1, PhD 
Lisa Anderson1, RN 
Julie Richardson2, PharmD 
Timothy Jacobs2, PharmD 
Guolian Kang3, PhD 
Jeffrey Gossett3, MS 
Departments of Hematology1, Pharmaceutical Sciences2, and Biostatistics3 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee  38105-3678 
Telephone:  (901) 595-3300 
Contents of this document may not be extracted without permission from the Principal Investigator. 
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Initial version, dated: 06/04/2018 
Protocol document date: 03/14/2019 
 Protocol Summary 
Protocol MNEMONIC and Title: HOPE18 - Hydroxyurea therapy: Optimizing Access in 
Pediatric Populations Everywhere 
Principal Investigator: Jeremie, Estepp, MD 
IND Holder: St. Jude Children’s Research Hospital, # 141719 
Brief Overview: This trial is an open label, single center assessment of the 
pharmacokinetics of two formulations of hydroxyurea (HU) designed to (1) determine the 
pharmacokinetic profile of a liquid formulation in infants and to (2) determine the 
bioavailability of “sprinkles”, a novel method of administration for older children. The 
study aims to generate data to facilitate FDA approval for HU in children and potentially 
validate a new mode of administration (“sprinkles”) that will optimize access and adherence 
for children in the US and globally. 
Intervention: Participants will receive either a single dose of oral liquid formulation of HU 
(20 mg/kg/day) followed by PK sampling or HU sprinkle formulation and capsules 
(Droxia® 200 mg) administered on 2 separate occasions. 
Brief Outline of Treatment Plan: HOPE18 will be an open label, 2-arm study of HU 
disposition in 48 children with SCD. In Arm 1, n=18 infants ages 9 months to 2 years will 
be administered an extemporaneous oral liquid formulation of HU on a single occasion 
followed by PK sampling. The dose administered will be ~20 mg/kg/day or the infant’s 
usual daily dose. In Arm 2, n=30 children who range in age from 2 to 18 years will be 
administered HU, both a sprinkle formulation and capsules (Droxia® 200 mg), on two 
separate occasions separated by at least 1 day but no more than 30 days in a randomized, 
crossover fashion. The doses of HU on each occasion will be rounded to the nearest 200 mg 
and will not exceed 35 mg/kg or 2000 mg. We hypothesize that the PK profile of the 
sprinkle formulation will not differ significantly from the PK profile of Droxia® capsules in 
children and adolescents ages ≥2 - 18 years of age. 
Study Design: The HOPE18 trial is designed as a randomized, open-label, cross-over study, 
to assess HU bioavailability using a liquid formulation of HU and to assess the relative 
bioavailability of HU capsules to “sprinkles” as a stable, reliable and convenient non-liquid 
formulation that will increase HU availability globally. 
Sample Size: 48 participants 
Data Management:  Data management and statistical analysis will be provided locally by 
the Hematology Division and Biostatistics Department at St. Jude Children’s Research 
Hospital. 
Human Subjects: risks to participants are related to hydroxyurea; however, since 
participants will receive only single dose HU or two doses HU on separate occasions at 20 
mg/kg, the risks are extremely unlikely and thus not anticipated. Adverse events will be 
monitored, reported and treated appropriately. 
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TABLE OF CONTENTS 
1.0 OBJECTIVES .......................................................................................................................4 
1.1. Primary Objective ................................................................................................... 4 
1.2. Secondary Objective ............................................................................................... 4 
1.3. Exploratory Objectives ........................................................................................... 4 
2.0 BACKGROUND AND RATIONALE .................................................................................4 
2.1. Background ............................................................................................................. 4 
2.2. Rationale ................................................................................................................. 7 
2.3. Background and Rationale for Exploratory Studies ............................................... 8 
3.0 RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY ENROLLMENT8 
3.1. Inclusion Criteria .................................................................................................... 8 
3.2. Exclusion Criteria ................................................................................................... 9 
3.3. Research Participant Recruitment and Screening .. Error! Bookmark not defined. 
3.4. Enrollment on Study at St. Jude ............................. Error! Bookmark not defined. 
3.5. Procedures for Identifying and Randomizing Research Participants ................... 10 
4.0 DESIGN AND METHODS ................................................................................................10 
4.1. Design and Study Overview ................................................................................. 10 
4.2. Study Interventions ............................................................................................... 11 
4.3. Study Measures ..................................................................................................... 12 
5.0 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ....................................12 
5.1. Pre-Study Evaluations ........................................................................................... 12 
5.2. Evaluations during Therapy .................................................................................. 12 
5.3. Follow-up on Study............................................................................................... 14 
6.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY 
CRITERIA ......................................................................................................................14 
6.1. Off-study criteria ................................................................................................... 14 
7.0 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ...........................15 
7.1. Reporting Adverse Experiences and Deaths to St. Jude IRB ............................... 15 
7.2. Reporting to the Federal Agencies ........................................................................ 17 
8.0 DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY ..............17 
8.1. Data Collection ..................................................................................................... 17 
8.2. Study Monitoring .................................................................................................. 17 
8.3. Confidentiality ...................................................................................................... 19 
9.0 STATISTICAL CONSIDERATIONS ................................................................................19 
9.1. Anticipated Completion Dates .............................................................................. 19 
9.2. Study Design and Sample Size Justification ......................................................... 19 
9.3. Statistical Analysis ................................................................................................ 21 
10.0 OBTAINING INFORMED CONSENT .............................................................................23 
10.1. Informed Consent Prior to Research Interventions ............................................... 23 
10.2. Consent at Age of Majority................................................................................... 23 
10.3. Consent When English is Not the Primary Language .......................................... 23 
11.0 REFERENCES ....................................................................................................................24 
12.0 APPENDIX I .......................................................................................................................26 
   13.0 
APPENDIX 
II……………………………………………………………………………..27 
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1.0 OBJECTIVES 
1.1. Primary Objective 
1.
Define the pharmacokinetics of liquid-formulated HU in infants (9 months to <2
years)
2.
Assess the relative bioavailability of HU “sprinkles” compared to capsules in
children and adolescents (≥2 to 18 years).
1.2. Secondary Objective 
Compare PK parameters in infants versus older children on this study and those from our 
previous “Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea 
in Pediatric Patients with Sickle Cell Anemia” (NCT01506544) trial. 
1.3. Exploratory Objectives 
Capture information regarding the taste of HU sprinkles using palatability questionnaire. 
2.0 BACKGROUND AND RATIONALE 
2.1. Background 
 Sickle Cell Disease (SCD) 
Every year, over 300,000 infants are born with either SCD or one of its variants with 
most births occurring in mid- to low-income countries1;2. A classic example of recessive 
Mendelian inheritance, SCD is caused by a HBB missense mutation (p.Glu6Val) and 
results in production of hemoglobin S (HbS). Deoxygenated HbS forms stiff polymers, 
leading to microvascular occlusion and chronic hemolytic anemia. Clinically, persons 
with SCD can experience a wide spectrum of debilitating problems including severe pain 
crises, acute chest syndrome, splenic sequestration, cholelithiasis, priapism, and stroke. 
SCD is associated with frequent acute events, chronic progressive organ damage, and 
early mortality3;4.  
 Hydroxyurea Therapy for children with SCD 
Hydroxyurea (HU) is a FDA approved medication for adults and children older than 2 
years of age, however based on the landmark BABY HUG trial5, current NIH guidelines 
recommend that HU be offered to most children with SCD, beginning at 9 months of 
age6. HU works in part by inducing fetal hemoglobin (HbF) expression7-9, but other 
benefits exist. For example, HU increases total hemoglobin concentration (Hb) and red 
cell mean corpuscular volume (MCV), and decreases the number of circulating white 
blood cells (WBC) and reticulocytes. All of these are beneficial effects because they 
reduce vaso-occlusion and increase blood flow, which ameliorates the clinical sequelae of 
SCD7-11.  
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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 
SCA12-15. 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 responses similar to those observed in adults and treatment was well-
tolerated without clinical AEs16.   
The first pilot trial in infants with SCD (HUSOFT) demonstrated that hydroxyurea 
therapy was feasible, well-tolerated, and it had hematologic efficacy17.  The long-term 
efficacy and safety of hydroxyurea for infants were subsequently reported in the 
HUSOFT extension study in patients receiving an escalated dose of hydroxyurea to 
MTD18.  Infants receiving continuous hydroxyurea at MTD for a total of 15 years 
exhibited normal growth and development into adolescence/young adulthood, displayed 
sustained hematologic efficacy and experienced very few vaso-occlusive and transfusion 
events19. 
Between October, 2003 and September, 2009, BABY HUG6 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’ concerns20, hydroxyurea was found to be safe in this 
young cohort. 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 creatinine21. Importantly, hydroxyurea did not adversely alter 
growth velocity22. Children treated with hydroxyurea had a normal clinical response to 
pneumococcal polysaccharide vaccines and a normal immune state23. Children did not 
suffer from an increased frequency or a delayed incidence of splenic sequestration, and 
importantly, hydroxyurea did not appear to be mutagenic24. 
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 Hydroxyurea Pharmacokinetics (PK) and Bioavailability 
Despite the safety and efficacy profiles for HU, limited data exists regarding the PK of 
HU, particularly for children under 2 years of age. Through a multicenter, prospective, 
open-label trial of 39 children (> 2 years to 17 years of age) with SCD, we compared: 1) 
bioavailability of the liquid formulation of HU administered in BABY HUG to capsules; 
and 2) HU PK profiles in younger and older children. Liquid and capsule formulations 
were bioequivalent; Younger and older children had similar PK profiles for every 
parameter tested10 (Table 1).  Furthermore, we demonstrated that that the weight-
normalized apparent clearance (CL/F/BW and CL/F/BW^0.75) of HU versus age 
supported the current weight-based dosing scheme, and that age-based dosing is not 
required in children greater than 2 years old6;11;25.  These studies provided definitive 
evidence that for children with SCD who are ≥2 years old, a weight-normalized HU 
dosing strategy results in consistent drug exposure independent of age. However, it is 
imperative to determine whether similar strategies apply to infants (≥9 months to 2 
years), by examining the PK of liquid-formulated HU in this age group.  
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; Cl/F/BW, clearance normalized for body weight. Parameters compared with 
a paired two-tailed t-test and none were significantly different. 
We have previously shown that a liquid formulation of HU was bioequivalent to a 
proprietary capsule (Droxia® 200mg) for children 2-18 years of age (Table 2). Capsules 
are the only FDA-approved formulation; however, most young children cannot swallow 
capsules. Liquid HU formulations are not standardized and require specialized 
compounding pharmacies, which are not available in many countries and in some US 
regions. Moreover, liquid formulations are unstable, particularly in hot, humid regions 
where SCD is most prevalent. Thus, new HU formulations with associated PK studies 
must be developed to optimize delivery of this proven beneficial medication to 
infants/very young children in the US and worldwide. To extend these results and 
increase HU availability in regions where liquid formulations are not available or 
unstable, there is a need to develop a stable, reliable and convenient non-liquid HU 
formulation and to assess its bioavailability in children with SCD. 
Table 1. PK parameters of a liquid HU formulation in children 
Parameters, mean (SD) 
Toddlers; n=17 
Older Children; 
n=22 
Age (y) 
4.5 (1.7) 
12.0 (3.6) 
Dose (mg/kg) 
22.7 (3.0) 
21.7 (6.4) 
Cmax (μg/mL) 
37.4 (9.3) 
34.0 (8.7) 
Tmax (hr) 
0.57 (0.34) 
0.74 (0.5) 
AUCINF (μg·hr/mL) 
104.5 (18.8) 
111.9 (29.4) 
t½ (hr) 
1.96 (0.18) 
2.3 (0.5) 
Cl/F/BW (L/hr/kg) 
0.23 (0.03) 
0.21 (0.04) 
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. 
 
Cmax, maximum observed plasma concentration;  AUClast (μg·hr/mL) indicates area under the concentration 
versus time curve calculated using the log-linear trapezoidal method from time 0 to the last quantifiable 
concentration;  AUCINF (μg·hr/mL) indicates area under the concentration versus time curve calculated 
using the log-linear trapezoidal method from time 0 extrapolated to time infinity    LS indicates least-
square. 
2.2. Rationale 
HU is the only FDA approved medication for adults with SCD and is frequently used 
“off-label” in children.  Based on the landmark BABY HUG trial, current NIH 
guidelines recommend that HU be offered to most children with SCD, beginning at 9 
months of age.  Insufficient PK data for HU in children under 2 years of age and the lack 
of a pediatric-friendly formulation impede the universal access and administration of HU 
to young SCD patients. The HOPE18 trial addresses these gaps as follows: 
1)
Insufficient PK data exist for HU in children less than 2 years of age. PK data
generated by the BABY HUG study from infants is limited due to a suboptimal PK
sampling time point10. Nevertheless, experts provided a “strong recommendation
based on high quality evidence” to begin this medication in most 9 month old
patients with SCD. Currently, the only FDA-approved HU formulations are
capsules, which infants and young children cannot swallow. Now we must generate
high quality PK parameters for drug absorption, metabolism, distribution and
excretion in infants which may differ from those observed in older children26.
2)
Universal access to HU therapy within the US and globally requires the
development of a non-liquid formulation. Young children cannot swallow capsules
and few patients (in the US or globally) have access to a liquid formulation. Liquid
formulations are costly and must be prepared in a specialized compounding
pharmacy. Additionally, liquid HU is more sensitive to heat degradation and has
limited long-term stability after compounding compared to powder27. All of these
limitations restrict the use of HU for young children in underdeveloped countries and
in some regions of the US. One potential answer could be to open capsules and
“sprinkle” the contents on food prior to administration. This is a common approach
in pediatrics and is often done without determining how the process impacts drug
stability or bioavailability. It is established that manipulating capsule formulations
Table 210. Assessment of HU bioavailability via FDA guidelines 
Parameters (units) 
Geometric LS mean 
Ratio (%) 90% Confidence limits 
Capsule 
Liquid 
Lower 
Upper 
Cmax (μg/mL) 
32.3 
33.1 
102.4 
91.8 
114.2 
AUClast (μg·hr/mL) 
100.3 
98.6 
98.3 
94.5 
102.3 
AUCINF (μg·hr/mL) 
113.3 
110.1 
97.2 
93.4 
101.1 
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may change drug absorption characteristics, destabilize the drug, cause local irritant 
effects, and/or result in a preparation with an unacceptable taste, all of which can 
alter drug exposure with significant clinical repercussions28, 29, 30. Prior to utilizing or 
endorsing HU “sprinkles” in children with SCD on a global scale, it is imperative 
that the PK of this formulation be determined in the relevant age group. 
In summary, HU is effective and for many people, the best or only therapy available, yet 
many treatment barriers hamper its universal application. The HOPE18 trial will address 
fundamental and critical knowledge gaps regarding HU availability by defining the PK 
of liquid HU in infants, and defining parameters for the use of HU “sprinkles” in 
children. The information gained could be game changing by supporting FDA approval 
in pediatric SCD and increasing drug availability for a vast number of young patients. 
2.3. Background and Rationale for Exploratory Studies 
Palatability is an important aspect of patient acceptability of an oral pediatric medicine 
and for the success of a drug and treatment outcomes.  One of our aims in this study is to 
determine bioavailability of HU capsules Droxia® to HU sprinkles in order to develop a 
pediatric-friendly formulation to allow for universal access to HU therapy globally. We 
propose to develop a palatability questionnaire to gather data related to taste.  We will 
adapt the facial hedonic scale, a commonly used scale for palatability.  
3.0 RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY 
ENROLLMENT 
3.1. Inclusion Criteria 
Participants will be eligible for this study if only if all of the following inclusion criteria 
apply: 
1.
Laboratory (i.e. electrophoretic, chromatographic or DNA) confirmation of HbSS
or HbSβ0thalassemia. 
2.
Participants may or may not be currently receiving HU. If participants are taking
HU, then their most recent dose must be ≥24 hours prior to the start of the study.
3.
Participant is in the “well” state (defined by ≥ 2 weeks since the last SCD-related
complication).
4.
Clinical evidence of normal gastrointestinal function and structure.
5.
No clinical evidence of hepatic compromise, including transaminases < 3 times
the upper limit of normal.
6.
Estimated glomerular filtration rate (Schwartz equation) > 70 ml/min/1.73m2.
7.
Body mass index (BMI) ≥5th and ≤95th percentile as per CDC growth charts.
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In addition: 
For the Pharmacokinetic Study (Arm 1): 
1.
Age ≥ 9 months and < 2 years.
2.
Able to consume a minimum of 30 ml of water following ingestion of the study
article.
 For the Bioavailability Study (Arm 2): 
1.
Age ≥ 2 years and ≤ 18 years.
2.
Weight of ≥ 10 kg
3.
Females of child-bearing potential must have a negative pregnancy test prior to
dosing and be willing to practice appropriate contraceptive measures, including
abstinence, from the time of the initial pregnancy testing through the remainder of
the study (30 days after last administration of investigational agents).
4.
Males of child-bearing potential must be willing to practice appropriate
contraceptive measures, including abstinence, during study participation (30 days
after last administration of investigational agents).
5.
Able to ingest both sprinkles and capsule study articles and consume a minimum
of 30 ml of water following ingestion of each agent.
3.2. Exclusion Criteria 
1.
Chronic transfusion therapy, or transfused within 3 months of study participation.
2.
Known renal impairment (creatinine >1.5x the upper limit of normal for age). See
Appendix II for reference ranges.
3.
Known hepatic impairment or Grade 2 or higher transaminases and bilirubin
levels. See Appendix II for reference ranges. Known malignancy.
4.
Diagnoses other than sickle cell anemia or sickle beta-zero thalassemia (i.e., other
sickle cell variants or sickle/ hereditary persistence of fetal hemoglobin).
5.
Blood count parameters as follows: hemoglobin <6.0 gm/dL, absolute reticulocyte
count <80,000/mm3, absolute neutrophil count <1000/mm3, or platelet count
<80,000/mm3.
6.
The participant has used opiates, H2 blockers, proton pump inhibitors, antacids,
other GI motility agents or any other medication that, in the opinion of the
investigator, will interfere with the study procedures or affect the interpretation of
the results of the study for 3 days prior to the first dose of study.
7.
Participants taking antiretroviral drugs (including didanosine and stavudine) due
to increased risk of toxicity with concomitant use.
8.
Participation in another clinical intervention trial utilizing an IND/IDE agent, but
can participate in HUGKISS since same drug agent.
3.3.  Research Participant Recruitment and Screening 
Universal newborn screening data will be utilized to identify potentially eligible 
children. In light of the recent NIH/NHLBI treatment guidelines for SCD recommending 
that HU therapy be offered to all infants at 9 months of age and our team’s experience 
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with the HUG KISS trial, we will approach all available eligible participants. The local 
PI and/or study coordinator will discuss the trial objectively with the families of eligible 
patients until enrollment goals are met. 
3.4     Enrollment on Study at St. Jude 
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): 
. 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 CST, Monday through Friday. A staff member 
is on call Saturday, Sunday, and holidays from 8:00 am to 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). 
 
      
3.4. 3.5  Procedures for Identifying and Randomizing Research Participants 
Older children (n=30 children; ≥2 to 18 years) will participate in a randomized crossover 
study designed to determine the relative bioavailability of opening HU capsules and 
mixing them with food (sprinkles) compared to the standard clinically utilized 
formulation for age (unmanipulated capsules). Participants will be randomized in a 1:1 
ratio to receive sprinkle formulation and capsules (Droxia® 200 mg), on two separate 
occasions separated by at least 1 but no more than 30 days in a randomized, crossover 
fashion. Assignment to treatment groups will be determined by a computer-generated 
random sequence housed within the Department of Biostatistics (see section 9.2). 
 
4.0 DESIGN AND METHODS 
4.1. Design and Study Overview 
This trial will be an open label, 2-arm study of HU disposition in 48 children with SCD.  
 
In Arm 1 of this study, n=18 infants ages 9 months to 2 years will be administered an 
extemporaneous oral liquid formulation of HU on a single occasion followed by PK 
sampling. The dose administered will be ~20 mg/kg/day or the infant’s usual daily dose.  
 
In Arm 2, n=30 children who range in age from 2 to 18 years will be administered HU, 
both a sprinkle formulation and capsules (Droxia® 200 mg), on two separate occasions 
separated by at least 1 but no more than 30 days in a randomized, crossover fashion. The 
doses of HU on each occasion will be rounded to the nearest 200 mg and will not exceed 
35 mg/kg or 2000 mg (Figure 1)(Appendix 1).  
 
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Participants in both arms will be followed up to 30 days from receiving last HU dose. 
 
 
              Figure 1: Study Design  
 
 
4.2. Study Interventions 
Two different formulations of hydroxyurea will be used in this study: a liquid 
formulation and capsules. 
 
Purchased hydroxyurea, USP will be hand filled into amber wide-mouth bottles with 
poly-seal-lined caps at KP Pharmaceutical Technology, Inc. (Bloomington, IN) a cGMP 
compliant facility. Due to limited stability of liquid formulations, clinical trial material 
will be reconstituted on site within the St. Jude Investigational Pharmacy with Syrpalta® 
(without color) and purified water to achieve a final liquid concentration of 100 mg/mL. 
We have performed microbial examination and stability testing on HU liquid 
formulation (100 mg/ml) stored at room temperature for 6-weeks.  All samples meet 
USP release testing and specifications listed under the currently approved IND 
(#132032) for HUGKISS protocol.  A single dose of this preparation will be dispensed 
to a participant and any remainder of the study drug will be stored and destroyed in a 
manner consistent with St. Jude Children’s Research Hospital Pharmaceutical Services 
standard operating procedures. 
 
Purity (95-105%) of Hydroxyurea, USP validated by GC-MS. 
Source: Spectrum Pharmacy Products (New Brunswick, NJ) 
 
Capsules (Droxia® 200 mg) will be purchased commercially and supplied to the St. Jude 
Children's Research Hospital Investigational Pharmacy without modification or 
disturbance of the commercially obtained bottles. Following USP795 and USP800, the 
capsule(s) will be opened by pharmacist/pharmacy technician and contents mixed in 10 
mL of sterile water in a powder containment hood and transferred to participant in a 
labeled, child-resistant bottle.  The diluted hydroxyurea will be mixed with 2 ounces of 
rice cereal or pudding by the participant/caregiver or clinic nurse if assistance is needed.  
The bottle will be rinsed with additional 10 mL of water and mixed with the rice cereal 
or pudding. It will be administered as soon as possible (ideally within 15 minutes and no 
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later than 1 hour after mixing).  PK sampling will occur in clinic at predefined time 
points.  Participant’s dosing will be rounded to the nearest 200 mg of hydroxyurea and 
will only be administered in increments of an entire capsule.  
 
4.3. Study Measures 
The main study measures are pharmacokinetic parameters for 1) HU liquid formulation 
in infants (9 months to <2 years) and 2) HU “sprinkles” compared to capsules in children 
and adolescents (≥2 to 18 years). 
 
HU levels will be determined via validated gas chromatography-mass spectrometry (GC-
MS). This technique is linear from 0.1–100 µg/mL of HU and has an intra- and inter-
assay coefficient of variation of <10% across concentrations spanning the range of 
linearity31. 
 
5.0 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
5.1. Pre-Study Evaluations 
Eligibility screening (ES) and baseline evaluations (BE) will be performed prior to 
administration of the study drug.  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 (Table 3). Collection of hydroxyurea dosing history including dose and time of 
administration for at least 2 days prior to study doses for participants taking hydroxyurea 
prior to enrollment.  
5.2. Evaluations during Therapy 
Participants on the study will receive the following evaluations as detailed in Table 3. 
 
Table 3. Schedule of Evaluations 
Evaluation 
ES1 
BE 
Day 1 
Day 2-302 
Off Study 
 
-4 to 0 
0 
within 30 
days of 
enrollment 
 
± 4 weeks 
 
Informed Consent 
X 
 
 
 
 
Weight, height & vital signs 
X 
X 
X 
X 
X 
History, physical exam 
X 
X 
X 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Hemoglobin identification3 
X 
 
 
 
 
Pregnancy Test 
 
X 
 
X 
 
CBC with WBC count 
 
X 
 
X 
 
Reticulocyte count 
 
X 
 
X 
 
Hydroxyurea Dose 
 
 
X 
X 
 
Pharmacokinetic Sampling Pre dose 
 
  
X 
 
 
Pharmacokinetic Sampling Post dose 
 
 
X 
X 
 
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Palatability Questionnaire4 
 
 
X 
 
 
 
ES, eligibility screening; BE, baseline evaluation which should be performed prior to administration of 
study drug.1Eligibility screening may be performed the same time as baseline evaluations. 
2Assessments on Day 2-30 will only occur for children enrolled on Arm 2 of the HOPE18 trial. This is 
a single visit that could occur any day between 2-30 days after the first dose. 3A 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. 4 Only completed by participants on Arm 2 of the HOPE18 
trial. 
 
Pharmacokinetic Blood Sampling. Blood sampling for HU levels will occur via an indwelling 
peripheral vein catheter at pre-dose, then 10 min, 15 min, 30 min, 45 min, and 1, 1.5, 2, 4, 6, and 
8 hours after a directly observed dose of HU. At each time point, 1 ml whole blood will be 
collected into heparinized tubes, inverted a minimum of 8-10 times, held on ice, centrifuged at 
750 x g for 10 minutes at 4°C, plasma will then be stored at -80°C within 30 minutes of sample 
collection. Batches of 50 frozen samples will be shipped to Children’s Mercy Hospital (Kansas 
City, MO) for HU level determination via validated gas chromatography-mass spectrometry 
(GC-MS).  Participants will be allowed clear liquids from the approved list as desired up to 1 
hour before and then one hour after Hydroxyurea administration. Participants can then eat an age 
appropriate meal 2 hour after dosing.  (Estepp 2016) See Table below:  
 
 
Table 4. PK Blood collection log  
Day 
Scheduled time point 
PK collection number 
Sample volume (mL) 
1 
Pre-dose (±3 min) 
1 
1 
1 
Post-dose 10 min (±3 min) 
2 
1 
1 
Post-dose 15 min (±3 min) 
3 
1 
1 
Post-dose 30 min (±3 min) 
4 
1 
1 
Post-dose 45 min (±5 min) 
5 
1 
1 
Post-dose 1 hour (±5 min) 
6 
1 
1 
Post-dose 1.5 hour (±5 min) 
7 
1 
1 
Post-dose 2 hour (±10 min) 
8 
1 
1 
Post-dose 4 hour (±10 min) 
9 
1 
1 
Post-dose 6 hour (±10 min) 
10 
1 
1 
Post-dose 8 hour (±10 min) 
11 
1 
2-30* 
Pre-dose (±3 min) 
12 
1 
2-30* 
Post-dose 10 min (±3 min) 
13 
1 
2-30* 
Post-dose 15 min (±3 min) 
14 
1 
2-30* 
Post-dose 30 min (±3 min) 
15 
1 
2-30* 
Post-dose 45 min (±5 min) 
16 
1 
2-30* 
Post-dose 1 hour (±5 min) 
17 
1 
2-30* 
Post-dose 1.5 hour (±5 min) 
18 
1 
2-30* 
Post-dose 2 hour (±10 min) 
19 
1 
2-30* 
Post-dose 4 hour (±10 min) 
20 
1 
2-30* 
Post-dose 6 hour (±10 min) 
21 
1 
2-30* 
Post-dose 8 hour (±10 min) 
22 
1 
*Arm 2 only 
 
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Table 5. Approved Clear Liquids 
 
• Ice chips 
• Gelatin (Jell-O, etc.; sweetened, with no fruit) 
• Popsicles (sweetened, made from flavored water) 
• Beverages made with flavored drink mix (Kool-Aid, etc.) 
• Soda pop 
• Clear broth 
• Sports drinks (Gatorade, etc.) 
• Other electrolyte drinks (Pedialyte, etc) 
            *Fruit juice and fruit juice-containing products (including those containing apple juice) are not 
permitted.  
 
 
5.3. Follow-up on Study 
Participants in both arms of the study will be followed up 30 days from their 
hydroxyurea dose and will receive baseline labs, CBCs, Reticulocyte counts, toxicity 
discussions and adverse events collection.  The follow-up visit will be scheduled to 
coincide with a routine clinical visit. 
 
6.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND 
OFF-STUDY CRITERIA 
6.1. 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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7.0 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
7.1. Reporting Adverse Experiences and Deaths to St. Jude IRB 
The Common Terminology Criteria for Adverse Events (CTCAE) version 5 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.  
 
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 
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• 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.  
 
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 
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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.  
7.2. Reporting to the Federal Agencies 
Study coordinator will assist PI with protocol submissions for review by federal or 
institutional committees as applicable. 
 
 
8.0 DATA 
COLLECTION, 
STUDY 
MONITORING, 
AND 
CONFIDENTIALITY 
 
8.1. Data Collection  
Data will be captured during each study visit (Table 3). The Clinical Trials Group within 
the Department of Hematology at SJCRH will assist in creating and managing a secure 
HOPE18 database. All data entered will have verifiable source documents in the medical 
record, which will be made available for review at site monitoring and audit visits. Study 
staff will complete a Manual of Operations (MOO) for the study and will complete data 
entry as outlined in the MOO. The protocol coordinator will monitor database entries for 
protocol and regulatory compliance.  
8.2. Study Monitoring 
High Risk 3 (HR-3) – Phase II, Phase III or Pilot Therapeutic Studies with an IND 
or IDE 
 
This study is considered high risk (HR-3) for monitoring purposes. Protocol and 
regulatory compliance, including essential regulatory documentation, will be assessed as 
well as the accuracy and completeness of all data points relating to the primary and 
secondary objectives semi-annually.  If the study design has strata, accrual will be 
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tracked continuously.  The first two enrollees will be monitored and 15 % of the study 
enrollees thereafter, semi-annually.  
The PI and study team are responsible for protocol and regulatory compliance, and for 
data accuracy and completeness.  The study team will meet at appropriate intervals to 
review case histories or quality summaries on participants and retain copies of the 
minutes which are signed by the PI. 
 
The Eligibility Coordinators in the Central Protocol and Data Monitoring Office 
(CPDMO) will verify informed consent documentation and eligibility status on 100% of 
St. Jude participants within 5 working days of enrollment completion. 
 
The Clinical Research Monitor (CRM) will verify informed consent documentation and 
eligibility status of all non-St. Jude participants and perform a quality verification of 
select St. Jude participants during routine monitoring intervals (every 6 months). Overall 
study conduct, compliance with primary and secondary objectives, age of majority 
consenting, safety assessments and reporting, and the timeliness and accuracy of 
database entries are monitored routinely.   
 
Study documents routinely monitored on selected participants include medical records, 
database entries, study worksheets, and case report forms.  Study documents are 
monitored for participant status, demographics, staging, subgroup assignment, 
treatments, investigational drug accountability, evaluations, responses, participant 
protocol status, off-study and off-therapy criteria, and for all other specifics as detailed 
in a separate study-specific monitoring plan. The study-specific monitoring plan may be 
revised over time, to adapt monitoring frequency and/ or intensity to a changing 
environment when appropriate (for example:  new safety signals; positive history of 
compliance; all participants are in long term follow-up; or the enrollment period has 
ended). 
 
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness 
and appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate a 
formal report which is shared with the Principal Investigator (PI), study team and the 
Internal Monitoring Committee (IMC). 
 
Continuing reviews by the Internal Review Board (IRB) and Clinical Trials- Scientific 
Review Committee (CT-SRC) will occur at least annually.  In addition, unanticipated 
problems are reviewed in a timely manner by the IRB. 
 
St. Jude affiliates and domestic collaborating study sites will be monitored on-site by a 
representative of St. Jude as needed.  International collaborators will be monitored by a 
Contract Research Organization (CRO), or other mechanism according to the study 
specific monitoring plan. 
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8.3. Confidentiality 
Blood samples sent for PK analysis will be de-identified and replaced with unique study 
codes. The list containing the study number and the medical record number will be 
maintained in a locked file and will be retained indefinitely. Samples will be stored and 
batched in the St. Jude Biorepository by trained personnel used to handling human 
specimens and with strict procedures for protecting participant confidentiality. Samples 
sent for PK analysis to Children’s Mercy Hospital (Kansas City, MO) will be sent in a 
de-identified manner.  
 
9.0 STATISTICAL CONSIDERATIONS 
9.1. Anticipated Completion Dates 
 
9.2. Study Design and Sample Size Justification 
This is a prospective, open-label, trial composed of 2 arms. Arm 1 is to define the 
pharmacokinetics of liquid-formulated HU in infants (9 months to <2 years). Arm 2 is to 
assess the relative bioavailability of HU “sprinkles” compared to capsules in children 
and adolescents (≥2 to 18 years). In arm 1, n = 18 infants ages 9 months to 2 years will 
be administered an extemporaneous oral liquid formulation of HU on a single occasion 
followed by PK sampling. In arm 2, n = 30 children who range in age from 2 to 18 years 
will be administered HU, both a sprinkle formulation and capsules (Droxia® 200 mg), on 
two separate occasions separated by at least 1 but no more than 30 days in a randomized, 
crossover fashion. All infants in arm 1 will receive one dose of liquid HU and will be 
followed up to 30 days post HU to monitor any potential adverse toxicities per FDA 
safety mandate. All older patients in arm 2 with two doses of HU will be followed up to 
30 days post second dose of HU to monitor any potential adverse toxicities per FDA 
safety mandate. The patients enrolled on arm 1 can be enrolled on arm 2 later on. Thus, 
in total, a maximum of 48 patients will be needed to answer the primary and secondary 
objectives of this HOPE18 study. On our current ongoing frontline HUGKISS study, 
there were 6 patients aged 9 months to 24 months enrolled at St. Jude in the last three 
months (The first patient was enrolled on study on June 19, 2017). Based on this accrual 
rate of about 2 patients each month, we are able to enroll 18 patients in arm 1 within 
approximately one year. As of today, 244 children with sickle cell disease aged 5-18 
years are receiving hydroxyurea therapy as per best clinical practices as St. Jude 
Children’s Research Hospital.  We anticipate an accrual rate of 2 patients each month, 
which would allow for completion of enrollment of arm 2 (n=30) within approximately 
15 months. 
 
Anticipated Primary Completion Date: 06/30/2020 
Anticipated Study Completion Date: 06/30/2022 
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Statistical planning for primary and secondary objectives is based on PK data that we 
generated from the multicenter, HU PK trial11, in compliance with published FDA 
guidance 
on 
the 
determination 
of 
bioequivalence 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/ucm070244.pdf). From this study, 22 individuals aged from 2 to 17 years were 
randomized to liquid and capsule based on a cross-over design. The mean ± SD are 
AUCinf (Mean±SD: 114.1±29.4), AUClast (Mean±SD: 101.7±24.7), and Cmax (Mean±SD: 
33.8±8.3) based on 44 samples (22 individuals), respectively.  
 
In arm 1, children (n = 18; ages 9 months to <2 years) with SCD being treated with HU 
will participate in Arm 2 of the HOPE18 trial. A comparison of PK parameters in infants 
versus older children from the HOPE18 Arm 2 and from our previous 
“Pharmacokinetics and Bioavailability of a Liquid Formulation of Hydroxyurea in 
Pediatric Patients with Sickle Cell Anemia” (NCT01506544) trial11 will be performed. 
Assuming all samples are independent and SDs are the same between two groups, this 
comparison in 18 infants compared to 74 older children (30 patients from HOPE18 trial 
and 44 patients from HU PK trial) will provide 82.9%, 87% and 86.3% power with a 
significance level 0.05 to detect a 20% difference in AUCinf, AUClast, or Cmax using two-
sample t-test with two-sided test, respectively.  
 
In arm 2, older children (n = 30 children; ≥2 to 18 years) will participate in a randomized 
crossover study designed to determine the relative bioavailability of opening HU 
capsules and mixing them with food (sprinkles) compared to the standard clinically 
utilized formulation for age (unmanipulated capsules). Bioequivalence studies between 
treatment and control groups will be performed in 30 individuals. These tests are based 
on a 2-sided ratio of means in a 2x2 crossover design with continuous response variable, 
and they assume equivalence limits (upper and lower) of 0.8 and 1.2. By randomizing 30 
individuals to the test article versus the standard of care with an allocation ratio of 1, we 
will have 82.4%, 85.9% and 82.4% power with a significance level of 0.05 for AUCinf 
(mean = 114.1), AUClast (mean = 101.7) , and Cmax (mean = 33.8) with a root mean 
square error of the log ratio of 0.25 using two-sample t-test with two-sided test, 
respectively (for example for AUCinf: the coefficient of variation (CV) is 29.4/114.1 = 
0.258; thus, the mean square error (MSE) is equal to log(1+0.258^2) = 0.064; so, the 
square root of MSE is 0.25) using two-sample t-test with two-sided test, respectively. In 
addition, point estimates (PEs) for AUCinf, AUClast, and Cmax are 97.2, 98.3, and 102.4 
(NCT01506544)11. Per Diletti E, Hauschke D, and VW Steinijans method, (Int J Cli 
Pharmacol Ther Toxicol 29, 1-8, 1991), the sample size to reach 80% power with a 
significance level of 0.05 to detect a CV of 0.25 with PEs ranging from 97.2 to 102.4 
would be 28 which is slightly smaller than 30. 
 
Randomization: In arm 2, eligible patients will be consented and randomized in a 1:1 
ratio in an open label fashion based on a 2×2 cross-over design to receive either Capsule-
Sprinkle or Sprinkle-Capsule. Randomization will be performed by CRA based on the 
registration identifiers, using the randomization 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.  
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9.3. Statistical Analysis 
 
9.3.1 Primary Objective 
 
Define the pharmacokinetics of liquid-formulated HU in infants (9 months to <2 
years) 
 
Summary statistics including mean, SD, median and range will be reported for all 
pharmacokinetics parameters including Cmax, Tmax, AUClast, AUCinfinity, Mean Residence 
Time (MRT), CL/F/BW, λz, and t1/2. Here all these pharmacokinetics parameters are 
summary statistics calculated from all pharmacokinetics samples as below.   
Cmax: The maximum concentration observed after dosing. 
Tmax: The time of maximum observed concentration (Cmax) relative to time of dosing. 
AUClast: The area under the concentration-time curve from time of dosing of the drug to 
the time of the last measurable concentration or when concentrations were Below the 
Limit of Quantitation (BLQ) were calculated using either the linear (concentration 
before Cmax) or log trapezoidal rule (concentrations after Cmax). 
AUCinfinity: The AUC extrapolated from the last measured concentration (Clast) to time 
infinity using the formula AUClast + Clast / λz 
MRT: Mean Residence Time as generated by WinNonlin (AUMC/AUC). 
CL/F: Apparent clearance calculated from Dose/ AUCINF 
CL/F/BW: Apparent clearance normalized for Body Weight (BW) 
λz: (Elimination slope): The first-order linear slope associated with the terminal (log-
linear) portion of the curve and estimated via linear regression of log concentrations vs. 
time. 
t½: Terminal elimination half-life obtained from: t½ = ln(2)/ λz. 
 
Assess the relative bioavailability of HU “sprinkles” compared to capsules in 
children and adolescents (≥2 to 18 years).  
 
Summary statistics similar to the first objective will be reported for “sprinkles” and 
capsules and will be compared using two-sample t-test or Wilcoxon rank sum test 
depending on the normality of the data at a significance level of 0.05 per study design 
above. Logarithmic transformation will be applied if data do not follow normal. Mixed 
effects linear model (e.g., SAS PROC MIXED) will also be used as a secondary analysis 
to account for the repeated measurements that yield period and carryover effects and to 
model the various sources of intra-patient and inter-patient variability.     
  
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9.3.2 Secondary Objective 
 
Compare PK parameters in infants versus older children on this study and those 
from our previous “Pharmacokinetics and Bioavailability of a Liquid Formulation 
of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia” (NCT01506544) 
trial. 
 
We will compare PK parameters as listed in first primary objective in two groups: 
infants versus older children. The older children will include children on arm 2 on this 
study and those from our previous “Pharmacokinetics and Bioavailability of a Liquid 
Formulation of Hydroxyurea in Pediatric Patients with Sickle Cell Anemia” 
(NCT01506544) trial. Statistical analysis methods are similar to those for the second 
primary objective. In detail, summary statistics will be reported for the infants and older 
children and will be compared using two sample t-test or Wilcoxon rank sum test 
depending on the normality of the data. Logarithmic transformation will be applied if 
data do not follow normal. Due to the repeated measurements in the older children, 
mixed effects linear model (e.g., SAS PROC MIXED) will also be used to account for 
the repeated measurements. Depending on the conclusion from the second primary 
objective after the study is completed, appropriate statistical models will be used to 
compare PK parameters in infants versus the older children. For example, after the study 
is completed, if the second primary objective shows the relative bioavailability of HU 
“sprinkles” versus capsules in children and adolescents and no yield period and 
carryover effect, then we will not include yield period, treatment and sequences in the 
model as a covariate. Otherwise, if the second primary objective does not show the 
relative bioavailability, we will compare the infants with the older children with 
Sprinkles on this study and with capsules and liquid on this study and NCT01506544, 
separately.  
 
9.3.3 Exploratory Objective 
 
Capture information regarding the taste of HU sprinkles using palatability 
questionnaire. 
 
Descriptive statistics will be reported. 
 
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10.0 
OBTAINING INFORMED CONSENT 
10.1. 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 the Hematology clinic. 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 HOPE18 pilot 
study. 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 $100 payment for participation over the 
course of the study other than the costs of medical care performed as part of the study 
and modest reimbursement for parking, food, and travel. Subjects and families will be 
informed of any information that becomes available during the trial that might impact 
their continued participation. 
10.2. Consent at Age of Majority 
The age of majority in the state of Tennessee is 18 years old.  Research participants will 
be consented at the next clinic visit after their 18th birthday.   
10.3. 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 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. 
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11.0 
REFERENCES 
 
1.  
Piel FB, Patil AP, Howes RE et al. Global epidemiology of sickle haemoglobin in 
neonates: a contemporary geostatistical model-based map and population estimates. 
The Lancet 2012;381:142-151. 
 2.  
Piel F, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global Burden of Sickle Cell 
Anaemia in Children under Five, 2010-2050: Modelling Based on Demographics, 
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Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. 
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12.0 
APPENDIX I 
 
Dosing for Hydroxyurea Naïve  
kg 
Dose Administered in Clinic 
10-14.9 
200 
15.0-24.9 
400 
25.0-34.9 
600 
35.0-44.9 
800 
45.0-54.9 
1000 
55.0-64.9 
1200 
65.0-74.9 
1400 
75.0-84.9 
1600 
85.0-94.9 
1800 
95.0-100.0 
2000 
 
 
Dosing for Chronic Hydroxyurea Therapy 
Daily Dose 
Dose Administered in Clinic 
150-299.9 
200 
300-499.9 
400 
500-699.9 
600 
700-899.9 
800 
900-1099.9 
1000 
1100-1299.9 
1200 
1300-1499.9 
1400 
1500-1699.9 
1600 
1700-1899.9 
1800 
1900-2000 
2000 
 
 
 
 
 
 
 
 
 
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13.0 
APPENDIX II 
 
Reference Ranges  
 
Serum Creatinine 
Male                                                                
Age  
mg/dL 
0-30d  
0.22-0.48 
31d-1y 
0.13-0.34 
2-3y 
0.17-0.45 
4-6y 
0.22-0.53 
7-9y 
0.26-0.66 
10-12y 
0.30-0.80 
13-15y 
0.41-1.05 
>15y  
0.55-1.33 
 
Female  
Age  
mg/dL 
0-30d  
0.22-0.48 
31d-1y 
0.13-0.34 
2-3y 
0.17-0.45 
4-6y 
0.22-0.53 
7-9y 
0.26-0.66 
10-12y 
0.30-0.80 
13-15y 
0.41-1.05 
>12y 
0.40-1.01 
 
ALT- Alanine aminotransferase   
 
Range 
<41 U/L 
 
AST- Aspartate aminotransferase 
 
Age 
U/L 
0-3y 
<61 
4-6y 
<51 
>6y 
<41 
 
 
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