Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial

Abstract

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

Keywords: Hydroxyurea; Sub-Saharan Africa; primary stroke prevention; sickle cell anemia.

Figure 1:

Preliminary data from the Primary Prevention of Stroke in Nigeria (SPIN) feasibility trial. The data indicates 23 participants with SCA treated with moderate fixed-dose hydroxyurea at a dose of 20 mg/kg/day and followed with serial TCDs, TCD velocity declined significantly after three months and was maintained at 12 months. The proposed trial will determine whether moderate versus low-dose hydroxyurea therapy can potentially prevent thousands of strokes in children at high risk in Africa, while simultaneously training the next cadre of physician-scientists and research staff for clinical research in Nigeria. The results will provide evidence for hydroxyurea therapy as an initial alternative to blood transfusion therapy for patients with elevated TCD values living in resource-limited settings where blood transfusion therapy is not reasonable.

Figure 2:

A pooled analysis of the impact of hydroxyurea and decreasing transcranial Doppler (published in Blood 2016, 127: 829–838, online): A pooled analysis of 8 studies documenting TCD measurement before and after hydroxyurea therapy. The pooled analysis is based on the random-effect model demonstrating the average drop in TCD measurement after starting hydroxyurea therapy of 25 cm per second.[, –39] The figure also includes the observation that the decrease in TCD measurements can be seen as early as three months after starting hydroxyurea therapy with a sustained impact of hydroxyurea therapy on decreasing TCD measurements for at least 36 months. The black diamond represents the results of random-effect models. The edges of the diamonds represent the 95% CI of the meta-analyses for the random-effect models.[24]