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Introduction: Stroke is a severe complication of sickle cell anemia (SCA), with devastating sequelae. Transcranial Doppler (TCD) ultrasonography predicts stroke risk, but implementing TCD screening with suitable treatment for primary stroke prevention in low-resource environments remains challenging. SPHERE (NCT03948867) is a prospective phase 2 open-label hydroxyurea trial for SCA in Tanzania. Methods: After formal training and certification, local personnel screened children 2–16 years old; those with conditional (170–199 cm/s) or abnormal (≥200 cm/s) time-averaged mean velocities (TAMVs) received hydroxyurea at 20 mg/kg/day with dose escalation to maximum tolerated dose (MTD). The primary study endpoint is change in TAMV after 12 months of hydroxyurea; secondary endpoints include SCA-related clinical events, splenic volume and function, renal function, infections, hydroxyurea pharmacokinetics, and genetic modifiers. Results: Between April 2019 and April 2020, 202 children (average 6.8 ± 3.5 years, 53% female) enrolled and underwent TCD screening; 196 were deemed eligible by DNA testing. Most had numerous previous hospitalizations and transfusions, with low baseline hemoglobin (7.7 ± 1.1 g/dL) and %HbF (9.3 ± 5.4%). Palpable splenomegaly was present at enrollment in 49 (25%); average sonographic splenic volume was 103 mL (range 8–1,045 mL). TCD screening identified 22% conditional and 2% abnormal velocities, with hydroxyurea treatment initiated in 96% (45/47) eligible children. Conclusion: SPHERE has built local capacity with high-quality research infrastructure and TCD screening for SCA in Tanzania. Fully enrolled participants have a high prevalence of elevated baseline TCD velocities and splenomegaly. SPHERE will prospectively determine the benefits of hydroxyurea at MTD for primary stroke prevention, anticipating expanded access to hydroxyurea treatment across Tanzania. [ABSTRACT FROM AUTHOR]

Summary HbSC disease is a common form of sickle cell disease with significant morbidity and early mortality. Whether hydroxyurea is beneficial for HbSC disease is unknown. Prospective Identification of Variables as Outcomes for Treatment (PIVOT, Trial ID PACTR202108893981080) is a double‐blind, randomised, placebo‐controlled phase II trial of hydroxyurea for people with HbSC, age 5–50 years, in Ghana. After screening, participants were randomised to placebo (standard of care) or hydroxyurea. The primary outcome is the cumulative incidence of haematological toxicities during 12 months of blinded treatment; secondary outcomes include multiple laboratory and clinical assessments. Between April 2022 and June 2023, 112 children and 102 adults were randomised, including 44% females and average age 21.6 ± 14.5 years. Participants had substantial morbidity including previous hospitalisations (93%), vaso‐occlusive events (86%), malaria (79%), often received transfusions (20%), with baseline haemoglobin 11.0 ± 1.2 g/dL and foetal haemoglobin 1.8% ± 1.5%. The spleen was palpable in six children and one adult, and ultrasonographic volumes were collected. Proliferative sickle retinopathy was common (30% children, 75% adults), but proteinuria was less common (3% children, 8% adults). Whole blood viscosity, ektacytometry, point‐of‐sickling, transcranial Doppler, near‐infrared spectrometry (NIRS), 6‐minute walk, and quality of life were also measured. Now fully enrolled, PIVOT will document the safety and potential benefits of hydroxyurea on clinical and laboratory outcomes in HbSC disease. [ABSTRACT FROM AUTHOR]

Introduction: People with sickle cell anemia (SCA) may require frequent blood transfusions to treat acute and chronic complications. Hydroxyurea is a life-saving treatment for SCA that could also decrease the need for blood transfusions. Inadequate medication access and challenges in dose optimization limit the widespread use of hydroxyurea in Africa. If feasible, pharmacokinetic (PK) dosing might improve dose determination to minimize toxicities and maximize clinical benefits. The Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) trial will analyze the impact of hydroxyurea on transfusion rate and serve as a pilot study to evaluate the feasibility of PK-guided hydroxyurea dosing in Uganda., Methods: Herein we describe the rationale and design of ADAPT, a prospective cohort study of ∼100 children with SCA in Jinja, Uganda. The primary hypothesis is that hydroxyurea will decrease blood transfusion use by ≥ 50%, comparing the transfusion incidence rate ratio between a 3-month pretreatment and a 12-month treatment period. A key secondary hypothesis is that our PK-dosing approach will generate a suitable hydroxyurea dose for ≥80% of participants. Every ADAPT participant will undergo hydroxyurea PK testing, and if a dose is generated within 15-35 mg/kg/day, participants will start on their individualized dose. If not, they will start on a default dose of 20 mg/kg/day. Hydroxyurea dose optimization will occur with periodic dose adjustments., Conclusion: Overall, demonstrating the reduction in blood transfusion utilization with hydroxyurea treatment would provide leverage to increase hydroxyurea access, and PK-guided hydroxyurea dosing should optimize the safe and effective treatment of SCA across sub-Saharan Africa., (© 2024 S. Karger AG, Basel.)