Moderate Dose Hydroxyurea for Secondary Stroke Prevention in Children With Sickle Cell Disease in Sub-Saharan Africa
Condition: Sickle Cell Disease; Sickle Cell Anemia; Stroke
MeSH terms: Stroke; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      The overall goal of the proposed study is to determine the effectiveness of hydroxyurea
      therapy for secondary stroke prevention and prevention of other neurological events in
      children with SCA with an acute overt stroke.
    

Detailed description: 
      Sub-Saharan Africans are disproportionately affected with sickle cell disease (SCD). In the
      most populous country in sub-Saharan Africa, Nigeria, over 150,000 children with the most
      severe form of SCD, sickle cell anemia (SCA), are born per year as compared to about 1,100
      births in the United States. In Nigeria, for every birth year cohort of children with SCA
      followed to their 18th birthday with no premature deaths, there are at least 15,000 overt
      strokes. The prevalence of stroke among children with SCA, particularly in low-income
      countries, is associated with an increased rate of morbidity and premature death. If
      untreated, 50% of children who have had their first overt stroke will have a recurrent stroke
      within two years of the event. Regular blood transfusion is standard therapy for secondary
      stroke prevention in this high stroke risk population. However, monthly blood transfusion
      therapy is not a feasible option for children with SCA in sub-Saharan Africa for several
      reasons, including the high cost of monthly transfusion and limited blood supplies.
      Preliminary data from observational studies suggest that hydroxyurea (HU) therapy may be an
      effective alternative strategy for secondary stroke prevention in children with SCA. In
      sub-Saharan Africa, the critical unanswered question is what appropriate HU dose for
      secondary stroke prevention maximizes therapeutic benefit while minimizing toxicity to
      children.

      In preparation for this application, over the last 9 months, we achieved the following
      milestones with the SPIN trial (NCT01801423; NIH/NINDS Grant number 1R21NS080639-01): 1)
      demonstrated the feasibility of HU therapy for primary stroke prevention in Africa, with 92%
      of the eligible participants enrolled; 2) showed favorable data that moderate dose HU therapy
      (20 mg/kg/day) is safe; 3) demonstrated that HU therapy may be effective for primary stroke
      prevention (3 months after starting HU therapy, two-thirds of the children in the SPIN Trial
      (n=25) with baseline elevated transcranial Doppler (TCD) measurements decreased their TCD
      values to normal levels); 4) demonstrated short-term safety of HU therapy, with no deaths or
      increase in hospitalizations when compared to a prospectively followed comparison group
      (n=210) that had 7 deaths and a higher rate of all-cause hospitalizations; 5) revealed very
      good adherence to HU therapy based on the biological correlate, mean corpuscular volume
      (MCV), and the validated Morisky Medication Adherence Scale; and 6) conducted a one-month
      intensive clinical research training at Vanderbilt University, paired with ongoing mentoring
      for more than one year with multi-disciplinary teams from Aminu Kano Teaching Hospital (AKTH)
      and an affiliated satellite clinic, Murtala Muhammad Specialist Hospital (MMSH) both located
      in Kano, Nigeria. Our results to date indicate that no children have developed a stroke while
      on HU therapy, and the rate of adverse events has been lower than in the comparison group
      with a normal TCD measurement at baseline who were followed for the same period of time
      (median of 25 months). In the SPIN trial, both the treatment and the comparison group are
      being followed for 3 years.

      Based on our encouraging early results for primary stroke prevention in the SPIN Trial among
      children with SCA in Kano, Nigeria, we propose a definitive partial phase III trial with the
      same study team, wherein we will test the hypothesis that moderate dose HU therapy (20
      mg/kg/day) results in 80% relative risk reduction when compared to low dose HU therapy (10
      mg/kg/day) for secondary stroke prevention among children 1 - 16 years of age with SCA and
      acute overt stroke.

      The aims for the two center randomized partial double-blind Phase III clinical trial are: 1)
      to assess the efficacy of moderate dose HU therapy for secondary stroke prevention when
      compared to low dose HU therapy among children with SCA; 2) to determine whether moderate HU
      therapy decreases the rate of all-cause hospitalizations when compared to low dose HU
      therapy; and 3) to assess prevalence of strokes and incidence of recurrent strokes among
      individuals with SCD ages 1 - 16 at active study site from January 1, 2014 to June 30, 2017.
      We will randomly allocate up to 120 children who meet the inclusion criteria in a ratio of
      1:1 with follow-up for at least 36 months per participant from a pool of over 10,000 children
      with SCA who attend the two study sites, AKTH and MMSH, both located in Kano, Nigeria.
      Similar methods of operation and procedures from the SPIN Trial with participants from both
      sites will be used to conduct this proposed trial.

      Among the study population of over 10,000 children with SCA in Kano, < 1% receive a TCD
      measurement between the two study sites; therefore, we expect ≥ 100 children will have an
      initial stroke annually, based on an incidence of 1 per 100 patient years. Among those with
      an initial stroke who are untreated, which includes most of the children with strokes at the
      study sites, we expect at least 50% will have a recurrent stroke within two years. Rarely do
      we have an opportunity to conduct a trial that will likely result in a paradigm shift of
      medical care for children who have strokes. Completion of the trial will provide a targeted
      strategy for secondary stroke prevention in regions of the world where regular blood
      transfusion therapy is not routinely available, and children with strokes are left with no
      reasonable alternative for stroke prevention.
    

Intervention name(s): Moderate Dose Hydroxyurea; Low Dose Hydroxyurea
Intervention type(s): Drug; Drug
Intervention description(s): Hydroxyurea therapy at 20 mg/kg/day for primary stroke prevention.; Hydroxyurea therapy at 10 mg/kg/day (range 7 - 15 mg/kg/day) for primary stroke prevention.
Other intervention name(s): Hydrea; Hydrea
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: hydroxyurea; sub-Saharan Africa; secondary stroke prevention