Acceptability and Safety of Hydroxyurea for Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria
Authors: DeBaun Michael R. , Galadanci Najibah Aliyu , Abdullahi Shehu U. , Tabari Musa A. , Abubakar Shehi , Belonwu Raymond , Salihu Auwal , Neville Kathleen A , Kirkham Fenella J. , Inusa Baba PD , Shyr Yu , Phillips Sharon , Kassim Adetola A. , Jordan Lori C. , Aliyu Muktar H. , Covert Brittany V. 
Published: October 2019

Abstract
Background: Nigeria has the highest prevalence of sickle cell disease (SCD), a common cause of pediatric ischemic stroke. In sub-Saharan Africa monthly blood transfusions for primary stroke prevention carries risks; hydroxyurea (HU) may be an alternative. We conducted the first, US NIH funded, SCD feasibility trial in sub-Saharan Africa (5R21NS080639-02) to: 1) assess the acceptability and willingness of families to participate in a HU trial; 2) develop a safety protocol for using HU in a trial setting in sub-Saharan Africa; and 3) prepare for a definitive phase III Trial. In the Sickle Cell Disease Stroke Prevention in Nigeria (SPIN) trial, our primary hypothesis in the internal feasibility trial is that 80% adherence for daily HU administration is feasible.
Procedure: The internal pilot is a single site; single arm trial enrolling 40 children aged 5 to 12 years with hemoglobin SS or SB0 thalassemia at risk of developing stroke with a high transcranial Doppler (TCD) velocity in the middle cerebral artery (MCA) ≥ 200 cm/sec. Each participant is scheduled to receive low dose HU therapy (~20mg/kg/day) for 36 months. Acceptability was determined by the number of families who consented for screening. The adherence rate of HU was based on monthly parental assessment of the Morisky Medical Adherence Sore (MMAS) and monthly complete blood count (CBC) to monitor the serial change in mean corpuscular volume (MCV) from baseline level. Assessment of toxicity attributable to HU was based on comparing adverse events between the HU and control groups. Controls were identified as participants that met the criteria for the trial, but had TCD measurements < 200 cm/sec. From Baby HUG, adverse events were defined as hospitalization for any cause, severe anemia and myelosuppression (severe neutropenia and thrombocytopenia based on monthly CBC).
Results: A total of 269 participants were approached, of which 96% (23 of 24) and 86% (211 of 245) with an elevated or normal TCD measurement agreed to enroll in the HU therapy or control groups with a median age of 8 and 7.6 years, respectively. At the current milestone, 100% of the participants enrolled in the treatment arm demonstrated at least average to high monthly adherence rate (MMAS of 6-8 points). This adherence rate was consistent with an increase in MCV from baseline to 3 months after starting HU therapy with a minimum increase in MCV of at least 3 fl in 8 of 11 participants. One child on HU therapy was hospitalized for 5 days for hypovolemia and dehydration associated with cholera. The table below shows no excessive rate of adverse events when HU therapy and control groups are compared.
Conclusion: These early results demonstrate the ability for a sub-Saharan African clinical research team to plan and initiate a complex SCD trial. Our preliminary data provide strong evidence for acceptability and potential safety of low dose HU therapy in Nigerian children with SCD. Completion of the internal pilot should provide sufficient evidence to pursue a phase III trial of low dose HU therapy to prevent strokes in children living in sub-Saharan Africa.
Table. Rates of Hospitalization within the first 12 months of the SCD Stroke Prevention in Nigeria (SPIN) Trial. Reason for Hospitalization Hydroxyurea Therapy Group (15 total person years; n = 23) Rate per 100 patient years Control Group (52 total person years; n = 211) Rate per 100 patient years Acute Chest Syndrome 0 2 Osteomyelitis 0 2 Infection requiring hospitalization 0 6 Pain requiring hospitalization 0 72 Transfusion 0 8 Malaria requiring hospitalization 7 34 Fever requiring hospitalization 7 0 Other reasons for hospitalizations 0 10

Disclosures
Neville: American Academy of Pediatrics; Food and Drug Administration; NICHD: Membership on an entity's Board of Directors or advisory committees; Children's Oncology Group; Therapeutic Advances in Childhood Leukemia; Neuroblastoma/Medulloblastoma Treatment Consortium; Pediatric Oncology Experimental Therapeutics Investigators Consortium; Midwest Cancer Alliance; Dell; Braden's Hope Foundation: Research Funding; Sanofi; Novartis; Amgen; Medimmune; United Therapeutics; Bristol Myers Squibb: IND for hydroxyurea, IND for hydroxyurea Other.