Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease
Condition: Sickle Cell Disease; Stroke
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a pilot study of hydroxyurea versus placebo to reduce central nervous system
      complications (abnormally fast blood flow to the brain, silent cerebral infarct or stroke) in
      young children with sickle cell disease. The investigators plan to identify children 12 to 48
      months old without central nervous system complications and randomly assign 20 to treatment
      with hydroxyurea and 20 to treatment with placebo for 36 months. Neither the study doctors
      nor the participants will know which treatment they are receiving.
    

Detailed description: 
      Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly
      morbid complications of sickle cell disease (SCD) in children. Current approaches to the
      prevention and treatment of neurological complications in SCD include screening by
      transcranial Doppler ultrasound (TCD) to identify children with elevated cerebral blood flow
      velocity who are at increased risk for strokes; these children are then typically treated
      with chronic transfusions indefinitely. Hydroxyurea (HU) may have beneficial effects on
      central nervous system (CNS) complications in SCD and reduces the frequency of painful
      crisis, acute chest syndrome and transfusion. The safety of HU in infants and children has
      been suggested in a National Institutes of Health (NIH) sponsored phase III trial; however,
      the exact indications for the use of HU in children remain unclear, as well as its efficacy
      in preventing central nervous system (CNS) complications of SCD. Our preliminary data suggest
      that, if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%,
      the majority of pediatric hematologists would prescribe HU to all young children with SCD.
      The long term goal of this project is to perform a primary prevention trial to demonstrate
      the neuroprotective effect of HU and broaden the indications for HU in children. The goals of
      this proposal are to: 1) conduct an internal pilot randomized placebo-controlled trial of HU
      to reduce the CNS complications of SCD (the term internal pilot is used, as the results from
      the participants in the pilot will be analyzed as part of a definitive phase III trial to
      follow); 2) demonstrate the safety of hydroxyurea and study procedures in young children with
      SCD; and 3) create the leadership, network of clinical centers and other procedures necessary
      to conduct a definitive phase III trial demonstrating the efficacy of HU for primary
      prevention of the neurological complications of SCD.

      The primary endpoint for the internal pilot and definitive phase III trials will be the
      development of abnormal TCD, SCI, transient ischemic attack (TIA) or stroke. To begin the
      internal pilot trial, the investigators obtained Clinical and Translational Science Award
      (CTSA) support at Johns Hopkins and Washington University; these sites will screen 40
      participants 9-48 months of age and randomly assign and follow 20 participants for three
      years. Four additional centers (Children's Hospital of Philadelphia, Vanderbilt University,
      Children's Hospital Medical Center, Cincinnati and the University of Alabama, Birmingham)
      began enrollment (up to 20 patients screened and 10 participants randomly assigned per site),
      to provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70
      participant years of follow-up. Additional sites have been added. Participants must have TCD
      measurements that are well below transfusion thresholds and magnetic resonance imaging (MRI)
      of the brain without evidence of SCI. Participants in the internal pilot will continue into a
      phase III trial, to complete 3 years on HU or placebo. The information from the internal
      pilot trial will be used to improve the design of the definitive phase III trial. The results
      of these studies could lead to true primary prevention of CNS complications of SCD, including
      abnormal TCD, SCI, neurocognitive impairment and stroke. In doing so, this study could also
      reduce the burden of chronic transfusions and change clinical practice by broadening the
      indications for HU.
    

Intervention name(s): Hydroxyurea; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an Absolute Neutrophil Count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.; Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Other intervention name(s): Droxia; Hydrea; Sugar
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: sickle cell disease; stroke; silent cerebral infarct; children