Hydroxyurea with Dose Escalation to Reduce Primary Stroke Risk in Children with Sickle Cell Anemia in Dominican Republic: The Sacred Trial

Introduction: Sickle cell anemia (SCA) is common across the Caribbean. In Dominican Republic (DR), SCA has a high prevalence and leads to serious morbidity and mortality due to lack of resources and treatments. We designed a prospective clinical trial, Stroke Avoidance for Children in REpública Dominicana (SACRED), to build local capacity for clinical research and transcranial Doppler (TCD) screening, and to use hydroxyurea with dose escalation to maximum tolerated dose (MTD) to reduce the incidence of primary stroke in high-risk children with SCA. We now report the primary results of the SACRED trial.

Methods: SACRED (NCT02769845) is a single center prospective phase 2 open-label trial at Hospital Infantil Robert Reid Cabral (HIRRC), the main public pediatric hospital in Santo Domingo, DR. Local medical school graduates were recruited to spend at least one year with the project, to increase their research skills and learn TCD techniques. Each received hands-on TCD training on a Nicolet Sonara/tek non-imaging instrument from a US-based super-examiner, and completed 20-30 examinations before certification as an official SACRED TCD examiner. These graduates also received training in Good Clinical Practices and REDCap, using a database created specifically for the SACRED trial. Children with SCA receiving care at HIRRC were recruited and received a screening TCD exam; those with conditional time-averaged mean velocities (TAMV 170-199 cm/sec) were offered hydroxyurea for primary stroke prophylaxis, while those with abnormal TAMV (≥200 cm/sec) were referred for monthly transfusions for stroke prevention per local guidelines. Study participants with normal TCD velocities (<170 cm/sec) were rescreened 12 and 24 months later, to identify additional children with conditional velocities eligible for treatment. Locally-sourced 500mg hydroxyurea capsules were purchased for the study and prescribed at 20 mg/kg/day for 6 months, followed by dose escalation to MTD based on blood counts to achieve a target of mild myelosuppression with the absolute neutrophil count (ANC) = 2.0-4.0 x 10⁹/L. TCD exams were performed every 6 months and the primary study endpoint was reduction in TCD velocity after 24 months of hydroxyurea treatment.

Results: Between July 2016 and July 2017, 283 children were recruited and received laboratory and TCD screening. The average age at enrollment was 8.7 ± 2.4 years, and 46% were female. A total of 279 study participants had DNA-confirmed HbSS, of whom 50 had conditional TCD velocities and were offered hydroxyurea treatment. Subsequent TCD screening repeated annually for two years identified another 14 and 13 children, respectively, who developed conditional TCD velocities. Among 77 eligible children, 2 withdrew from the study and 1 died of acute respiratory failure before starting treatment, while the remaining 74 initiated hydroxyurea. Baseline laboratory parameters included hemoglobin = 7.7 ± 1.0 g/dL, fetal hemoglobin (HbF) = 16.0 ± 7.1%, and ANC = 7.5 ± 2.8 x 10⁹/L. The average baseline TAMV was 180 ± 8 cm/sec (median 178, IQR 173-186). After 6-months of fixed-dose hydroxyurea, expected laboratory changes included Hb = 8.4 ± 1.1 g/dL and HbF = 25.2 ± 9.5%, while TCD velocities decreased by an average of 20 ± 17 cm/sec. Dose escalation to MTD was achieved in 59 (80%) of the study participants, with a Stable Dose established in the remaining 20% of children. At Month 24 of hydroxyurea, the average dose was 25.8 ± 6.1 mg/kg/day with sustained treatment effects including Hb = 9.0 ± 1.5 g/dL, HbF = 30.2 ± 13.6%, and ANC = 4.3 ± 2.1 x 10⁹/L (all p<0.0001). The primary endpoint analysis revealed the average TCD value at Month 24 was 157 ± 22 cm/sec, documenting a sustained decline of 23 ± 21 cm/sec from baseline, and most children (65%) reverted to normal TCD velocities. There were no clinical strokes and no deaths during the 24-month hydroxyurea treatment period.

Conclusions: In the prospective SACRED trial, local capacity building in the DR led to a robust screening and treatment program to prevent primary stroke. Children with SCA and conditional TCD velocities were successfully treated with hydroxyurea at MTD with excellent laboratory effects, lowering of TCD velocities, and no clinical strokes. Wider access to TCD screening and increased use of hydroxyurea treatment at MTD are warranted across the Caribbean.

Ware:BMS: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.