Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease
Condition: Sickle Cell Disease; Stroke
MeSH terms: Anemia, Sickle Cell
Intervention: Hydroxyurea; Placebo
Intervention description: 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.
Intervention MeSH terms: Hydroxyurea
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 28.0
Sex: All
Minimum age: 12 Months
Maximum age: 54 Months
Healthy volunteers: No
Keywords: sickle cell disease; stroke; silent cerebral infarct; children

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.
    

Eligibility criteria:

        Inclusion Criteria for Screening

          1. Participant must have sickle cell anemia (hemoglobin SS) or sickle Beta-zero (null)
             thalassemia (hemoglobin S-B0) as confirmed at the local institution by hemoglobin
             analysis after six months of age.

          2. Participant must be 9 to 48 months of age. All screening procedures except MRI can be
             completed between 9 and 12 months of age, with the exception of the MRI, for which the
             child must have reached the age of 12 months.

          3. Informed consent must be signed by the participant's legally authorized guardian
             acknowledging written consent to join the study.

        Exclusion Criteria for Screening

          1. History of a focal neurologic event lasting more than 24 hours with medical
             documentation or a history of prior overt stroke.

          2. Other neurological problems, such as neurofibromatosis, lead poisoning, non-febrile
             seizure disorder, or tuberous sclerosis.

          3. Known human immunodeficiency virus (HIV) infection.

          4. Treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipated
             treatment during the course of the study.

          5. Chronic blood transfusion therapy, ongoing or planned.

          6. Poor adherence likely per his/her hematologist and study coordinator based on previous
             compliance in clinic appointments and following advice.

          7. Presence or planned permanent (or semi-permanent) metallic structures attached to
             their body. (e.g., braces on teeth), which their physicians believe will interfere
             with the MRI of the brain.

          8. History of two or more TCD studies with a velocity ≥ 200 cm/sec by the non-imaging
             technique, or ≥185 cm/sec for the imaging technique or a indeterminate TCD.

          9. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets
             <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias
             will be considered transient exclusions.

         10. Other significant organ system dysfunction

         11. Known allergy or intolerance of hydroxyurea

         12. Significant prematurity (gestational age of < 32 weeks)

        Inclusion Criteria for MRI of the Brain with Sedation

        1. The parents or guardians must provide consent for sedation.

        Exclusion Criteria for MRI of the Brain with Sedation

          1. Failure to pass MRI screening checklist

          2. Obstructive sleep apnea (OSA) and receiving therapy [e.g. continuous positive airway
             pressure], or being evaluated or followed by a specialist for management of severe OSA

          3. Less than 12 months of age.

          4. Allergic reactions such as urticaria or bronchospasm or previous adverse reactions to
             propofol, eggs, or soy products, if used at the participating center.

          5. Allergy or previous adverse reaction to pentobarbital, if used at the participating
             center

          6. Known major chromosomal abnormalities

          7. Known airway abnormalities that would increase the risk of sedation/anesthesia.

             Temporary Exclusions

          8. Room air oxygen saturation greater than or equal to 5% below the participant's
             baseline on the day of the MRI with sedation.

          9. Room air oxygen saturation <90% on the day of the MRI with sedation.

         10. Hemoglobin <6.5 g/dl (must be measured within 30 days of MRI).

         11. Temperature >38˚ C on the day of sedation

        8. Upper or lower respiratory infection, active bronchospasm, acute chest syndrome, splenic
        sequestration or other acute complications of sickle cell disease other than pain in the
        last 4 weeks (from resolution of symptoms) 9. Pain crisis within two weeks requiring
        treatment with opiates

        Inclusion Criteria for Randomization

          1. Participant must be 12 to 54 months of age

          2. Participant must have successfully completed screening procedures (TCD, MRI of the
             brain, neurology exam, and cognitive evaluation)

        Exclusion Criteria for Randomization

          1. Participants whose MRI show a silent or overt cerebral infarct.

          2. Participants who have a non-imaging TCD study with a velocity ≥ 185 cm/sec or a TCD
             that is indeterminate.

          3. Participants with abnormal kidney function (creatinine > 0.8 mg/dl)

          4. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets
             <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias
             will be considered transient exclusions.