Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea
Condition: Sickle Cell Anemia
MeSH terms: Anemia; Anemia, Sickle Cell
Intervention: Hydroxyurea
Intervention description: Capsules (300 mg, 400 mg, or 500 mg) taken once daily liquid formulation (100 mg/mL)
Intervention MeSH terms: Hydroxyurea
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 159.0
Sex: All
Minimum age: 4 Years
Maximum age: 15 Years
Healthy volunteers: No
Keywords: Phase III; Sickle cell anemia; Abnormally high Transcranial Doppler velocities.; Reduce risk of primary stroke; Pediatric patients; Chelation therapy

Summary:

      The primary goal of the Phase III TWiTCH trial is to compare 24 months of alternative therapy
      (hydroxyurea) to standard therapy (transfusions) for pediatric subjects with sickle cell
      anemia and abnormally high (≥200 cm/sec) Transcranial Doppler (TCD) velocities, who currently
      receive chronic transfusions to reduce the risk of primary stroke. For the alternative
      treatment regimen (hydroxyurea) to be declared non-inferior to the standard treatment regimen
      (transfusions), after adjusting for baseline differences, the hydroxyurea-treated group must
      have a mean TCD velocity similar to that observed with transfusion prophylaxis.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0
             thalassemia,HbSOArab)

          2. Age range of 4.0-15.99 years, inclusive, at the time of enrollment

          3. Documented index (pre-treatment) abnormally high TCD Velocity by Transcranial Doppler
             ultrasonography. An abnormally high index TCD is defined as TCD V greater than or
             equal to 200 cm/sec, or abnormally high TCDi V greater than or equal to185cm/sec, or
             TCD maximum V greater than or equal to 250 cm/sec.

          4. At least 12 months of chronic monthly erythrocyte transfusions since the index
             abnormal TCD examination

          5. Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45%
             (the upper limit of the established academic community standard) for the past 6 months
             before enrollment

          6. Parent or guardian willing and able to provide informed consent with verbal or written
             assent from the child

          7. Ability to comply with study related treatments, evaluations, and follow-up

        Exclusion Criteria:

          1. Completed overt clinical stroke or TIA

          2. Inability to obtain TCD velocities due to anatomical abnormalities such as a)
             Inadequate bone windows b) Previous revascularization procedures (e.g., EDAS)

          3. Known severe vasculopathy or moya-moya disease on brain MRA

          4. Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due
             to any of the following: a) Multiple RBC alloantibodies making cross-matching
             difficult or impossible b) RBC autoantibodies making cross-matching difficult or
             impossible c) Religious objection to transfusions that preclude their chronic use d)
             Non-compliance with transfusions over the past 6 months before enrollment (temporary
             exclusion)

          5. Inability to take or tolerate daily oral hydroxyurea, including a) Known allergy to
             hydroxyurea therapy b) Positive serology to HIV infection c) Malignancy d) Current
             lactation e) Previous stem cell transplant or other myelosuppressive therapy

          6. Clinical and laboratory evidence of hypersplenism (temporary exclusions): a) Palpable
             splenomegaly greater than 5cm below the left costal margin AND b) Transfusion
             requirement greater than 250 mL/kg over the previous 12 months

          7. Abnormal laboratory values at initial evaluation (temporary exclusions): a)
             Pre-transfusion hemoglobin concentration less than 8.0 gm/dL b) WBC count less than
             3.0 x 10^9/L c) Absolute neutrophil count (ANC) less than 1.5 x 10^9/L d) Platelet
             count less than 100 x 10^9/L e) Serum creatinine more than twice the upper limit for
             age OR greater than or equal to 1.0 mg/dL

          8. Current participation in other therapeutic clinical trials

          9. Current use of other therapeutic agents for sickle cell disease (e.g., arginine,
             decitabine, magnesium). Subjects must have been off hydroxyurea for at least 3- months
             prior to enrollment.

         10. Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in
             the opinion of the CI makes participation ill-advised.

         11. Inability or unwillingness to complete required screening and exit studies, including
             TCD ultrasonography, brain MRI/MRA, liver MRI and blood tests.

         12. A sibling enrolled in TWiTCH

         13. Pregnancy or unwillingness to use a medically acceptable form of contraception if
             sexually active (male OR female).