Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial

Abstract

Background: Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers.

Procedure: A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA.

Results: The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of four different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose.

Conclusions: REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa.

Keywords: Africa; hydroxyurea; sickle cell anemia.

© 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

Figures

Figure 1

REACH Clinical Sites. After a careful screening and selection process, four unique sites across sub‐Saharan Africa with large sickle cell patient populations were selected as the clinical sites for the REACH trial.

Figure 2

REACH Study and Treatment Phases. After obtaining informed consent, participants will proceed through each of four phases of the REACH study. Prior to initiation of hydroxyurea, there is a 2‐month screening phase, followed by 6‐month fixed dose phase, 6 months of dose escalation to maximum tolerated dose (MTD), and a maintenance phase that will continue for all participants through the Common Termination Date.

Figure 3

REACH Statistical Flowchart. The REACH study has an adaptive, two‐stage design allowing for early identification of hydroxyurea toxicity. The first stage will enroll 53 participants; if 15 or fewer hematological toxicities occur, study enrollment can continue to reach the final required number of 133. If there are greater that 15 hematological toxicities during this first stage, the starting dose will be reduced to 10–15 mg/kg/day and enrollment will begin again. In order to account for participant drop‐out, 60 participants will be enrolled in the first stage and 150 participants in the entire study at each site. This study algorithm will occur with independent analysis at each individual site.