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.

Project Narrative Sickle cell anemia is an inherited blood disorder that affects millions of children across the world, mostly in sub- Saharan Africa, who will suffer from serious complications, including death, if treatment is not available. Hydroxyurea, a once daily oral medication has been shown to improve most symptoms and reduce mortality for children and adults with sickle cell anemia but is rarely used in many limited-resource settings due in part to concerns about appropriate dosing and monitoring. The primary objectives of this research study are to establish the feasibility and evaluate the clinical benefits of personalized hydroxyurea dosing and to evaluate the safety of hydroxyurea use with limited laboratory monitoring for children with sickle cell anemia living in Angola and Tanzania to provide evidence that will allow for expanded access to this lifesaving medication.