Primary Prevention of Stroke in Children With SCD in Sub-Saharan Africa II
Condition: Sickle Cell Disease; Stroke
MeSH terms: Stroke; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      The overall goal of this proposal is to conduct a partial double-blind randomized Phase III
      clinical trial for primary stroke prevention in children with sickle cell anemia (SCA) in
      sub-Saharan Africa.
    

Detailed description: 
      Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are
      associated with significant morbidity and an increased risk of premature death. In the US,
      primary stroke prevention in children with SCA involves screening for elevated transcranial
      Doppler ultrasound (TCD) velocity coupled with regular blood transfusion therapy for those
      with elevated velocities. However, regular blood transfusion therapy is not feasible in
      Africa due to inadequate supply of safe blood and the reluctance of parents to accept regular
      blood transfusion therapy for their children. Promising preliminary data from our feasibility
      trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423; October 2012 - August 2014) support
      the potential use of moderate dose hydroxyurea (HU) therapy of 20 mg/kg/day for primary
      prevention of stroke in children with SCA. In the feasibility trial, we screened 331
      participants; 92% (25 of 27) of participants with elevated TCD measurements elected to enroll
      and receive HU therapy. About 75% (210 of 280) of the screened participants with non-elevated
      TCD measurements agreed to be followed for a minimum of three years to assess the background
      rate of morbidity and mortality. Among those on HU therapy, 80% (20 of 25) of the
      participants who reached their third month on HU therapy dropped their elevated TCD value to
      below 200 cm/sec in both middle cerebral arteries. Based on the results from the recently
      completed Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea trial
      (NCT01425307), demonstrating that children with an elevated TCD measurement can be switched
      to HU therapy after one year of blood transfusion, coupled with our preliminary trial results
      indicating a decrease in TCD velocities in 2/3rds of the participants over 3 months, we
      propose a three center randomized partial double-blind Phase III clinical trial
      (1R01NS094041-01; September 2015 - July 2020) to test the following hypothesis: There will be
      a 66% relative risk reduction of primary strokes in children with SCA, and elevated TCD
      measurements (n=220), randomly allocated to moderate dose vs. low dose HU therapy (10 vs. 20
      mg/kg/day) for 3 years. The aims of the randomized partial double-blind Phase III clinical
      trial are to: 1) determine the efficacy of moderate vs. low dose HU therapy for primary
      stroke prevention; 2) determine the efficacy of moderate dose HU therapy for decreasing the
      incidence of all cause-hospitalization for any cause (pain, acute chest syndrome, infection,
      or other) when compared to low dose HU therapy; and 3) assess long-term safety of HU therapy
      (mean 6.5 years) in participants from the feasibility trial with an elevated TCD measurement
      (n=25), when compared to children with an initial normal TCD (n= 210, followed for at least 3
      years). In preparation for this application, the teams from Nigeria have received 1 month of
      patient-oriented research training at Vanderbilt University School of Medicine. This trial
      will help us to determine whether moderate dose HU therapy can prevent thousands of strokes
      in children at high risk in Africa, while simultaneously helping build research capacity
      among the next cadre of physician scientists in Nigeria.
    

Intervention name(s): Hydroxyurea (Moderate Dose); Hydroxyurea (Low Dose)
Intervention type(s): Drug; Drug
Intervention description(s): The study intervention will include moderate dose hydroxyurea therapy at 20 mg/kg/day (range 17.5 - 26 mg/kg/day) for 36 months.; The study intervention will include random allocation to low dose hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day) for 36 months.
Other intervention name(s): Hydrea; Hydrea
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: primary stroke prevention; hydroxyurea; low income country; sub-Saharan Africa