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Background The majority of children with sickle cell disease (SCD), approximately 75%, are born in sub-Saharan Africa. For children with elevated transcranial Doppler (TCD) velocity, regular blood transfusion therapy for primary stroke prevention is standard care in high income countries, but is not feasible in sub-Saharan Africa. Procedure In the first U.S. National Institute of Health (NIH) sponsored SCD clinical trial in sub-Saharan Africa, we describe the protocol and challenges unique to starting a clinical trial in this region. We are conducting a single arm internal pilot of hydroxyurea therapy in children with TCD velocity ≥ 200 cm/sec in the middle cerebral arteries. Eligible children will be placed on hydroxyurea (n=40) and followed for 3 years at Aminu Kano Teaching Hospital, Nigeria. Adherence will be measured via the Morisky Scale and adverse events will be determined based on hospitalization. Results Originally, a randomized placebo trial was planned; however, placebo was not approved by the local Ethics Committee. Hence a single-arm trial of hydroxyurea will be conducted and five controls per patient with normal TCD measurements will be followed to compare the rate of adverse events to those with abnormal TCD measurements taking hydroxyurea. Using non-NIH funding, over nine months, multiple face-to-face investigator meetings were conducted to facilitate training. Conclusion A hydroxyurea trial (NCT01801423) for children with SCD is feasible in sub-Saharan Africa; however, extensive training and resources are needed to build a global patient oriented multi-disciplinary research team with a common purpose.

Background: In children with sickle cell anemia (SCA), the routine use of transcranial Doppler (TCD) measurements and regular blood transfusion therapy for those with elevated velocities > 200 cm/sec, has dramatically decreased the rate of strokes. However, blood transfusion therapy for primary stroke prevention is not an option for most children in Africa. In preparation for a phase III trial of hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for primary prevention of strokesin children with SCA in Africa, we conducted a single site, single-arm feasibility trial of hydroxyurea therapy for primary stroke prevention in children with SCA. Participants were between 5 and 12 years of age, attending the pediatric sickle cell disease clinic of Aminu Kano Teaching Hospital, in Kano, Nigeria. The main objectives of the feasibility trial were to determine the acceptability rate of a hydroxyurea therapy trial to families, and to obtain preliminary evidence of hydroxyurea safety in Africa. Methods: All eligible participants were screened with TCD, non-imaging technique, to determine increased stroke risk; defined as time-averaged maximum velocity (TAMV) greater than or equal to 200cm/sec in the middle cerebral artery (MCA). Families were offered moderate fixed dose hydroxyurea (~20mg/kg/day) for initially 2 years. Primary outcome measures of acceptability were based on three key components required for phase II randomized controlled trial: recruitment rate, retention rate and adherence to the study medication. To determine the expected background rate of adverse events and serious adverse events in this population, children with TCD velocities less than 200cm/sec who were not on hydroxyurea therapy were enrolled. Results: A total of 375 families were approached to be screened for elevated TCD measurements, of which 90% (330 of 375) enrolled; 8% (27 of 330) had two consecutive elevated TCD measurements; and 92% (25 of 27) participated in the trial. A total of 210 participants were identified with TCD velocities less than 200 cm, signed informed consents, and agreed to be followed prospectively in a comparison group. The median age for the trial participants and comparison group were 8 and 6.8 years, respectively. No statistically significant difference was observed in age, sex, ethnicity, height and weight of the treatment and comparison groups. The median time on therapy was 2.1 years (range: 0 to 2.8 years), and the average mean cell volume increased from 85 fl at baseline to 101.3 fl at 2 years. As per protocol, all patients were expected to attend monthly research visits and none were missed (n=total 603 visits). No participant in the treatment group dropped voluntarily from the trial, though one participant was withdrawn due to development of progressive renal failure. After follow up visits, participants in the comparison group with subsequent TCD measurements, were given the option to receive hydroxyurea therapy, and the only 2 with elevated TCD values elected to do so. No stroke occurred in the treatment group and 1 stroke occurred in the comparison group. Hospitalization rates in treatment and comparison groups were 35.1 and 48.0 per 100 patient years respectively, (p=0.06). A total of 9 deaths occurred, 1 death in the treatment group, but after participant withdrew from the trial because of progressive renal disease (1.76 per 100 patient-years) and 8 deaths in the comparison group (1·88 per 100 patient-years) p = 0.94. No participants that died received any PCV-13 vaccinations and only 2 received Hib vaccinations. At the time of death, all participants were prescribed malaria prophylaxis, and 8 of 9 participants were prescribed penicillin prophylaxis. Conclusion: In Nigeria, participants in SPIN Trial with elevated TCD measurements treated with moderate dose of hydroxyurea, showed high rates of successful recruitment, retention and adherence rates to trial medication. Importantly hydroxyurea therapy did not reveal any evidence of excessive toxicity when compared to those not treated with hydroxyurea. Our results provide strong preliminary evidence supporting the current multi-center randomized controlled trial comparing hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for preventing primary strokes in children with SCA living in Nigeria (1R01NS094041-01;clinical trials.gov NCT 02560935). Disclosures No relevant conflicts of interest to declare.

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