Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Follow-up Observational Study II Protocol (BABY HUG)

• ClinicalTrials.gov Identifier: NCT01783990
• Recruitment Status: Completed
• First Posted: February 5, 2013
• Results First Posted: August 20, 2020
• Last Update Posted: August 20, 2020
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborator: National Institutes of Health (NIH)
• Information provided by (Responsible Party): National Heart, Lung, and Blood Institute (NHLBI)

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Condition: Sickle Cell Anemia
• Intervention: Drug: Hydroxyurea
• Enrollment: 150

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Active	Passive
Arm/Group Description	Complete blood counts (CBCs), reticulocytes, differential, lactate dehydrogenase (LDH), bilirubin and alanine transaminases (ALTs), cystatin C, blood urea nitrogen (BUN), Creatinine, fetal hemoglobin (HbF), pit counts, Howell Jolly Body (HJB), and urine microalbumin:creatinine ratio were collected at study entry, annually, and exit to Follow-Up Study II. Variable-diversity-joining (VDJ) and a stored blood sample were collected at study entry and study exit. Additional tests that include liver/spleen scan, abdominal sonogram, pulmonary function testing, magnetic resonance imaging (MRI) / magnetic resonance angiography (MRA), cardiac echocardiogram, or neuropsychology testing were collected once during the study when the child was 10 years old.	Complete blood counts (CBCs), reticulocytes, differential, lactate dehydrogenase (LDH), bilirubin and alanine transaminases (ALTs), cystatin C, blood urea nitrogen (BUN), Creatinine, fetal hemoglobin (HbF), pit counts, Howell Jolly Body (HJB), variable-diversity-joining (VDJ), urine microalbumin:creatinine ratio and a stored blood sample were collected at study entry and exit to Follow-Up Study II. Additional tests that include liver/spleen scan, abdominal sonogram, pulmonary function testing, MRI/MRA, cardiac echocardiogram, or neuropsychology testing were collected as part of clinical care.
Period Title: Overall Study
Started	130	20
Completed	125	18
Not Completed	5	2

Baseline Characteristics

Arm/Group Title		Active	Passive	Total
Arm/Group Description		Blood and urine specimens, and questionnaires related to the child's health status.; Liver Spleen Scan; Abdominal Ultrasound; Brain magnetic resonance imaging (MRI) / magnetic resonance angiography (MRA); Cardiac Echocardiogram/Pulmonary Function Testing; Transcranial Doppler; Neuropsychology Testing (Vineland, Wechsler Intelligence Scale for Children (WISC-IV), Connor Continuous Performance Test 2nd Edition (CPT II) and Pediatric Quality of Life Inventory(PedsQOL)) Patients could be on or off hydroxyurea at the start of Follow-Up Study II, and could change treatment during the study.	Information from usual clinical care of sickle cell disease. We will collect information from routine tests ordered by the child's clinical sickle cell doctors. Patients could be on or off hydroxyurea at the start of Follow-Up Study II, and could change treatment during the study.	Total of all reporting groups
Overall Number of Baseline Participants		130	20	150
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	130 participants	20 participants	150 participants
	<=18 years	130 100.0%	20 100.0%	150 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	130 participants	20 participants	150 participants
		8.16 (1.13)	8.06 (1.26)	8.15 (1.14)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	130 participants	20 participants	150 participants
	Female	70 53.8%	14 70.0%	84 56.0%
	Male	60 46.2%	6 30.0%	66 44.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	130 participants	20 participants	150 participants
	Hispanic or Latino	5 3.8%	1 5.0%	6 4.0%
	Not Hispanic or Latino	125 96.2%	19 95.0%	144 96.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	130 participants	20 participants	150 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	122 93.8%	18 90.0%	140 93.3%
	White	0 0.0%	0 0.0%	0 0.0%
	More than one race	4 3.1%	0 0.0%	4 2.7%
	Unknown or Not Reported	4 3.1%	2 10.0%	6 4.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	130 participants	20 participants	150 participants
		130	20	150

Outcome Measures

1. Primary Outcome

Title	Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo
Description	The change in splenic function from the randomized control trial baseline measurement was one of the primary outcomes. The change in splenic function (worse vs not-worse) was compared between the randomized treatment groups (hydroxyurea vs placebo). The change in splenic function from baseline (before treatment initiation) to age 10 years (a visit when child turned 10 years old) was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, decreased to normal, absent to absent, or absent to decreased.
Time Frame	baseline and when child turned 10 years old

Outcome Measure Data

Analysis Population Description

All subjects who had age 10 years and baseline spleen function measurement.

Arm/Group Title	Randomized to Hydroxyurea	Randomized to Placebo
Arm/Group Description:	Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Subjects randomized to Placebo in the randomized phase III clinical trial.
Overall Number of Participants Analyzed	58	50
Measure Type: Count of Participants; Unit of Measure: Participants
Splenic function - worse from baseline	26 44.8%	28 56.0%
Splenic function - not worse from baseline	32 55.2%	22 44.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized to Hydroxyurea, Randomized to Placebo
	Comments	The primary analysis compared the frequency of worsening spleen function (from normal to decreased or absent, or from decreased to absent).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.33
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

2. Primary Outcome

Title	Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea at Study Visit
Description	The change in splenic function from the randomized control trial baseline measurement was one of the primary outcomes. The change in splenic function (worse vs not-worse) was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit. The change in splenic function from baseline (before treatment initiation) to age 10 years (a visit when child turned 10 years old) was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, decreased to normal, absent to absent, or absent to decreased.
Time Frame	baseline and when child turned 10 years old

Outcome Measure Data

Analysis Population Description

All subjects who were known to be on hydroxyurea vs. off hydroxyurea at age 10 years, and had age 10 years and baseline spleen function measurement.

Arm/Group Title	On Hydroxyurea at the Time of Visit	Off Hydroxyurea at the Time of Visit
Arm/Group Description:	Subjects who were on hydroxyurea at the time of study visit	Subjects who were off hydroxyurea at the time of study visit
Overall Number of Participants Analyzed	88	17
Measure Type: Count of Participants; Unit of Measure: Participants
Splenic function - worse from baseline	43 48.9%	9 52.9%
Splenic function - not worse from baseline	45 51.1%	8 47.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	On Hydroxyurea at the Time of Visit, Off Hydroxyurea at the Time of Visit
	Comments	The primary analysis compared the frequency of worsening spleen function (from normal to decreased or absent, or from decreased to absent).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.80
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

3. Primary Outcome

Title	Change in the Percentage of Pitted Cell From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo
Description	The change in the percentage of pitted cell from randomized control trial baseline measurement was one of the primary outcomes. The change in the percentage of pitted cell was compared between the randomized treatment groups (hydroxyurea vs placebo).
Time Frame	Baseline and End of follow-up II study (up to 13 years from randomization date)

Outcome Measure Data

Analysis Population Description

All subjects who had end of study and baseline pitted cell measurement.

Arm/Group Title	Randomized to Hydroxyurea	Randomized to Placebo
Arm/Group Description:	Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Subjects randomized to Placebo in the randomized phase III clinical trial.
Overall Number of Participants Analyzed	70	68
Median (Inter-Quartile Range); Unit of Measure: Percentage of pitted cell
	-1.60; (-5.00 to -0.60)	-1.75; (-6.25 to -0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized to Hydroxyurea, Randomized to Placebo
	Comments	Kruskal-Wallis test was used to test if there were a statistically significant difference between the two treatment groups.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.87
	Comments	[Not Specified]
	Method	Kruskal-Wallis
	Comments	[Not Specified]

4. Primary Outcome

Title	Change in the Percentage of Pitted Cell From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea at Study Visit
Description	The change in the percentage of pitted cell from the randomized control trial baseline measurement was one of the primary outcomes. The change in the percentage of pitted cell was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit.
Time Frame	Baseline and End of follow-up II study (up to 13 years from randomization date)

Outcome Measure Data

Analysis Population Description

All subjects who were known to be on hydroxyurea vs. off hydroxyurea at the end of study visit, and had end of study and baseline pitted cell count measurement.

Arm/Group Title	On Hydroxyurea at the Time of Visit	Off Hydroxyurea at the Time of Visit
Arm/Group Description:	Subjects who were on hydroxyurea at the time of study visit	Subjects who were off hydroxyurea at the time of study visit
Overall Number of Participants Analyzed	116	22
Median (Inter-Quartile Range); Unit of Measure: Percentage of pitted cell
	-1.80; (-6.40 to -0.40)	-0.80; (-5.00 to -0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	On Hydroxyurea at the Time of Visit, Off Hydroxyurea at the Time of Visit
	Comments	Kruskal-Wallis test was used to test if there were a statistically significant difference between the two treatment groups.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.28
	Comments	[Not Specified]
	Method	Kruskal-Wallis
	Comments	[Not Specified]

5. Primary Outcome

Title	Change in Howell Jolly Body (HJB) From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo
Description	The change in Howell Jolly Body from the randomized control trial baseline measurement was one of the primary outcomes. The change in Howell Jolly Body was compared between the randomized treatment groups (hydroxyurea vs placebo).
Time Frame	Baseline and End of follow-up II study (up to 13 years from randomization date)

Outcome Measure Data

Analysis Population Description

All subjects who had end of follow-up study II and baseline howell jolly body count measurement.

Arm/Group Title	Randomized to Hydroxyurea	Randomized to Placebo
Arm/Group Description:	Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Subjects randomized to Placebo in the randomized phase III clinical trial.
Overall Number of Participants Analyzed	65	62
Median (Inter-Quartile Range); Unit of Measure: Number of HJB per 10⁶ red blood cell
	2719.88; (1373.90 to 4080.50)	2248.55; (908.88 to 3758.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Randomized to Hydroxyurea, Randomized to Placebo
	Comments	Kruskal-Wallis test was used to test if there were a statistically significant difference between the two treatment groups.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.31
	Comments	[Not Specified]
	Method	Kruskal-Wallis
	Comments	[Not Specified]

6. Primary Outcome

Title	Change in Howell Jolly Body (HJB) Count From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea
Description	The change in Howell Jolly Body count from the randomized control trial baseline measurement was one of the primary outcomes. The change in Howell-Jolly Bodies was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit.
Time Frame	Baseline and End of follow-up II study (up to 13 years from randomization date)

Outcome Measure Data

Analysis Population Description

All subjects who were known to be on hydroxyurea vs. off hydroxyurea at the end of study visit, and had end of study and baseline Howell Jolly Body count measurement.

Arm/Group Title	On Hydroxyurea at the Time of Visit	Off Hydroxyurea at the Time of Visit
Arm/Group Description:	Subjects who were on hydroxyurea at the time of study visit	Subjects who were off hydroxyurea at the time of study visit
Overall Number of Participants Analyzed	107	20
Median (Inter-Quartile Range); Unit of Measure: Number of HJB per 10⁶ red blood cell
	2645.43; (1373.90 to 4010.52)	1833.73; (326.15 to 2713.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	On Hydroxyurea at the Time of Visit, Off Hydroxyurea at the Time of Visit
	Comments	Kruskal-Wallis test was used to test if there were a statistically significant difference between the two treatment groups.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.04
	Comments	[Not Specified]
	Method	Kruskal-Wallis
	Comments	[Not Specified]

Adverse Events

Time Frame	The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years
Adverse Event Reporting Description	Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Arm/Group Title	Randomized to Hydroxyurea		Randomized to Placebo
Arm/Group Description	Subjects randomized to Hydroxyurea in the randomized phase III clinical trial. 150 subjects (130 in active and 20 in passive follow-up group) consented to follow-up II study. Of the 150 subjects, 77 subjects were randomized to the hydroxyurea treatment group during the randomized phase III clinical trial.		Subjects randomized to Placebo in the randomized phase III clinical trial. 150 subjects (130 in active and 20 in passive follow-up group) consented to follow-up II study. Of the 150 subjects, 73 subjects were randomized to the placebo treatment group during the randomized phase III clinical trial.
All-Cause Mortality
	Randomized to Hydroxyurea		Randomized to Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/77 (0.00%)		0/73 (0.00%)
Serious Adverse Events
	Randomized to Hydroxyurea		Randomized to Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/77 (31.17%)		31/73 (42.47%)
Blood and lymphatic system disorders
Vaso-occlusive crisis †	2/77 (2.60%)	4	3/73 (4.11%)	3
Pain Crisis †	4/77 (5.19%)	7	5/73 (6.85%)	6
Splenic sequestration crisis †	1/77 (1.30%)	2	1/73 (1.37%)	3
Sickle cell anemia with crisis †	1/77 (1.30%)	1	0/73 (0.00%)	0
Aplastic crisis †	0/77 (0.00%)	0	2/73 (2.74%)	2
Eye disorders
Binocular diplopia and new onset left esotropia †	1/77 (1.30%)	1	0/73 (0.00%)	0
Gastrointestinal disorders
Pain †	0/77 (0.00%)	0	1/73 (1.37%)	1
Hepatobiliary disorders
Cholelithiasis †	0/77 (0.00%)	0	2/73 (2.74%)	2
Acute hepatic crisis with component of hepatic sequestration. †	1/77 (1.30%)	1	0/73 (0.00%)	0
Infections and infestations
VOC. Acute hematogenous Osteomyelitis †	0/77 (0.00%)	0	1/73 (1.37%)	1
Pneumonia †	2/77 (2.60%)	2	1/73 (1.37%)	1
Osteomyelitis radial †	1/77 (1.30%)	1	0/73 (0.00%)	0
Tonsilitis †	0/77 (0.00%)	0	1/73 (1.37%)	1
Fever rhinovirus †	1/77 (1.30%)	1	0/73 (0.00%)	0
Injury, poisoning and procedural complications
Delayed hemolytic transfusion reaction †	0/77 (0.00%)	0	1/73 (1.37%)	1
Musculoskeletal and connective tissue disorders
Pain †	1/77 (1.30%)	1	0/73 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangioma †	0/77 (0.00%)	0	1/73 (1.37%)	1
Nervous system disorders
Stroke, TIA †	1/77 (1.30%)	1	1/73 (1.37%)	1
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome †	16/77 (20.78%)	23	22/73 (30.14%)	36
Bilateral infiltrates on chest x-ray. †	1/77 (1.30%)	1	0/73 (0.00%)	0
Hypoxia †	0/77 (0.00%)	0	1/73 (1.37%)	1
Fever, cough, runny nose, sore throat and difficulty breathing. †	1/77 (1.30%)	1	0/73 (0.00%)	0
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Randomized to Hydroxyurea		Randomized to Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/77 (0.00%)		0/73 (0.00%)

Limitations and Caveats

Most children used hydroxyurea (HU) for at least part of the FUS-II observation period. This may dilute any effect of randomized group.

Most children were on HU at the specified time points, which reduces power to compare on/off HU.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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

Results Point of Contact

• Name/Title: Julie Miller
• Organization: New England Research Institutes, Inc
• Phone: 617-972-3197
• EMail: JMiller@healthcore.com

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT01783990
• Other Study ID Numbers: HHSN268201200023C
• First Submitted: February 1, 2013
• First Posted: February 5, 2013
• Results First Submitted: March 1, 2020
• Results First Posted: August 20, 2020
• Last Update Posted: August 20, 2020