November-December 2015, Volume 12, Issue 6
Extending the Global REACH of Hydroxyurea
Published on: October 19, 2015
Study Title: Realizing Effectiveness Across Continents With Hydroxyurea (REACH)
ClinicalTrials.Gov Identifier: NCT01966731
Sponsor: Cincinnati Children’s Hospital Medical Center
Funding: Cincinnati Children’s Research Foundation, Bristol Myers-Squibb Foundation
Clinical Sites: Angola, Democratic Republic of the Congo, Kenya, and Uganda
Accrual Goal: 600 patients
Study Design: REACH is a prospective, phase I/II open-label dose escalation study of hydroxyurea for the treatment of children with sickle cell anemia (SCA) in sub-Saharan Africa, specifically Angola, Democratic Republic of the Congo, Kenya, and Uganda (McGann PT, et al. Pediatr Blood Cancer. doi:10.1002/pbc.25705). The main eligibility criteria include a documented diagnosis of SCA, age 1 to 9.99 years, and weight greater than or equal to10 kg at the time of enrollment. The main exclusion criteria are serious comorbid illnesses (e.g., acute or chronic infectious disease, HIV, or malignancy); severe malnutrition; or pre-existing severe hematologic abnormalities. Open-label hydroxyurea will be given initially at a fixed dose (15-20 mg/kg) for six months, followed by another six months with dose escalation to 20-30 mg/kg/day or the maximum tolerated dose (MTD). The primary study endpoint is safety, primarily severe hematologic toxicity that occurs during the fixed-dose treatment phase. Secondary endpoints include feasibility (adherence to medication and monthly clinic visits) and benefits of hydroxyurea (assessed by fetal hemoglobin, other laboratory measurements, and clinical events).
Rationale: SCA is one of the most common monogenic diseases in the world. It is a severe disease associated with early mortality and significant morbidity. SCA is most prevalent in sub-Saharan Africa, where more than 300,000 affected babies are born annually. This figure likely underestimates the true burden of SCA because of the lack of universal newborn screening (NBS) across the continent of Africa. The impact of SCA on child mortality in these same areas is also poorly characterized and underestimated. Most babies in Africa with SCA die of acute anemia or infection in the first several years of life, often without a known diagnosis of SCA, because there is no early identification by NBS and little access to simple preventive measures and disease-modifying therapies (Grosse SD, et al. Am J Prev Med. 2010;41:S398-S405; Piel FB, et al. PLoS Med. 2013;10:e1001484). To begin to address this need and challenge, a partnership between investigators in North America and Africa (the REACH investigators) was formed to generate and carry out a consensus-based, prospective, therapeutic research protocol. Moreover, this trial was made possible by a donation of hydroxyurea from a partner in the pharmaceutical industry.
Hydroxyurea is an oral medicine with an established safety and efficacy profile for individuals with SCA who are treated in high-resource nations. It is also the most plausible treatment for the majority of individuals with SCA around the world who happen to live in resource-poor nations, where chronic blood transfusions or stem cell transplantation may not be available, affordable, or safe. Despite inclusion in the World Health Organization Model List of Essential Medications for Children (WHO Model List of Essential Medicines for Children, 4th List. April 2013, Geneva, Switzerland), hydroxyurea is also unavailable or too expensive in much of Africa, especially considering the cost of concomitant laboratory monitoring. Additionally, there is no prospective evidence that demonstrates the feasibility, safety, and benefits of hydroxyurea in this setting.
A placebo-controlled trial of hydroxyurea was deemed unethical by the African site investigators, so REACH will assess benefits by using comparison to baseline and the known dismal natural history of untreated SCA in low-resource nations. In addition to these clinical objectives, the REACH study will also evaluate the economic cost of hydroxyurea therapy (including associated clinic visits and laboratory monitoring) at each of the clinical sites. These economic data, it is hoped, will inform the design and implementation of strategies to increase access to hydroxyurea in these same countries. Indeed, the long-term goal of the REACH study is to engage and collaborate with local governments to increase the availability of hydroxyurea for children with SCA in Africa.
Comment: REACH is joined by a growing number of studies of hydroxyurea in sub-Saharan Africa (and elsewhere), including the Novel use Of Hydroxyurea in an African Region With Malaria (NOHARM) and Stroke Prevention in Nigeria (SPIN) trials, each of which takes a different approach to the problem. The NOHARM trial (NCT01976416), conducted in Uganda, aims to demonstrate the safety of hydroxyurea therapy in areas endemic for malaria. A theoretical concern is that hydroxyurea might increase the risk of severe malarial syndromes, such as cerebral malaria, because it up-regulates the endothelial cell surface expression of ICAM-1, a major receptor in the brain for Plasmodium falciparum–infected erythrocytes (Brun M, et al. Pharmacogenomics J. 2003;3:215-226). However, fetal hemoglobin has been shown to retard parasite growth in vitro (Pasvol G, et al. Lancet. 1976;1:1269-1272), and an animal model has demonstrated a protective effect of hydroxyurea against cerebral malaria (Pino P, et al. Parasite Immunol. 2006;28:675-680). The SPIN trial (NCT01976416) is designed on the premise that widespread use of hydroxyurea therapy for SCA in Africa may not initially be feasible, but that targeted use of hydroxyurea for the highest-risk patients would be. In particular, the trial aims to determine the feasibility of using hydroxyurea for primary prevention of strokes in Nigerian children with SCA and abnormal transcranial Doppler (TCD) velocities.
The REACH, NOHARM, and SPIN trials align with (ASH’s Research Priorities for Sickle Cell Disease), specifically the call for expansion of global initiatives to fund “training, treatment, and research in [SCA] in sub-Saharan Africa and India.” The long-term goals of these and related studies are to create ongoing, mutually beneficial partnerships across continents, establish local expertise with the use of hydroxyurea, and develop regional treatment guidelines to transform the care of children with SCA in Africa. Hopefully, governments and funding agencies will provide the resources to continue these vital efforts.
Conflict of Interests
Dr. Quinn has no affiliation with the REACH trial, but he is employed by the sponsor of the trial.
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