SUMMARY: We propose a multicenter open-label, single-arm type I hybrid trial to assess the effectiveness of hydroxyurea therapy for primary stroke prevention in children with sickle cell anemia (SCA) living in Nigeria. Our team just completed a double-blind, parallel-group phase III randomized controlled trial (SPRING), where we compared low-dose to moderate-dose hydroxyurea for primary stroke prevention in children with SCA and abnormal transcranial Doppler (TCD) velocities (>200 cm/sec). Children with abnormal TCD velocities have a high stroke risk of approximately 10.7 events per 100 person-years (observation arm in the STOP trial). In the low- (n=109) and moderate-dose (n=111) hydroxyurea groups, the stroke incidence rates were 1.2 and 1.9 per 100 person- years, respectively, p=0.77 (combined incidence rate 1.5 per 100 person-year). Despite equal efficacy for stroke prevention in both treatment groups, moderate- when compared to low-dose hydroxyurea, was more effective in preventing severe acute pain and all-cause hospitalizations. Our findings supported the American Society of Hematology's evidence-based guidelines for hydroxyurea therapy for primary stroke prevention in low-income settings. Our hypothesis to be tested: in a multicenter single-arm type I hybrid trial, for children with abnormal TCD velocities treated with hydroxyurea, the stroke incidence rate will be non-inferior to the SPRING trial results, with an upper non-inferiority margin of 4 strokes per 100-person-years. The point estimate method was used to determine the non-inferiority margin based on the Nigerian pediatrician's judgment of what maximum stroke rate would be clinically meaningful to demonstrate the effectiveness and justify treatment for the high-risk stroke group. A non-inferiority test with an overall sample size of 220 participants will achieve 91% power at a 0.050 significance level to detect non-inferiority when the expected proportion of strokes is 0.035, a minimum follow-up period of 2.5 years and a loss to follow-up of 10% per year. Participants will be followed as per standard care, including clinic visits every 3 months and complete blood cell counts every 6 months. We will conduct the following aims:1) Determine the incidence of the first stroke and TIA in children with abnormal TCD velocities treated with hydroxyurea for 2.5 years in the type 1 hybrid trial; 2) Evaluate the implementation and sustainability of the intervention within the extended RE-AIM framework; 3) Evaluate the cost-effectiveness of low- compared to a higher dose of hydroxyurea for primary stroke prevention in children with abnormal TCD velocities. Capacity building for the three Nigerian Multiple Principal Investigators, the statisticians, and nurses will be focused on three areas- a) developing a Nigerian data coordinating center and the required skills to support a clinical trial; b) developing a regional TCD course for nurses, enhancing task shifting and reach, and c) performing cost-effective analysis for the type I hybrid trial comparing low-and moderate dose hydroxyurea.

PROJECT NARRATIVE: In 2020, our research team completed a multicenter phase III randomized controlled trial for primary stroke prevention in children with sickle anemia, demonstrating that children with an annual 10% stroke risk because of a high velocity of blood flow in their brain could be treated with either low or moderate dose hydroxyurea for a significant decrease in strokes. We propose an open-label, single-arm, type I hybrid trial (phase IV trial) for primary stroke prevention initially with low-dose hydroxyurea and subsequently with moderate-dose hydroxyurea based after at least two severe pain events requiring physician contacts during the trial and assessment of ways to maintain the sustainability of stroke prevention programs. We will conduct a cost- effective analysis to determine the sustainability, relative cost, and effectiveness of the hydroxyurea dose on stroke prevention and healthcare utilization.