Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia

Hematologic Diseases Clinical Trial

Official title:

Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00006400
• Other study ID #: 89
• Secondary ID: N01 HB07150N01 H
• Status: Completed
• Phase: Phase 3
• Start date: August 2000
• Est. completion date: September 2009

Study information

• Verified date: April 2011
• Source: National Heart, Lung, and Blood Institute (NHLBI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 193
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 9 Months to 18 Months

Eligibility

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:

1. Hemoglobin less than 6.0 gm/dL

2. Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL

3. Neutrophil count less than 2,000/cu mm

4. Platelet count less than 130,000/cu mm

5. Blood transfusion in the 2 months prior to study entry unless HbA is less than 10%

6. ALT greater than twice the upper limit of normal

7. Ferritin less than 10 ng/ml

8. Serum creatinine greater than twice the upper limit of normal for age

9. Bayley standardized mental score below 70

Related Conditions & MeSH terms

• Anemia
• Anemia, Sickle Cell
• Hematologic Diseases

Intervention

Drug:
• Hydroxyurea
Participants will receive hydroxyurea.
• Placebo
Participants will receive placebo.

Locations

Country	Name	City	State
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	SUNY Health Science Center, Brooklyn	Brooklyn	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Texas SW Medical Center	Dallas	Texas
United States	Children's Hospital of Michigan/Wayne State Univ.	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	Drexel University	Philadelphia	Pennsylvania
United States	Children's National Medical Center	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (10)

Heeney MM, Whorton MR, Howard TA, Johnson CA, Ware RE. Chemical and functional analysis of hydroxyurea oral solutions. J Pediatr Hematol Oncol. 2004 Mar;26(3):179-84. — View Citation

Miller ST, Wang WC, Iyer R, Rana S, Lane P, Ware RE, Li D, Rees RC; BABY-HUG Investigators. Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatr Blood Cancer. 2010 Feb;5 — View Citation

Pavlakis SG, Rees RC, Huang X, Brown RC, Casella JF, Iyer RV, Kalpatthi R, Luden J, Miller ST, Rogers ZR, Thornburg CD, Wang WC, Adams RJ; BABY HUG Investigators. Transcranial doppler ultrasonography (TCD) in infants with sickle cell anemia: baseline data — View Citation

Rogers ZR, Wang WC, Luo Z, Iyer RV, Shalaby-Rana E, Dertinger SD, Shulkin BL, Miller JH, Files B, Lane PA, Thompson BW, Miller ST, Ware RE; BABY HUG. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial. — View Citation

Thompson BW, Miller ST, Rogers ZR, Rees RC, Ware RE, Waclawiw MA, Iyer RV, Casella JF, Luchtman-Jones L, Rana S, Thornburg CD, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik S, Howard TH, Luck L, Wang WC. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer. 2010 Feb;54(2):250-5. doi: 10.1002/pbc.22269. — View Citation

Thornburg CD, Rogers ZR, Jeng MR, Rana SR, Iyer RV, Faughnan L, Hassen L, Marshall J, McDonald RP, Wang WC, Huang X, Rees RC; BABY HUG Investigators. Adherence to study medication and visits: data from the BABY HUG trial. Pediatr Blood Cancer. 2010 Feb;54 — View Citation

Wang WC, Pavlakis SG, Helton KJ, McKinstry RC, Casella JF, Adams RJ, Rees RC; BABY HUG Investigators. MRI abnormalities of the brain in one-year-old children with sickle cell anemia. Pediatr Blood Cancer. 2008 Nov;51(5):643-6. doi: 10.1002/pbc.21612. Erra — View Citation

Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, Rana S, Thornburg CD, Rogers ZR, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik SA, Howard TH, Wynn LW, Kutlar A, Armstrong FD, Files BA, Goldsmith JC, Waclawiw MA, Huang X, Thompson BW; BABY HUG — View Citation

Ware RE, Rees RC, Sarnaik SA, Iyer RV, Alvarez OA, Casella JF, Shulkin BL, Shalaby-Rana E, Strife CF, Miller JH, Lane PA, Wang WC, Miller ST; BABY HUG Investigators. Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. — View Citation

Wynn L, Miller S, Faughnan L, Luo Z, Debenham E, Adix L, Fish B, Hustace T, Kelly T, Macdermott M, Marasciulo J, Martin B, McDuffie J, Murphy M, Rackoff B, Reed C, Seaman P, Thomas G, Wang W. Recruitment of infants with sickle cell anemia to a Phase III t — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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