Feasibility Trial for Primary Stroke Prevention in Children with Sickle Cell Anemia in Nigeria (SPIN Trial)

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).