Hydroxyurea Management in Kids: Intensive Versus Stable Dosage Strategies

• ClinicalTrials.gov Identifier: NCT03020615
• Recruitment Status: Completed
• First Posted: January 13, 2017
• Results First Posted: June 25, 2021
• Last Update Posted: June 25, 2021
• Sponsor: St. Jude Children's Research Hospital
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): St. Jude Children's Research Hospital

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Investigator); Primary Purpose: Treatment
• Condition: Sickle Cell Anemia
• Intervention: Drug: Hydroxyurea
• Enrollment: 58

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 Details

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
Reason Not Completed
Physician Decision	3	1	2
Parent/guardian/patient choice	3	0	4
Screen failure	0	0	1
Death	1	0	0
Lost to Follow-up	0	1	0

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 Number of Baseline Participants		26	25	7	58
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	26 participants	25 participants	7 participants	58 participants
	<=18 years	26 100.0%	25 100.0%	7 100.0%	58 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Median (Full Range); Unit of measure: Months
	Number Analyzed	26 participants	25 participants	7 participants	58 participants
		9; (9 to 36)	10; (9 to 32)	18; (10 to 23)	10; (9 to 36)
Age, Continuous; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	26 participants	25 participants	7 participants	58 participants
		12.9 (7.9)	12.8 (6.2)	18.1 (4.7)	13.5 (7.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	26 participants	25 participants	7 participants	58 participants
	Female	15 57.7%	8 32.0%	2 28.6%	25 43.1%
	Male	11 42.3%	17 68.0%	5 71.4%	33 56.9%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	26 participants	25 participants	7 participants	58 participants
Black		25 96.2%	25 100.0%	6 85.7%	56 96.6%
White		1 3.8%	0 0.0%	0 0.0%	1 1.7%
Unknown		0 0.0%	0 0.0%	1 14.3%	1 1.7%
Non-Spanish speaking Non Hispanic		26 100.0%	23 92.0%	6 85.7%	55 94.8%
Non-Spanish speaking Non Hispanic (Unknown)		0 0.0%	2 8.0%	1 14.3%	3 5.2%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	26 participants	25 participants	7 participants	58 participants
	St. Jude Children's Research Hospital	16 61.5%	17 68.0%	0 0.0%	33 56.9%
	Children's Healthcare of Atlanta	8 30.8%	5 20.0%	4 57.1%	17 29.3%
	University of Mississippi Medical Center	1 3.8%	2 8.0%	2 28.6%	5 8.6%
	University of Texas Southwestern Medical Center	1 3.8%	1 4.0%	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.
Overall Number of Participants Analyzed	58
Measure Type: Count of Participants; Unit of Measure: Participants
	58 100.0%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Count of Participants; Unit of Measure: Participants
	26 100.0%	25 100.0%

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.
Overall Number of Participants Analyzed	51
Measure Type: Count of Participants; Unit of Measure: Participants
	41 80.4%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Number; Unit of Measure: Participants
	19	23

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
Overall Number of Participants Analyzed	154
Measure Type: Count of Participants; Unit of Measure: Participants
Does not meet eligibility criteria	33 21.4%
Family wants more time to consider participation	31 20.1%
Child on hydroxyurea (HU)	29 18.8%
Unknown reason	17 11.0%
Not interested in HU	16 10.4%
Poor clinic visit compliance	13 8.4%
Not interested in research	10 6.5%
Logistics - travel distance to site, frequency of appointments	5 3.2%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Count of Participants; Unit of Measure: Participants
	2 7.7%	2 8.0%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Number; Unit of Measure: 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
Overall Number of Participants Analyzed	19	23	42
Mean (Standard Deviation); Unit of Measure: g/dL
	0.42 (0.84)	1.15 (1.21)	0.82 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.033
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	19	23	42
Median (Full Range); Unit of Measure: g/dL
	0.40; (-1.30 to 1.50)	1.20; (-1.90 to 3.35)	1.05; (-1.90 to 3.35)

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
Overall Number of Participants Analyzed	19	23	42
Mean (Standard Deviation); Unit of Measure: 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
Overall Number of Participants Analyzed	19	23	42
Median (Full Range); Unit of Measure: percentage of Hemoglobin F
	0.20; (-60.70 to 4.80)	8.00; (-23.50 to 24.70)	1.70; (-60.70 to 24.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitley), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	19	23	42
Mean (Standard Deviation); Unit of Measure: 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
Overall Number of Participants Analyzed	19	23	42
Median (Full Range); Unit of Measure: fL
	8.00; (-7.10 to 16.00)	9.60; (5.40 to 20.10)	8.70; (-7.10 to 20.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	19	22	41
Mean (Standard Deviation); Unit of Measure: *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	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.030
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	19	22	41
Median (Full Range); Unit of Measure: *10^3 reticulocytes/µL
	-91.6; (-202.3 to 55.1)	-175.9; (-300 to 109.1)	-120.5; (-300 to 109.1)

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
Overall Number of Participants Analyzed	19	23	42
Mean (Standard Deviation); Unit of Measure: *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
Overall Number of Participants Analyzed	19	23	42
Median (Full Range); Unit of Measure: *10^3 white blood cells/µL
	-0.77; (-8.07 to 12.46)	-4.50; (-20.35 to 4.23)	-3.14; (-20.35 to 12.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0009
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	18	23	41
Mean (Standard Deviation); Unit of Measure: *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
Overall Number of Participants Analyzed	18	23	41
Median (Full Range); Unit of Measure: *10^3 neutrophils/µL
	0.35; (-2.13 to 9.30)	-1.43; (-8.10 to 1.49)	-0.52; (-8.10 to 9.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	19	23	42
Mean (Standard Deviation); Unit of Measure: *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
Overall Number of Participants Analyzed	19	23	42
Median (Full Range); Unit of Measure: *10^3 platelets/µL
	-48; (-241 to 407)	-18; (-324 to 484)	-22; (-324 to 484)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.75
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	17	23	40
Mean (Standard Deviation); Unit of Measure: 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
Overall Number of Participants Analyzed	17	23	40
Median (Full Range); Unit of Measure: mg/dL
	0.30; (-0.80 to 1.30)	-0.30; (-4.60 to 1.00)	-0.07; (-4.60 to 1.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0013
	Comments	[Not Specified]
	Method	Exact Wilcoxon (Mann-Whitney), two-sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	18	23	41
Mean (Standard Deviation); Unit of Measure: units/L
	-11.94 (101.99)	-129.17 (181.47)	-77.71 (161.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stable Dosing, Intensive Dosing
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.013
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

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
Overall Number of Participants Analyzed	18	23	41
Median (Full Range); Unit of Measure: units/L
	4.5; (-189.0 to 219.0)	-94.0; (-477.0 to 248.0)	-54.0; (-477.0 to 248.0)

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.
Overall Number of Participants Analyzed	5	6
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	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.
Overall Number of Participants Analyzed	26	25
Measure Type: Count of Participants; Unit of Measure: Participants
	3 11.5%	9 36.0%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Count of Participants; Unit of Measure: Participants
	2 7.7%	2 8.0%

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.
Overall Number of Participants Analyzed	26	25
Measure Type: Count of Participants; Unit of Measure: Participants
Neutropenia	9 34.6%	15 60.0%
Reticulocytopenia	3 11.5%	4 16.0%
Thrombocytopenia	1 3.8%	3 12.0%
Anemia	0 0.0%	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.
Overall Number of Participants Analyzed	26	25
Measure Type: Number; Unit of Measure: Toxicities
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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	19.1 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	15 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	-25 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	20 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	20 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	0 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	37.5 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	50 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Overall Number of Participants Analyzed	1	0
Mean (Standard Deviation); Unit of Measure: score on a scale
	8.3 [1] (NA)

[1]

Only 1 patient had data at both baseline and exit visit.

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.
Adverse Event Reporting Description	[Not Specified]
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 (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/26 (3.85%)		0/25 (0.00%)		0/58 (0.00%)
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 (11.54%)		2/25 (8.00%)		1/58 (1.72%)
Immune system disorders
Immune system disorders,- Other specify † 1 [1]	0/26 (0.00%)	0	0/25 (0.00%)	0	1/58 (1.72%)	1
Neutropenia † 1	0/26 (0.00%)	0	1/25 (4.00%)	1	0/58 (0.00%)	0
Infections and infestations
Infections and infestations - Other, specify † 1 [2]	1/26 (3.85%)	1	0/25 (0.00%)	0	0/58 (0.00%)	0
Sepsis † 1	1/26 (3.85%)	1	0/25 (0.00%)	0	0/58 (0.00%)	0
Investigations
Platelet count decreased † 1	0/26 (0.00%)	0	1/25 (4.00%)	1	0/58 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Other (Specify_) † 1 [3]	0/26 (0.00%)	0	0/25 (0.00%)	0	1/58 (1.72%)	1
Surgical and medical procedures
Surgical and medical procedures - Other specify † 1 [4]	1/26 (3.85%)	1	0/25 (0.00%)	0	0/58 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment; [1] Fever in pediatric patient; [2] Norovirus/rotovirus diarrhea; [3] "breath holding spell"; [4] Removal of foreign object
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	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 (7.69%)		8/25 (32.00%)		3/58 (5.17%)
Blood and lymphatic system disorders
Febrile neutropenia † 1	2/26 (7.69%)	2	6/25 (24.00%)	6	3/58 (5.17%)	3
Investigations
Platelet count decreased † 1	0/26 (0.00%)	0	2/25 (8.00%)	4	0/58 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Jeremie Estepp, MD
• Organization: St. Jude Children's Research Hospital
• Phone: (901) 595-5703
• EMail: jeremie.estepp@stjude.org

• Responsible Party: St. Jude Children's Research Hospital
• ClinicalTrials.gov Identifier: NCT03020615
• Other Study ID Numbers: HUGKISS; R34HL127162 ( U.S. NIH Grant/Contract )
• First Submitted: January 11, 2017
• First Posted: January 13, 2017
• Results First Submitted: May 6, 2021
• Results First Posted: June 25, 2021
• Last Update Posted: June 25, 2021