BackgroundIn the Dominican Republic, where the burden of sickle cell anemia (SCA) is high, many children lack access to routine screening and preventative care. Children with SCA are at risk for stroke, an event that leads to significant morbidity and mortality. In the United States, screening via transcranial Doppler (TCD) identifies children with SCA at highest stroke risk, allowing early intervention with blood transfusions. The need for indefinite transfusions for primary stroke prevention limits their practicality in limited-resource countries. Hydroxyurea has been shown to lower TCD velocities and to prevent conversion from conditional (170 to 199 cm/sec) to abnormal (greater than or equal to 200 cm/sec) velocities. In resource-limited settings, implementation of a TCD screening program, coupled with hydroxyurea therapy, could reduce the burden of SCA and stroke.ObjectiveThe aims of the Stroke Avoidance for Children in REpública Dominicana (SACRED) trial are (1) to screen children with SCA for stroke risk using TCD and to determine the prevalence of elevated velocities in a cross-sectional sample; (2) to identify clinical and laboratory correlates of elevated velocities; and (3) to obtain longitudinal data on the natural history of TCD velocities and to measure therapeutic effects of hydroxyurea.MethodsThis prospective trial, designed and conducted by Cincinnati Children’s Hospital Medical Center (CCHMC) and Hospital Infantil Robert Reid Cabral (HIRRC) with Centro de Obstetricia y Ginecología, includes a baseline cross-sectional epidemiological survey of the distribution of TCD velocities across a large cohort of children with SCA in the Dominican Republic. Children with conditional velocities are eligible to begin protocol-directed hydroxyurea if laboratory criteria are met. The treatment schedule begins with a fixed-dose of approximately 20 mg/kg/day for 6 months, after which it escalates to maximum tolerated dose (MTD). All participants undergo longitudinal annual TCD evaluation, while those on hydroxyurea have semi-annual evaluations during the 3-year study period. Data are collected using an Internet-based Research Electronic Data Capture (REDCap) system with forms translated into Spanish; both remote and on-site monitoring are used.ResultsTo date, 122 children with SCA have enrolled in SACRED including 85 (69.7%, 85/122) with normal, 29 (23.8%, 29/122) with conditional, 5 (4.1%, 5/122) with abnormal, and 3 (2.5%, 3/122) with inadequate TCD velocities. Of the 29 children with conditional TCD velocities, 17 (59%, 17/29) have initiated hydroxyurea per protocol, with plans for escalation to MTD.ConclusionsThe SACRED trial will provide novel epidemiologic data about the prevalence of children with SCA and increased stroke risk in the Dominican Republic. The study also includes an investigation of the impact of hydroxyurea at MTD on elevated TCD velocities, as well as clinical and laboratory parameters. The design and implementation of SACRED reflect a successful international institutional partnership, one...

Background c The prevalence of sickle cell anemia (SCA) in the Dominican Republic is approximately 4 times that in the United States. c In the pediatric sickle cell clinic at Hospital Infantil Dr. Robert Reid Cabral (HIRRC) located in the capital city of Santo Domingo, Dominican Republic, 5% to 10% of children with HbSS (homozygous for hemoglobin S) develop primary stroke, with substantial morbidity and mortality. c Transcranial Doppler (TCD) ultrasonography has been shown to effectively identify the risk for primary stroke in the United States but is not routinely accessible or available in the Dominican Republic. c Hydroxyurea is a potent disease-modifying therapy for SCA that can reduce TCD velocities and prevent conversion of conditional to abnormal velocities. Hydroxyurea is available in the Dominican Republic, but health care providers do not have experience with dosing, and most families cannot afford the cost.

No abstract

Introduction. The burden of sickle cell anemia (SCA) is high across the Caribbean, including the Dominican Republic where the morbidity of SCA is substantial due to limited resources. Approximately 10% of affected children will develop primary stroke, with serious medical and neurocognitive sequelae. In the US, transcranial Doppler (TCD) ultrasonography is an effective screening tool to identify children at risk for primary stroke, which then allows preventive therapy with either hydroxyurea or blood transfusions. To date, however, no routine TCD screening and treatment program for stroke prevention has been established in the Dominican Republic. We designed a prospective screening and treatment study (SACRED, NCT02769845) for prevention of primary stroke in children with SCA using open-label hydroxyurea at maximum tolerated dose (MTD). Methods. Children with SCA between age 3-15 years and receiving medical care at Robert Reid Cabral Children's Hospital in Santo Domingo, Dominican Republic were recruited over a 12-month period. Treatment depended on the baseline TCD examination: children with abnormal time-averaged mean velocities (≥200 cm/sec, high stroke risk) were recommended to receive monthly transfusions for primary stroke prevention, as per standard treatment preferences at the Robert Reid Hospital; those with conditional velocities (170-199 cm/sec, moderate stroke risk) were offered hydroxyurea study treatment unless they were currently receiving chronic transfusions for other clinical indications. Oral open-label hydroxyurea using 500mg capsules was prescribed at fixed-dose (20 mg/kg/day) for 6 months, followed by dose escalation to MTD. TCD examinations were repeated every 6 months, with the main study endpoints being changes in laboratory parameters and TCD velocities after 18 months of study treatment. Results. A total of 283 children were enrolled with the following baseline TCD velocities: 200 (70.7%) normal, 63 (22.3%) conditional, 11 (3.9%) abnormal, and 9 (3.1%) inadequate velocities. Among 50 children eligible for hydroxyurea study treatment, the average age was 6.8 ± 2.8 years and included 27 males/23 females with evidence of substantial SCA-related morbidity (88% with previous transfusions, 60% with >5 hospitalizations). A total of 48 children initiated hydroxyurea at 20.2 ± 1.2 mg/kg/day, which was maintained for 6 months followed by dose escalation, reaching MTD at 24.1 ± 6.0 mg/kg/day. Laboratory changes from baseline to Month 18 included significant increases in hemoglobin (7.5 ± 0.9 to 8.9 ± 1.3 g/dL, P<0.0001) and fetal hemoglobin (16.4 ± 7.4 to 30.9 ± 13.6%, P<0.0001). Serial TCD examinations revealed a significant decline over the treatment period, with the average TCD velocity decreasing from 180 ± 8 cm/sec at baseline to 159 ± 21 cm/sec at Month 18, P<0.0001. At Month 18, 68% of the originally conditional TCD examinations had reverted to a normal velocity, while only 4% had converted to abnormal velocity. No clinical strokes occurred in the hydroxyurea treatment cohort. Conclusion. Conditional TCD velocities are common (>20%) in the Dominican Republic, which documents an elevated stroke risk for children with SCA. The SACRED trial established a local TCD screening program and provided open-label hydroxyurea treatment for children with conditional TCD velocities. Hydroxyurea treatment at MTD led to improved hematological parameters, lower TCD velocities, and decreased stroke risk. SACRED represents an important international partnership and prospective collaborative research trial providing capacity building and valuable epidemiological data regarding TCD screening, stroke risk, and hydroxyurea effects for children with SCA. Hydroxyurea at MTD is a suitable treatment to reduce primary stroke risk for children with SCA living in the Dominican Republic or other low-resource settings. Disclosures Jeste: Jannsen: Employment. Ware:Novartis: Other: DSMB; Nova Laboratories: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Other: Research Drug Donation; Addmedica: Other: Research Drug Donation; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees.