Realizing Effectiveness Across Continents with Hydroxyurea(REACH): A Phase I/II Pilot Study of Hyroxyurea for Children with Sickle Cell Anemia

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ABSTRACT Sickle cell anemia (SCA) is among the world’s most common inherited blood disorders, and causes both morbidity and early mortality. SCA is highly prevalent in Africa, affecting over 300,000 births annually, with projections for an increasing burden in the next generation. In the US, infants with SCA are identified by newborn screening; simple interventions have dramatically reduced morbidity and mortality. In Africa, by contrast, neonatal screening is not available, and most affected infants will die before age 5 years, without proper diagnosis and treatment of SCA. The World Health Organization (WHO) notes SCA contributes substantially to under-5 mortality for many African countries. Several pilot SCA screening programs have begun in sub-Saharan Africa, which document a large burden (10-25% sickle trait and 1-2% SCA). With better screening and early care and treatment programs, more children with SCA in Africa will likely survive, but their medical needs will strain the limited healthcare resources. Accordingly, there is an urgent need to investigate the role of hydroxyurea for children with SCA in Africa, since hydroxyurea is the only realistic and affordable disease-modifying therapy in this setting. To date, hydroxyurea has been studied only in developed countries, with virtually no data available regarding its safe and effective use in Africa. To address this critical unmet need, we developed and launched the REACH (Realizing Effectiveness Across Continents with Hydroxyurea) trial, ClinicalTrials.gov NCT01966731, a prospective study of hydroxyurea designed to gather critical data regarding the safety, feasibility, and benefits of hydroxyurea for young children in sub-Saharan Africa. REACH is also designed to gather important data about why children have different responses to hydroxyurea treatment; using novel and innovative approaches, we will collect data regarding the inter-patient variability by analysis of hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics. A total of 600 children with SCA between 1-10 years of age will enroll and first receive fixed dose hydroxyurea, then dose escalation to the maximum tolerated dose (MTD), followed by maintenance treatment to a common study termination date. We have obtained all drug supply in donation from Bristol-Myers Squibb, performed a rigorous site selection process to identify sites able to perform high-quality research, and four locations (Luanda Angola, Kinshasa DRC, Kilifi, Kenya; and Mbale, Uganda) are actively enrolling children and providing protocol-directed hydroxyurea treatment. Using an adaptive study design and the REDCap electronic database system through our Clinical & Translational Science Award program, we are collecting data on the safety, feasibility, and benefits of hydroxyurea for SCA within Africa. We will also collect novel information about inter-patient variability by creating a hydroxyurea pharmacokinetics profile for each participant, and then investigate associations with pharmacodynamics parameters like HbF responses. We will also perform Whole Exome Sequencing on this cohort, to allow pharmacogenomics analysis that should yield important insights into the variable treatment responses. Over the long term, the REACH trial will teach local African physicians how to administer hydroxyurea and help establish a robust research infrastructure for future collaborations. REACH data will provide better understanding and characterization of inter-patient variability of hydroxyurea-related toxicities and responses, and will guide future research and evidence-based hydroxyurea treatment guidelines for wider usage in Africa.