Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia

Study Overview
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Brief Summary
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The purpose of this study is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in pediatric patients with sickle cell anemia.

Detailed Description
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BACKGROUND: In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months demonstrated that the drug is tolerated well by small infant, and that the fetal hemoglobin switch can be forced to remain in the on position by hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the PED HUG study. The SEP recommended that NHLBI undertake the BABY HUG trial. DESIGN NARRATIVE: BABY HUG is a randomized, double-blind, placebo-controlled study to determine if hydroxyurea can prevent the onset of chronic end organ damage in young children with sickle cell anemia. Approximately 200 children with sickle cell disease will be recruited to receive either hydroxyurea or placebo. The children will be screened at study entry for signs of abnormal brain, kidney, pulmonary, and splenic function, and developmental milestones. They will then be randomly assigned to receive either hydroxyurea or placebo and followed yearly to assess chronic end organ damage of the major organ systems. The primary endpoint will be a 50% reduction in rates of damage to the major organs with surrogate markers of organ function during follow-up in Phase II of the trial.

Official Title
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Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)

Conditions
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Hematologic Diseases, Anemia, Sickle Cell

Intervention / Treatment
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* Drug: Hydroxyurea
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis (screening may begin at 7 months of age) Exclusion Criteria: Chronic transfusion therapy Cancer Less than 5th percentile (10th percentile for the pilot study) height, weight, or head circumference for age Severe developmental delay (e.g., cerebral palsy or other mental retardation, Grade III/IV intraventricular hemorrhage) Stroke with neurological deficit Surgical splenectomy Participating in other clinical intervention trials Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin Known hemoglobin S-beta plus thalassemia (hemoglobin A present) Any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/sec results in ineligibility) Previous or current treatment with hydroxyurea (HU) or another anti-sickling drug The following exclusion criteria are transient; patients can be re-evaluated for eligibility: Hemoglobin less than 6.0 gm/dL Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL Neutrophil count less than 2,000/cu mm Platelet count less than 130,000/cu mm Blood transfusion in the 2 months prior to study entry unless HbA is less than 10% ALT greater than twice the upper limit of normal Ferritin less than 10 ng/ml Serum creatinine greater than twice the upper limit of normal for age Bayley standardized mental score below 70

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 18 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxyurea<br>Participants will receive hydroxyurea. | Drug: Hydroxyurea<br>* Participants will receive hydroxyurea.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo. | Drug: Placebo<br>* Participants will receive placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Differences of the Change in Qualitative Splenic Function From Baseline | Primary Endpoint: Spleen function was assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment (baseline) and 2 years later (exit). The results of each of the two scans were categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. The proportion of patients whose paired scans demonstrated a decline in splenic function was compared in the hydroxyurea versus placebo groups. The change in splenic function from baseline to 2 years 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, or decreased to normal. | Before initiation of treatment and at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) | DTPA GFR was originally a co-primary efficacy outcome for the study. Later in May 29, 2009, this measurement was discontinued because of statistical futility (an extremely small chance that the difference between treatment groups would be statistically significant for this outcome) and the small risk posed by the radiation exposure involved with performing the DTPA GFR test. Subjects who had missing data at baseline or 2 years measurement were excluded from the analysis (29 subjects from the hydroxurea, and 31 subjects from the placebo group excluded). | Before initiation of treatment and at 2 years | 
| Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) | Schwartz formula used to calculate GFR is: 0.55× height (cm)/serum creatinine (mg/dL). Where height is in cm and serum creatinine is in mg/dL. Children with missing baseline or 2 years GFR were excluded from the analysis. | Before initiation of treatment and at 2 years | 
| Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) | GFR was calculated using new Schwartz formula: 39.1× [height (cm)/serum creatinine (mg/dL)]0.516 × [1.8/cystatin C]0.294 × [30/blood urea nitrogen]0.169 × [1.099]if male × [height(m)/1.4]0.188. Children with missing baseline or 2 years GFR were excluded from the analysis. | Before initiation of treatment and at 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Diseases, Sickle Cell Anemia