Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia

August 5, 2020 updated by: National Heart, Lung, and Blood Institute (NHLBI)

Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

193

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham
    • District of Columbia
      • Washington, District of Columbia, United States, 20060
        • Howard University
      • Washington, District of Columbia, United States, 20010
        • Children's National Medical Center
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami
    • Georgia
      • Atlanta, Georgia, United States, 30342
        • Emory University School of Medicine
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Children's Hospital of Michigan/Wayne State Univ.
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • University of Mississippi Medical Center
    • New York
      • Brooklyn, New York, United States, 11203
        • SUNY Health Science Center, Brooklyn
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19134
        • Drexel University
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
    • Tennessee
      • Memphis, Tennessee, United States, 38105
        • St. Jude Children's Research Hospital
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas SW Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

9 months to 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Participants will receive placebo.
Drug: Placebo
Participants will receive placebo.
Active Comparator: Hydroxyurea
Participants will receive hydroxyurea.
Drug: Hydroxyurea
Participants will receive hydroxyurea.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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)
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).
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)
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.
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)
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.
Before initiation of treatment and at 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: James F. Casella, MD, Johns Hopkins University
  • Principal Investigator: Sherron Jackson, MD, Medical University of South Carolina
  • 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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2000

Primary Completion (Actual)

September 1, 2009

Study Completion (Actual)

September 1, 2009

Study Registration Dates

First Submitted

October 12, 2000

First Submitted That Met QC Criteria

October 12, 2000

First Posted (Estimate)

October 13, 2000

Study Record Updates

Last Update Posted (Actual)

August 19, 2020

Last Update Submitted That Met QC Criteria

August 5, 2020

Last Verified

April 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 89
  • N01 HB07160 (NHLBI)
  • N01 HB07150
  • N01 HB07151
  • N01 HB07152
  • N01 HB07153
  • N01 HB07154
  • N01 HB07155
  • N01 HB07156
  • N01 HB07157
  • N01 HB07158
  • N01 HB07159

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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