Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa

Project Summary/Abstract Sickle cell anemia (SCA) is among the world’s most common and devastating blood disorders, affecting more than 300,000 newborns per year. The majority of infants with SCA are born in the low-resource settings of sub- Saharan Africa, where an estimated 50-90% will die before 5-years of age due to lack of early diagnosis and

appropriate care. Hydroxyurea is a once-daily oral medication that has become the standard of care for the treatment of children with SCA in high-resource settings. There is now a growing body of evidence to support the safety and clinical benefits of hydroxyurea for the treatment of SCA in sub-Saharan Africa. The requirement

for frequent laboratory monitoring and the concern for hematologic laboratory toxicities, however, will limit widespread hydroxyurea utilization. We have recently developed and prospectively evaluated an individualized, pharmacokinetics-guided hydroxyurea dosing strategy for children with SCA that has demonstrated optimal

clinical and laboratory benefits with minimal toxicity. In this proposal, we aim to extend this precision medicine approach to Africa. This proposal includes a prospective, randomized clinical trial of hydroxyurea for children with SCA at two clinical sites in sub-Saharan African (Luanda, Angola and Mwanza, Tanzania). The study will

be the first to bring precision medicine to children with SCA through several novel features including measurement of hydroxyurea using a battery-powered HPLC machine and individualized dose calculations using an automated computer-based algorithm. The first phase of the study will compare dosing strategies and

determine the optimal dosing strategy, and the second phase will importantly address the safety of hydroxyurea therapy with limited laboratory monitoring. The primary objectives are to establish the feasibility and evaluate the clinical benefits of PK-guided hydroxyurea for children with SCA in Africa and to provide evidence to support

minimal laboratory monitoring with hydroxyurea therapy in these settings. We will accomplish these objectives through the following Specific Aims: Specific Aim 1: To compare the clinical benefits of two hydroxyurea dosing strategies for treatment of SCA in sub-Saharan Africa: a novel individualized, PK-guided initial dose without

subsequent escalation and a weight-based dose with subsequent dose escalation. We hypothesize that the PK- guided arm will have a reduction in sickle-related adverse events compared to the weight-based arm. Specific Aim 2: To evaluate the safety of hydroxyurea for children with SCA in sub-Saharan Africa with limited laboratory

monitoring. We hypothesize that there will be no difference in the frequency of adverse events (Grade ≥ 3) unrelated to SCA during the period of hydroxyurea treatment with limited monitoring compared to the no treatment run-in period. Exploratory Aim 3: To evaluate the utility and validity of two established measures of

health-related quality of life (HRQoL) for patients and families affected by SCA in Angola and Tanzania before and after hydroxyurea treatment. We hypothesize that baseline HRQoL measures will be low for both measures and will improve significantly with hydroxyurea treatment.