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

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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:
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
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Active Passive
Hide 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
Arm/Group Title Active Passive Total
Hide 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
Hide 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
1.Primary Outcome
Title Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had age 10 years and baseline spleen function measurement.
Arm/Group Title Randomized to Hydroxyurea Randomized to Placebo
Hide 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%
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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%
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
All subjects who had end of study and baseline pitted cell measurement.
Arm/Group Title Randomized to Hydroxyurea Randomized to Placebo
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
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
Hide 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%)    
Hide 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
Hide 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%)    

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.

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
Layout table for Results Point of Contact information
Name/Title: Julie Miller
Organization: New England Research Institutes, Inc
Phone: 617-972-3197
EMail: JMiller@healthcore.com
Layout table for additonal information
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