Low Dose Hydroxyurea for Secondary Stroke Prevention in Children With Sickle Cell Disease in Sub-Saharan Africa

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 supply of blood.
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 the first National Institutes of Health (NIH)-sponsored primary stroke
prevention trial1 in SCA in sub-Saharan Africa (SPIN Trial: NCT01801423), where children
with SCD and elevated transcranial Doppler (TCD) measurements, a risk factor for overt
stroke, received HU therapy at 20 mg/kg/day, we achieved the following milestones: 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 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
has had 4 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 who were followed for the same period of time (median of 15
months) with no deaths in the treatment group and three deaths in the comparison group. Both
the treatment group and the control group are being followed for 3 years. Based on our
encouraging early results for primary stroke prevention in children with SCA (SPIN Trial) in
Kano, Nigeria, we propose a definitive 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 - 18 years of age with SCA and acute overt stroke.

Inclusion Criteria:

- Children ages 1 to 18 years of age with sickle cell anemia confirmed by hemoglobin
electrophoresis evaluation or HPLC;

- Informed consent from a parent or legal guardian and assent of participants;

- Children with history of stroke with event up to and within 30 days prior to signing
the informed consent;

- Acceptance of HU therapy for at least two years.

Exclusion Criteria:

- Children with history of stroke with event occurring more than 30 days prior to
signing the informed consent;

- Confirmed pregnancy or considering family planning - due to possible
hydroxyurea-induced congenital anomalies or abnormal fetal growth. Adolescents who
have started their menses must have a pregnancy test done every month prior to
getting a prescription for HU;

- Children who are already on blood transfusion or HU therapy;

- Other exclusions: significant cytopenias [absolute neutrophil count (ANC) <1500/ul,
platelets <150,000/ul, reticulocytes <80,000/ul, unless Hb is > 9 g/dl], renal
insufficiency (creatinine > 0.8 mg/dl); other significant organ system dysfunction,
or other contraindication to HU therapy; and history of seizures or diagnosis of
epilepsy;

- Other significant organ system dysfunction based on the site investigators
discretion;

- Any other condition, such as malnutrition, or chronic illness, which in the opinion
of the site's Principal Investigator makes study therapy not advisable or unsafe;

- Active infections: bacterial, viral or fungal (tuberculosis, malaria, active
hepatitis, osteomyelitis);

- Active chronic leg ulcers.