Trial Outcomes & Findings for Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies (NCT NCT03020615)

NCT ID: NCT03020615

Last Updated: 2021-06-25

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 58 participants
• Primary outcome timeframe: at baseline
• Results posted on: 2021-06-25

Participant Flow

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.

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.

Participant milestones

Measure	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.	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.	Non-Randomized Participants who came off study prior to randomization
Overall Study STARTED	26	25	7
Overall Study COMPLETED	19	23	0
Overall Study NOT COMPLETED	7	2	7

Reasons for withdrawal

Measure	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.	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.	Non-Randomized Participants who came off study prior to randomization
Overall Study Physician Decision	3	1	2
Overall Study Parent/guardian/patient choice	3	0	4
Overall Study Screen failure	0	0	1
Overall Study Death	1	0	0
Overall Study Lost to Follow-up	0	1	0

Baseline Characteristics

Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

Baseline characteristics by cohort

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Non-Randomized Patients n=7 Participants Patients who came off study prior to randomization	Total n=58 Participants Total of all reporting groups
Age, Categorical <=18 years	26 Participants n=5 Participants	25 Participants n=7 Participants	7 Participants n=5 Participants	58 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	12.9 months STANDARD_DEVIATION 7.9 • n=5 Participants	12.8 months STANDARD_DEVIATION 6.2 • n=7 Participants	18.1 months STANDARD_DEVIATION 4.7 • n=5 Participants	13.5 months STANDARD_DEVIATION 7.0 • n=4 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	8 Participants n=7 Participants	2 Participants n=5 Participants	25 Participants n=4 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	17 Participants n=7 Participants	5 Participants n=5 Participants	33 Participants n=4 Participants
Race/Ethnicity, Customized Black	25 Participants n=5 Participants	25 Participants n=7 Participants	6 Participants n=5 Participants	56 Participants n=4 Participants
Race/Ethnicity, Customized White	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Non-Spanish speaking Non Hispanic	26 Participants n=5 Participants	23 Participants n=7 Participants	6 Participants n=5 Participants	55 Participants n=4 Participants
Race/Ethnicity, Customized Non-Spanish speaking Non Hispanic (Unknown)	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Region of Enrollment United States · St. Jude Children's Research Hospital	16 Participants n=5 Participants	17 Participants n=7 Participants	0 Participants n=5 Participants	33 Participants n=4 Participants
Region of Enrollment United States · Children's Healthcare of Atlanta	8 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	17 Participants n=4 Participants
Region of Enrollment United States · University of Mississippi Medical Center	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment United States · University of Texas Southwestern Medical Center	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

Timeframe: at baseline

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=58 Participants 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.	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.	Overall All subjects who completed protocol therapy
Number of Patients Enrolled.	58 Participants	—	—

PRIMARY outcome

Timeframe: Eight weeks (± 2 weeks) after study enrollment

Population: Fifty-one were randomized out of the 58 enrolled.

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

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Patients Randomized	26 Participants	25 Participants	—

PRIMARY outcome

Timeframe: At completion of therapy, up to 56 weeks after study enrollment

Population: 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.

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].

Outcome measures

Measure	Stable Dosing n=51 Participants 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.	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.	Overall All subjects who completed protocol therapy
Number of Randomized Patients With ≥80% Chronic Medication Compliance	41 Participants	—	—

PRIMARY outcome

Timeframe: At baseline and at completion of the protocol, up to 56 weeks after study enrollment

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

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

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Patients Who Have the % Fetal Hemoglobin (%HbF) Collected at Baseline and at Study Exit	19 Participants	23 Participants	—

SECONDARY outcome

Timeframe: Once, at enrollment

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

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

Outcome measures

Measure	Stable Dosing n=154 Participants 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.	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.	Overall All subjects who completed protocol therapy
Frequency by Reason Given for Refusal for Study Participation Does not meet eligibility criteria	33 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Family wants more time to consider participation	31 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Child on hydroxyurea (HU)	29 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Unknown reason	17 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Not interested in HU	16 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Poor clinic visit compliance	13 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Not interested in research	10 Participants	—	—
Frequency by Reason Given for Refusal for Study Participation Logistics - travel distance to site, frequency of appointments	5 Participants	—	—

SECONDARY outcome

Timeframe: From baseline through completion of therapy, up to 56 weeks

Population: The n=51 subjects that were randomized to treatment.

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.

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Patients With Hospitalizations by Arm	2 Participants	2 Participants	—

SECONDARY outcome

Timeframe: From baseline through completion of therapy, up to 56 weeks

Population: The n=51 subjects that were randomized to treatment.

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.

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Cumulative Number of Hospitalizations by Arms	4 hospitalizations	5 hospitalizations	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Mean Change in Hemoglobin (g/dL)	0.42 g/dL Standard Deviation 0.84	1.15 g/dL Standard Deviation 1.21	0.82 g/dL Standard Deviation 1.11

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Median Change in Hemoglobin (g/dL)	0.40 g/dL Interval -1.3 to 1.5	1.20 g/dL Interval -1.9 to 3.35	1.05 g/dL Interval -1.9 to 3.35

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Mean Change in Fetal Hemoglobin (%)	-6.97 percentage of Hemoglobin F Standard Deviation 18.97	7.67 percentage of Hemoglobin F Standard Deviation 12.09	1.05 percentage of Hemoglobin F Standard Deviation 17.06

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Median Change in Fetal Hemoglobin (%)	0.20 percentage of Hemoglobin F Interval -60.7 to 4.8	8.00 percentage of Hemoglobin F Interval -23.5 to 24.7	1.70 percentage of Hemoglobin F Interval -60.7 to 24.7

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Mean Change in Mean Corpuscular Volume (fL)	5.87 fL Standard Deviation 6.17	11.36 fL Standard Deviation 4.84	8.88 fL Standard Deviation 6.08

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Median Change in Mean Corpuscular Volume (fL)	8.00 fL Interval -7.1 to 16.0	9.60 fL Interval 5.4 to 20.1	8.70 fL Interval -7.1 to 20.1

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=22 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Mean Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)	-83.69 *10^3 reticulocytes/µL Standard Deviation 65.65	-145.43 *10^3 reticulocytes/µL Standard Deviation 107.10	-116.82 *10^3 reticulocytes/µL Standard Deviation 94.52

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=22 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Median Change in Absolute Reticulocyte Count (*10^3 Reticulocytes/µL)	-91.6 *10^3 reticulocytes/µL Interval -202.3 to 55.1	-175.9 *10^3 reticulocytes/µL Interval -300.0 to 109.1	-120.5 *10^3 reticulocytes/µL Interval -300.0 to 109.1

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Mean Change in White Blood Cell Count (*10^3 White Blood Cells/µL)	-0.32 *10^3 white blood cells/µL Standard Deviation 4.78	-5.64 *10^3 white blood cells/µL Standard Deviation 5.56	-3.23 *10^3 white blood cells/µL Standard Deviation 5.81

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Median Change in White Blood Cell Count (*10^3 White Blood Cells/µL)	-0.77 *10^3 white blood cells/µL Interval -8.07 to 12.46	-4.50 *10^3 white blood cells/µL Interval -20.35 to 4.23	-3.14 *10^3 white blood cells/µL Interval -20.35 to 12.46

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=18 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Mean Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)	0.74 *10^3 neutrophils/µL Standard Deviation 2.53	-1.69 *10^3 neutrophils/µL Standard Deviation 2.09	-0.62 *10^3 neutrophils/µL Standard Deviation 2.57

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=18 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Median Change in Absolute Neutrophil Count (*10^3 Neutrophils/µL)	0.35 *10^3 neutrophils/µL Interval -2.13 to 9.3	-1.43 *10^3 neutrophils/µL Interval -8.1 to 1.49	-0.52 *10^3 neutrophils/µL Interval -8.1 to 9.3

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Mean Change in Platelet Count (*10^3 Platelets/µL)	-10.92 *10^3 platelets/µL Standard Deviation 161.90	-11.20 *10^3 platelets/µL Standard Deviation 145.78	-11.07 *10^3 platelets/µL Standard Deviation 151.36

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=19 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=42 Participants All subjects who completed protocol therapy
Median Change in Platelet Count (*10^3 Platelets/µL)	-48 *10^3 platelets/µL Interval -241.0 to 407.0	-18 *10^3 platelets/µL Interval -324.0 to 484.0	-22 *10^3 platelets/µL Interval -324.0 to 484.0

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=17 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=40 Participants All subjects who completed protocol therapy
Mean Change in Bilirubin (mg/dL)	0.24 mg/dL Standard Deviation 0.56	-0.54 mg/dL Standard Deviation 1.05	-0.21 mg/dL Standard Deviation 0.95

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=17 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=40 Participants All subjects who completed protocol therapy
Median Change in Bilirubin (mg/dL)	0.30 mg/dL Interval -0.8 to 1.3	-0.30 mg/dL Interval -4.6 to 1.0	-0.07 mg/dL Interval -4.6 to 1.3

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=18 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Mean Change in Lactate Dehydrogenase (Units/L)	-11.94 units/L Standard Deviation 101.99	-129.17 units/L Standard Deviation 181.47	-77.71 units/L Standard Deviation 161.25

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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

Outcome measures

Measure	Stable Dosing n=18 Participants 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.	Intensive Dosing n=23 Participants 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.	Overall n=41 Participants All subjects who completed protocol therapy
Median Change in Lactate Dehydrogenase (Units/L)	4.5 units/L Interval -189.0 to 219.0	-94.0 units/L Interval -477.0 to 248.0	-54.0 units/L Interval -477.0 to 248.0

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

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

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

Outcome measures

Measure	Stable Dosing n=5 Participants 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.	Intensive Dosing n=6 Participants 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.	Overall All subjects who completed protocol therapy
Number of Participants Who do Not Have Normal Transcranial Doppler (TCD) Ultrasound Velocities	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From start of therapy through completion of therapy, up to 56 weeks

Population: Includes all randomized patients, n=51.

Any operative procedure will be included.

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Participants Who Undergo Surgery	3 Participants	9 Participants	—

SECONDARY outcome

Timeframe: From start of therapy through completion of therapy, up to 56 weeks

Population: Includes all randomized patients, n=51.

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

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Participants Who Undergo Transfusion	2 Participants	2 Participants	—

SECONDARY outcome

Timeframe: From start of therapy through completion of therapy, up to 56 weeks

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

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).

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Patients With Toxicities Related to Hydroxyurea Dosing Neutropenia	9 Participants	15 Participants	—
Number of Patients With Toxicities Related to Hydroxyurea Dosing Reticulocytopenia	3 Participants	4 Participants	—
Number of Patients With Toxicities Related to Hydroxyurea Dosing Thrombocytopenia	1 Participants	3 Participants	—
Number of Patients With Toxicities Related to Hydroxyurea Dosing Anemia	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From start of therapy through completion of therapy, up to 56 weeks

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

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).

Outcome measures

Measure	Stable Dosing n=26 Participants 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.	Intensive Dosing n=25 Participants 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.	Overall All subjects who completed protocol therapy
Number of Toxicities Related to Hydroxyurea Dosing Neutropenia	12 Toxicities	32 Toxicities	—
Number of Toxicities Related to Hydroxyurea Dosing Reticulocytopenia	3 Toxicities	4 Toxicities	—
Number of Toxicities Related to Hydroxyurea Dosing Thrombocytopenia	1 Toxicities	5 Toxicities	—
Number of Toxicities Related to Hydroxyurea Dosing Anemia	0 Toxicities	0 Toxicities	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Pain and Hurt Score	19.1 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Pain Impact Score	15 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Pain Management Score	-25 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Worry I Score	20 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Worry II Score	20 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Emotions Score	0 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Treatment Score	37.5 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Communication I Score	50 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

SECONDARY outcome

Timeframe: From baseline at study entry to completion of therapy, up to 56 weeks

Population: 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.

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.

Outcome measures

Measure	Stable Dosing n=1 Participants 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.	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.	Overall All subjects who completed protocol therapy
Change in Communication II Score	8.3 score on a scale Standard Deviation NA Only 1 patient had data at both baseline and exit visit.	—	—

Adverse Events

Stable Dosing - Post Randomization

Serious events: 3 serious events

Other events: 2 other events

Deaths: 1 deaths

Intensive Dosing - Post Randomization

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

All Participants - Pre Randomization

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Stable Dosing - Post Randomization n=26 participants at risk 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.	Intensive Dosing - Post Randomization n=25 participants at risk 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 - Pre Randomization n=58 participants at risk All participants enrolled
Investigations Platelet count decreased	0.00% 0/26 • 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.	4.0% 1/25 • Number of events 1 • 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.	0.00% 0/58 • 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.
Immune system disorders Immune system disorders,- Other specify	0.00% 0/26 • 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.	0.00% 0/25 • 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.	1.7% 1/58 • Number of events 1 • 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.
Respiratory, thoracic and mediastinal disorders Other (Specify_)	0.00% 0/26 • 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.	0.00% 0/25 • 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.	1.7% 1/58 • Number of events 1 • 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.
Immune system disorders Neutropenia	0.00% 0/26 • 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.	4.0% 1/25 • Number of events 1 • 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.	0.00% 0/58 • 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.
Infections and infestations Infections and infestations - Other, specify	3.8% 1/26 • Number of events 1 • 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.	0.00% 0/25 • 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.	0.00% 0/58 • 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.
Infections and infestations Sepsis	3.8% 1/26 • Number of events 1 • 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.	0.00% 0/25 • 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.	0.00% 0/58 • 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.
Surgical and medical procedures Surgical and medical procedures - Other specify	3.8% 1/26 • Number of events 1 • 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.	0.00% 0/25 • 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.	0.00% 0/58 • 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.

Other adverse events

Measure	Stable Dosing - Post Randomization n=26 participants at risk 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.	Intensive Dosing - Post Randomization n=25 participants at risk 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 - Pre Randomization n=58 participants at risk All participants enrolled
Blood and lymphatic system disorders Febrile neutropenia	7.7% 2/26 • Number of events 2 • 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.	24.0% 6/25 • Number of events 6 • 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.	5.2% 3/58 • Number of events 3 • 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.
Investigations Platelet count decreased	0.00% 0/26 • 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.	8.0% 2/25 • Number of events 4 • 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.	0.00% 0/58 • 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.

Additional Information

Jeremie Estepp, MD

St. Jude Children's Research Hospital

Phone: (901) 595-5703

Email: jeremie.estepp@stjude.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place