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Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00006400
Recruitment Status : Completed
First Posted : October 13, 2000
Results First Posted : August 19, 2020
Last Update Posted : August 19, 2020
Sponsor:
Information provided by (Responsible Party):
National Heart, Lung, and Blood Institute (NHLBI)

Brief 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.

Condition or disease Intervention/treatment Phase
Hematologic Diseases Anemia, Sickle Cell Drug: Hydroxyurea Drug: Placebo Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 193 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)
Study Start Date : August 2000
Actual Primary Completion Date : September 2009
Actual Study Completion Date : September 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Hydroxyurea

Arm Intervention/treatment
Active Comparator: Hydroxyurea
Participants will receive hydroxyurea.
Drug: Hydroxyurea
Participants will receive hydroxyurea.

Placebo Comparator: Placebo
Participants will receive placebo.
Drug: Placebo
Participants will receive placebo.




Primary Outcome Measures :
  1. Treatment Differences of the Change in Qualitative Splenic Function From Baseline [ Time Frame: Before initiation of treatment and at 2 years ]

    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.



Secondary Outcome Measures :
  1. Change From Baseline in the Renal Function That Was Measured by Diethylenetriaminepentaacetic Acid (DTPA) Glomerular Filtration Rate (GFR) [ Time Frame: Before initiation of treatment and at 2 years ]
    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).

  2. Change From Baseline in the Renal Function That Was Measured by Glomerular Filtration Rate (GFR) (Calculated Using Schwartz Formula) [ Time Frame: Before initiation of treatment and at 2 years ]
    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.

  3. Change From Baseline in the Renal Function That Was Measured by GFR (Calculated Using New Schwartz Formula) [ Time Frame: Before initiation of treatment and at 2 years ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   9 Months to 18 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00006400


Locations
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United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
Howard University
Washington, District of Columbia, United States, 20060
United States, Florida
University of Miami
Miami, Florida, United States, 33136
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30342
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Michigan
Children's Hospital of Michigan/Wayne State Univ.
Detroit, Michigan, United States, 48201
United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216
United States, New York
SUNY Health Science Center, Brooklyn
Brooklyn, New York, United States, 11203
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Pennsylvania
Drexel University
Philadelphia, Pennsylvania, United States, 19134
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
University of Texas SW Medical Center
Dallas, Texas, United States, 75390
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Sherron Jackson, MD Medical University of South Carolina
Principal Investigator: James F. Casella, MD Johns Hopkins University
Principal Investigator: Lori Luchtman-Jones, MD Children's National Research Institute
Principal Investigator: Rathi V. Iyer, MD University of Mississippi Medical Center
Principal Investigator: Scott T. Miller, MD SUNY Health Science Center, Brooklyn
Principal Investigator: Sohail R. Rana, MD Howard University
Principal Investigator: Zora R. Rogers, MD University of Texas SW Medical Center
Principal Investigator: Bruce W Thompson, Ph.D. Clinical Trials and Surveys Corp
Principal Investigator: Julio Barredo, MD University of Miami Medical Center
Study Chair: Winfred C. Wang, MD St. Jude Children's Research Hospital
Principal Investigator: Courtney Thornburg, MD Duke University
Principal Investigator: Thomas Howard, MD University of Alabama at Birmingham
Principal Investigator: Lori Luck, MD Drexel University
Principal Investigator: R. Clark Brown, MD, PhD Emory University
Principal Investigator: Sharada Sarnaik, MD Wayne State University
  Study Documents (Full-Text)

Documents provided by National Heart, Lung, and Blood Institute (NHLBI):
Informed Consent Form  [PDF] October 16, 2006

Publications of Results:

Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT00006400    
Other Study ID Numbers: 89
N01 HB07150
N01 HB07151
N01 HB07152
N01 HB07153
N01 HB07154
N01 HB07155
N01 HB07156
N01 HB07157
N01 HB07158
N01 HB07159
N01 HB07160
First Posted: October 13, 2000    Key Record Dates
Results First Posted: August 19, 2020
Last Update Posted: August 19, 2020
Last Verified: April 2011
Keywords provided by National Heart, Lung, and Blood Institute (NHLBI):
Blood Diseases
Sickle Cell Anemia
Additional relevant MeSH terms:
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Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors