Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

• Sponsor: St. Jude Children's Research Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03020615
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 58
• Locations: 4
• Arms: 2
• Actual Duration (Months): 36.9
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia	Drug: Hydroxyurea	Phase 2

Detailed Description

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Official Title: Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies
• Actual Study Start Date: May 12, 2017
• Actual Primary Completion Date: Jun 8, 2020
• Actual Study Completion Date: Jun 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Stable Dosing In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	Drug: Hydroxyurea; Given orally once daily.; Other Names: HU
Experimental: Intensive Dosing In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	Drug: Hydroxyurea; Given orally once daily.; Other Names: HU

Outcome Measures

Primary Outcome Measures

1. Number of Patients Enrolled. [at baseline]

   A count of the number of patients enrolled will be provided.

2. Number of Patients Randomized [Eight weeks (± 2 weeks) after study enrollment]

   A count of the number of patients randomized will be provided.

3. Number of Randomized Patients With ≥80% Chronic Medication Compliance [At completion of therapy, up to 56 weeks after study enrollment]

   Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].

4. Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit [At baseline and at completion of the protocol, up to 56 weeks after study enrollment]

   The number of patients who have successfully provided %HbF at baseline and study exit will be provided.

Secondary Outcome Measures

1. Frequency by Reason Given for Refusal for Study Participation [Once, at enrollment]

   Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.

2. Number of Patients With Hospitalizations by Arm [From baseline through completion of therapy, up to 56 weeks]

   The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.

3. Cumulative Number of Hospitalizations by Arms [From baseline through completion of therapy, up to 56 weeks]

   The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.

4. Mean Change in Hemoglobin (g/dL) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

5. Median Change in Hemoglobin (g/dL) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided.

6. Mean Change in Fetal Hemoglobin (%) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided.

7. Median Change in Fetal Hemoglobin (%) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

8. Mean Change in Mean Corpuscular Volume (fL) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided.

9. Median Change in Mean Corpuscular Volume (fL) [From baseline at study entry to completion of therapy, up to 56 weeks]

   Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

10. Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

11. Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

12. Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

13. Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

14. Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

15. Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

16. Mean Change in Platelet Count (*10^3 Platelets/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

17. Median Change in Platelet Count (*10^3 Platelets/µL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

18. Mean Change in Bilirubin (mg/dL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

19. Median Change in Bilirubin (mg/dL) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

20. Mean Change in Lactate Dehydrogenase (Units/L) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.

21. Median Change in Lactate Dehydrogenase (Units/L) [From baseline at study entry to completion of therapy, up to 56 weeks]

    Descriptive statistics of the change between baseline and completion of the study will be provided.

22. Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities [From baseline at study entry to completion of therapy, up to 56 weeks]

    Normal TCD velocities will be defined as TCD velocities <170 cm/s.

23. Number of Participants Who Undergo Surgery [From start of therapy through completion of therapy, up to 56 weeks]

    Any operative procedure will be included.

24. Number of Participants Who Undergo Transfusion [From start of therapy through completion of therapy, up to 56 weeks]

    Transfusion will be defined as the provision of red blood cells to correct anemia.

25. Number of Patients With Toxicities Related to Hydroxyurea Dosing [From start of therapy through completion of therapy, up to 56 weeks]

    Number of patients with toxicities to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).

26. Number of Toxicities Related to Hydroxyurea Dosing [From start of therapy through completion of therapy, up to 56 weeks]

    Number of toxicities will be reported to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).

27. Change in Pain and Hurt Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

28. Change in Pain Impact Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

29. Change in Pain Management Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

30. Change in Worry I Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

31. Change in Worry II Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

32. Change in Emotions Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

33. Change in Treatment Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

34. Change in Communication I Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

35. Change in Communication II Score [From baseline at study entry to completion of therapy, up to 56 weeks]

    Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 9 Months to 36 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Children with HbSS or sickle hemoglobin (HbS)/β^0thalassemia

• ≥9 to ≤ 36 months of age at study initiation

• Enrollment will occur irrespective of clinical severity

Exclusion Criteria:

Permanent:

• Receiving chronic red blood cell transfusion therapy.

• Condition or chronic illness, which in the opinion of the PI makes participation unsafe.

Transient (participants may be re-evaluated after ≥14 days):

• Recent (<30 days) participation in another clinical intervention trial utilizing an investigational new drug/investigational device exemption (IND/IDE) agent.

• Erythrocyte transfusion in the past 2 months.

• Laboratory Assessments:

• Hemoglobin <6.0 g/dL

• Absolute reticulocyte count <80 * 10^3/µL if hemoglobin <9.0 mg/dL

• Absolute neutrophil count <1.5 * 10^3/µL

• Platelet count <100 * 10^3/µL

• Serum creatinine > twice the upper limit of normal for age

• Alanine aminotransferase (ALT) > twice the upper limit of normal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University/Children's Health Care of Atlanta	Atlanta	Georgia	United States	30322
2	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
3	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
4	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390-9063

Sponsors and Collaborators

• St. Jude Children's Research Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Jeremie Estepp, MD, St. Jude Children's Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 9, 2020

More Information

Additional Information:

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Publications

None provided.

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT03020615
• Other Study ID Numbers: HUGKISS; R34HL127162
• First Posted: Jan 13, 2017
• Last Update Posted: Jun 25, 2021
• Last Verified: May 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by St. Jude Children's Research Hospital: Sickle cell; Hydroxyurea; Infants
• Additional relevant MeSH terms: Anemia, Sickle Cell; Hydroxyurea

Study Results

Participant Flow

Recruitment Details

The study planned to enroll up to 65 children with sickle cell anemia (SCA) to get 50 randomized in a 27-month period. All eligible participants who consented were enrolled on the study. The duration of the study is based on sample size of 50 patients randomized and/or 27-month period, whichever comes first. Actual recruitment occurred 5/3/2017 to 6/3/2019 and 58 subjects were enrolled to yield 51 randomized at 4 clinical centers.

Pre-assignment Detail

Participants without toxicity or with toxicity which requires discontinuation of hydroxyurea (HU) but resolved and participant continuing HU during those eight weeks (±2 weeks), were randomized to receive standard or intensive therapy based on a block randomization (block size of 4 used in each stratum) stratified by clinical center and by baseline age of the participant (9 to <24 months and 24 to 36 months) because of the natural physiologic decline of HbF with increasing age.

Arm/Group Title	Stable Dosing	Intensive Dosing	Non-Randomized
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	Participants who came off study prior to randomization
Period Title: Overall Study
STARTED	26	25	7
COMPLETED	19	23	0
NOT COMPLETED	7	2	7

Baseline Characteristics

Arm/Group Title	Stable Dosing	Intensive Dosing	Non-Randomized Patients	Total
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment. Hydroxyurea: Given orally once daily.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day. Hydroxyurea: Given orally once daily.	Patients who came off study prior to randomization	Total of all reporting groups
Overall Participants	26	25	7	58
Age (Count of Participants)
<=18 years	26 100%	25 100%	7 100%	58 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (months) [Median (Full Range) ]
Median (Full Range) [months]	9	10	18	10
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	12.9 (7.9)	12.8 (6.2)	18.1 (4.7)	13.5 (7.0)
Sex: Female, Male (Count of Participants)
Female	15 57.7%	8 32%	2 28.6%	25 43.1%
Male	11 42.3%	17 68%	5 71.4%	33 56.9%
Race/Ethnicity, Customized (Count of Participants)
Black	25 96.2%	25 100%	6 85.7%	56 96.6%
White	1 3.8%	0 0%	0 0%	1 1.7%
Unknown	0 0%	0 0%	1 14.3%	1 1.7%
Non-Spanish speaking Non Hispanic	26 100%	23 92%	6 85.7%	55 94.8%
Non-Spanish speaking Non Hispanic (Unknown)	0 0%	2 8%	1 14.3%	3 5.2%
Region of Enrollment (Count of Participants)
St. Jude Children's Research Hospital	16 61.5%	17 68%	0 0%	33 56.9%
Children's Healthcare of Atlanta	8 30.8%	5 20%	4 57.1%	17 29.3%
University of Mississippi Medical Center	1 3.8%	2 8%	2 28.6%	5 8.6%
University of Texas Southwestern Medical Center	1 3.8%	1 4%	1 14.3%	3 5.2%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Enrolled.
Description	A count of the number of patients enrolled will be provided.
Time Frame	at baseline

Outcome Measure Data

Analysis Population Description

58 subjects enrolled on study. Of those, n=7 came off study prior to randomization (N=2 came off study due to PI discretion, n=4 came off study due to Parent/guardian/patient choice, and n=1 was a screen failure (HBG)). The remaining n=51 were randomized.

Arm/Group Title	All Participants
Arm/Group Description	All Participants enrolled on study.
Measure Participants	58
Count of Participants [Participants]	58 223.1%

2. Primary Outcome

Title	Number of Patients Randomized
Description	A count of the number of patients randomized will be provided.
Time Frame	Eight weeks (± 2 weeks) after study enrollment

Outcome Measure Data

Analysis Population Description

Fifty-one were randomized out of the 58 enrolled.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Count of Participants [Participants]	26 100%	25 100%

3. Primary Outcome

Title	Number of Randomized Patients With ≥80% Chronic Medication Compliance
Description	Chronic medication compliance is defined based on medication possession ratio (MPR), a measure of the percentage of time that a patient has access to medication. Each participant's MPR is calculated as [(days medication in family's possession/days prescribed medication) * 100].
Time Frame	At completion of therapy, up to 56 weeks after study enrollment

Outcome Measure Data

Analysis Population Description

There were 51 subjects randomized to treatment of which 42 completed the protocol therapy. MPR was calculated on the full study period. The n=9 patients that were withdrawn were counted as <80% chronic medical compliance. Of the n=42 patients that completed protocol treatment, n=41 had ≥80% chronic medication compliance.

Arm/Group Title	Randomized Participants
Arm/Group Description	Number of participants randomized.
Measure Participants	51
Count of Participants [Participants]	41 157.7%

4. Primary Outcome

Title	Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit
Description	The number of patients who have successfully provided %HbF at baseline and study exit will be provided.
Time Frame	At baseline and at completion of the protocol, up to 56 weeks after study enrollment

Outcome Measure Data

Analysis Population Description

N=42 patients completed the protocol therapy and had labs collected at exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Number [Participants]	19 73.1%	23 92%

5. Secondary Outcome

Title	Frequency by Reason Given for Refusal for Study Participation
Description	Descriptive statistics of count and frequency will be provided for participants who were approached but refused to be enrolled on the study.
Time Frame	Once, at enrollment

Outcome Measure Data

Analysis Population Description

n=154 subjects declined to participate in HUGKISS and provided the following reasons for declining to participate.

Arm/Group Title	Subjects Approached Who Declined Participation
Arm/Group Description	Subjects who declined to participate in HUGKISS and provided reasons for declining
Measure Participants	154
Does not meet eligibility criteria	33 126.9%
Family wants more time to consider participation	31 119.2%
Child on hydroxyurea (HU)	29 111.5%
Unknown reason	17 65.4%
Not interested in HU	16 61.5%
Poor clinic visit compliance	13 50%
Not interested in research	10 38.5%
Logistics - travel distance to site, frequency of appointments	5 19.2%

6. Secondary Outcome

Title	Number of Patients With Hospitalizations by Arm
Description	The number of patients with hospitalizations will be provided by arm. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.
Time Frame	From baseline through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

The n=51 subjects that were randomized to treatment.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Count of Participants [Participants]	2 7.7%	2 8%

7. Secondary Outcome

Title	Cumulative Number of Hospitalizations by Arms
Description	The total number of hospitalization events will be provided by arms. This analysis approach is different than what was written in the protocol due to small number of participants with hospitalizations and small number of hospitalization events.
Time Frame	From baseline through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

The n=51 subjects that were randomized to treatment.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Number [hospitalizations]	4	5

8. Secondary Outcome

Title	Mean Change in Hemoglobin (g/dL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had HGB measurements at both baseline and at exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Mean (Standard Deviation) [g/dL]	0.42 (0.84)	1.15 (1.21)	0.82 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Median Change in Hemoglobin (g/dL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard arm.) N=42 subjects completed protocol therapy (n=23 to the intensive arm and n=19 to the standard arm.) All n=42 that completed the study had hemoglobin (HGB) measurements at both baseline and at exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Median (Full Range) [g/dL]	0.40	1.20	1.05

10. Secondary Outcome

Title	Mean Change in Fetal Hemoglobin (%)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (HbF) measurements at both baseline and at exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Mean (Standard Deviation) [percentage of Hemoglobin F]	-6.97 (18.97)	7.67 (12.09)	1.05 (17.06)

11. Secondary Outcome

Title	Median Change in Fetal Hemoglobin (%)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had Hemoglobin F (Hbf) measurements at both baseline and at exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Median (Full Range) [percentage of Hemoglobin F]	0.20	8.00	1.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Exact Wilcoxon (Mann-Whitley), two-sided
	Comments

12. Secondary Outcome

Title	Mean Change in Mean Corpuscular Volume (fL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Mean (Standard Deviation) [fL]	5.87 (6.17)	11.36 (4.84)	8.88 (6.08)

13. Secondary Outcome

Title	Median Change in Mean Corpuscular Volume (fL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had mean corpuscular volume (MCV) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Median (Full Range) [fL]	8.00	9.60	8.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments

14. Secondary Outcome

Title	Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	22	41
Mean (Standard Deviation) [*10^3 reticulocytes/µL]	-83.69 (65.65)	-145.43 (107.10)	-116.82 (94.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	t-test, 2 sided
	Comments

15. Secondary Outcome

Title	Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the n=42 subjects that completed the study had absolute reticulocyte count (ARC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	22	41
Median (Full Range) [*10^3 reticulocytes/µL]	-91.6	-175.9	-120.5

16. Secondary Outcome

Title	Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Mean (Standard Deviation) [*10^3 white blood cells/µL]	-0.32 (4.78)	-5.64 (5.56)	-3.23 (5.81)

17. Secondary Outcome

Title	Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had white blood cell (WBC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Median (Full Range) [*10^3 white blood cells/µL]	-0.77	-4.50	-3.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments

18. Secondary Outcome

Title	Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	18	23	41
Mean (Standard Deviation) [*10^3 neutrophils/µL]	0.74 (2.53)	-1.69 (2.09)	-0.62 (2.57)

19. Secondary Outcome

Title	Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) N=41 of the 42 that completed the study had absolute neutrophil count (ANC) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	18	23	41
Median (Full Range) [*10^3 neutrophils/µL]	0.35	-1.43	-0.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments

20. Secondary Outcome

Title	Mean Change in Platelet Count (*10^3 Platelets/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Mean (Standard Deviation) [*10^3 platelets/µL]	-10.92 (161.90)	-11.20 (145.78)	-11.07 (151.36)

21. Secondary Outcome

Title	Median Change in Platelet Count (*10^3 Platelets/µL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) All 42 that completed the study had platelet (PLT) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	19	23	42
Median (Full Range) [*10^3 platelets/µL]	-48	-18	-22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments

22. Secondary Outcome

Title	Mean Change in Bilirubin (mg/dL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	17	23	40
Mean (Standard Deviation) [mg/dL]	0.24 (0.56)	-0.54 (1.05)	-0.21 (0.95)

23. Secondary Outcome

Title	Median Change in Bilirubin (mg/dL)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=40 had bilirubin measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	17	23	40
Median (Full Range) [mg/dL]	0.30	-0.30	-0.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments

24. Secondary Outcome

Title	Mean Change in Lactate Dehydrogenase (Units/L)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided and will be compared between two treatment arms using two sample t-test or exact Wilcoxon Rank Sum test depending on the normality of the data tested by the Shapiro-Wilk test.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	18	23	41
Mean (Standard Deviation) [units/L]	-11.94 (101.99)	-129.17 (181.47)	-77.71 (161.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Participants, Intensive Dosing
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	t-test, 2 sided
	Comments

25. Secondary Outcome

Title	Median Change in Lactate Dehydrogenase (Units/L)
Description	Descriptive statistics of the change between baseline and completion of the study will be provided.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Change calculations require subjects to have values at both baseline and exit visits. N=51 patients were randomized (n=25 to the Intensive arm and n=26 to the standard therapy arm.) N=42 subjects completed protocol therapy (n=23 in the intensive arm and n=19 in the standard arm.) Of the 42 that completed the study, n=41 had lactate dehydrogenase (LDH) measurements at both baseline and exit visits.

Arm/Group Title	Stable Dosing	Intensive Dosing	Overall
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.	All subjects who completed protocol therapy
Measure Participants	18	23	41
Median (Full Range) [units/L]	4.5	-94.0	-54.0

26. Secondary Outcome

Title	Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities
Description	Normal TCD velocities will be defined as TCD velocities <170 cm/s.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Subjects that complete protocol therapy and have TCD ultrasound at exit visit. N=42 subjects completed protocol therapy.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	5	6
Count of Participants [Participants]	0 0%	0 0%

27. Secondary Outcome

Title	Number of Participants Who Undergo Surgery
Description	Any operative procedure will be included.
Time Frame	From start of therapy through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Includes all randomized patients, n=51.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Count of Participants [Participants]	3 11.5%	9 36%

28. Secondary Outcome

Title	Number of Participants Who Undergo Transfusion
Description	Transfusion will be defined as the provision of red blood cells to correct anemia.
Time Frame	From start of therapy through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Includes all randomized patients, n=51.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Count of Participants [Participants]	2 7.7%	2 8%

29. Secondary Outcome

Title	Number of Patients With Toxicities Related to Hydroxyurea Dosing
Description	Number of patients with toxicities to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).
Time Frame	From start of therapy through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

N=51 randomized patients (n=25 intensive arm and n=26 standard arm).

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Neutropenia	9 34.6%	15 60%
Reticulocytopenia	3 11.5%	4 16%
Thrombocytopenia	1 3.8%	3 12%
Anemia	0 0%	0 0%

30. Secondary Outcome

Title	Number of Toxicities Related to Hydroxyurea Dosing
Description	Number of toxicities will be reported to include: neutropenia (ANC <1000*/µL), reticulocytopenia (ARC <80*10^3/µL and concomitant anemia (hemoglobin <6 g/dL), and thrombocytopenia (platelets <100*10^3/µL).
Time Frame	From start of therapy through completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

N=51 randomized patients (n=25 intensive arm and n=26 standard arm).

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	26	25
Neutropenia	12	32
Reticulocytopenia	3	4
Thrombocytopenia	1	5
Anemia	0	0

31. Secondary Outcome

Title	Change in Pain and Hurt Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	19.1 (NA)

32. Secondary Outcome

Title	Change in Pain Impact Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	15 (NA)

33. Secondary Outcome

Title	Change in Pain Management Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	-25 (NA)

34. Secondary Outcome

Title	Change in Worry I Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	20 (NA)

35. Secondary Outcome

Title	Change in Worry II Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	20 (NA)

36. Secondary Outcome

Title	Change in Emotions Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	0 (NA)

37. Secondary Outcome

Title	Change in Treatment Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	37.5 (NA)

38. Secondary Outcome

Title	Change in Communication I Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	50 (NA)

39. Secondary Outcome

Title	Change in Communication II Score
Description	Change in PedsQL 4.0 score will be reported. Scores are based on a 100 point scale, 0-100 with higher scores indicating a better quality of life. We are taking the exit visit score and subtracting the baseline score.
Time Frame	From baseline at study entry to completion of therapy, up to 56 weeks

Outcome Measure Data

Analysis Population Description

Of the N=51 randomized patients (n=25 intensive arm and n=26 standard arm), only 1 patient had The PedsQL ™ Sickle Cell Disease Module data at both baseline and exit visit.

Arm/Group Title	Stable Dosing	Intensive Dosing
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.
Measure Participants	1	0
Mean (Standard Deviation) [score on a scale]	8.3 (NA)

Adverse Events

Time Frame	Subjects in both treatment arms will be followed for a maximum of 56 weeks regardless of the actual number of study visits. Upon completion of the 56 weeks, patients will be followed for an additional 30 days for toxicities and will then be taken off study.
Arm/Group Title	Stable Dosing - Post Randomization		Intensive Dosing - Post Randomization		All Participants - Pre Randomization
Arm/Group Description	In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 1 (Stable Dosing) continues standard treatment.		In the first 8 weeks (± 2 weeks) of this study, participants will receive standard treatment [a fixed dose of 20 (± 2.5) mg/kg/day of hydroxyurea]. After 8 weeks (± 2 weeks) of standard treatment, participants will be randomized (like flipping a coin) to one of two treatment groups. Group 2 (Intensive Dosing) will have their HU dose increased by 5 mg/kg/day every 8 weeks up to a maximum of 35 mg/kg/day.		All participants enrolled
All Cause Mortality
	Stable Dosing - Post Randomization		Intensive Dosing - Post Randomization		All Participants - Pre Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		0/25 (0%)		0/58 (0%)
Serious Adverse Events
	Stable Dosing - Post Randomization		Intensive Dosing - Post Randomization		All Participants - Pre Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)		2/25 (8%)		1/58 (1.7%)
Immune system disorders
Immune system disorders,- Other specify	0/26 (0%)	0	0/25 (0%)	0	1/58 (1.7%)	1
Neutropenia	0/26 (0%)	0	1/25 (4%)	1	0/58 (0%)	0
Infections and infestations
Infections and infestations - Other, specify	1/26 (3.8%)	1	0/25 (0%)	0	0/58 (0%)	0
Sepsis	1/26 (3.8%)	1	0/25 (0%)	0	0/58 (0%)	0
Investigations
Platelet count decreased	0/26 (0%)	0	1/25 (4%)	1	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
Other (Specify_)	0/26 (0%)	0	0/25 (0%)	0	1/58 (1.7%)	1
Surgical and medical procedures
Surgical and medical procedures - Other specify	1/26 (3.8%)	1	0/25 (0%)	0	0/58 (0%)	0
Other (Not Including Serious) Adverse Events
	Stable Dosing - Post Randomization		Intensive Dosing - Post Randomization		All Participants - Pre Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/26 (7.7%)		8/25 (32%)		3/58 (5.2%)
Blood and lymphatic system disorders
Febrile neutropenia	2/26 (7.7%)	2	6/25 (24%)	6	3/58 (5.2%)	3
Investigations
Platelet count decreased	0/26 (0%)	0	2/25 (8%)	4	0/58 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.