Primary Prevention of Stroke in Children With SCD in Sub-Saharan Africa II

Strokes in sickle cell anemia (SCA), particularly in children living in Africa, are
associated with significant morbidity and an increased rate of premature death. In the US,
primary prevention of strokes 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 is not
feasible in Africa due to inadequate supply of safe blood and the reluctance of parents to
accept blood transfusion therapy for primary stroke prevention. Promising preliminary data
from our feasibility trial in Kano, Nigeria (1R21NS080639-NCE, NCT01801423) 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, the investigators
screened 338 participants; 92% (25 of 27) of the participants with elevated TCD measurements
elected to enroll, 66% (15 of 23; of note 2 participants have not reached their 3 month
milestone) of the participants who reached their third month on HU therapy dropped their
elevated TCD value to below 200 cm/sec in both left and right middle cerebral arteries; and
89% (210 of 235) of the screened participants with non-elevated TCD measurements agreed to
be followed for three years for assessment of background rates of morbidity and mortality.
Based on the results from the recently completed NHLBI trial, Transcranial Doppler (TCD)
With Transfusions Changing to Hydroxyurea; 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, the investigators propose a two center randomized
clinical trial 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. In
preparation for this application, the team from Nigeria has received 1 month of
patient-oriented research training at Vanderbilt University School of Medicine. The aims 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 the long-term safety of HU
therapy in children with elevated TCD measurements. The investigators will continue to treat
cases in the feasibility trial (n=25) and follow controls with normal TCD measurements
(n=210), for an average of approximately 6.5 years, to compare the rates of adverse and
serious adverse events. After completion of this trial, the investigators will determine
whether moderate dose HU therapy can potentially prevent thousands of strokes in children at
high risk in Africa, while simultaneously training the next cadre of physicians in
sub-Saharan Africa.

Inclusion criteria for screening:

- Patients with hemoglobin SS or SB0 thalassemia confirmed by hemoglobin
electrophoresis;

- Informed consent from a parent or legal guardian and assent of participant ages 5
through 12;

- Two TCD flow velocity readings of ≥ 200 cm/sec, based on assessments conducted by two
trained study radiologists or study certified sonographers;

- Patient must be 5 through 12 years of age (i.e., must have attained their 5th but not
their 13th birthday when the consent is signed).

Exclusion Criteria for screening:

- Prior overt stroke (a focal neurological deficit of acute onset) by history, focal
neurological deficit on standardized neurological examination, or concern for
moderate or severe neurological deficit (which could be due to stroke) based on a
positive "10 questions" screening (an established tool in resource poor countries). A
"positive" screening is defined as answering yes to any one of the 10 questions. The
negative predictive value (child does not have moderate or several neurological
impairment) of the "10 questions" is greater than 94% in children;

- 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);

- Patients for whom are currently receiving HU therapy or under consideration prior to
study consent/education;

- Patients who have previously been treated with hydroxyurea and are being considered
to restart hydroxyurea therapy;

- Other significant organ system dysfunction;

- History of seizures or diagnosis of epilepsy;

- Any other condition illness, which in the opinion of the site's Principal
Investigator (PI) makes participation ill-advised or unsafe.

- Participants of child bearing age who are pregnant or may become pregnant should not
take hydroxyurea. If a participant becomes pregnant during the study, their
hydroxyurea treatment will be stopped immediately. The onsite will notify the
clinical coordinating center and the principal investigators of the case. The site
principal investigator and study principal investigators will determine what therapy
the participant should receive during pregnancy that is of standard care.

Inclusion Criteria for participants that will be randomized to hydroxyurea therapy for 36
months:

- Successful completion of screening procedures inclusive of cerebral blood flow
velocity greater than or equal to 200 cm/sec measured twice or at least one
measurement greater than or equal to 220 cm/sec in the middle cerebral artery;

- Informed consent from a parent or legal guardian for study therapy and assent of the
participant completed;

- Participant is able to swallow a capsule as observed by study personnel;

- Acceptance of hydroxyurea therapy for three years. Within the three years, the
participant will have the option to continue therapy with follow up visits to monitor
adherence to therapy.

Exclusion Criteria for study therapy:

- Unable to commit to follow up visits for the duration of the study.

Inclusion Criteria for iron supplementation and evaluation:

- Ferritin level <30 ug/L, with confirmatory CBC (see Table 9) showing anemia
suggestive of iron deficiency;

- Able to swallow iron pill(s);

- Able to commit to 3 month follow-up evaluation with transcranial Doppler.