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

利用羟基脲 (REACH) 在各大洲实现有效性：羟基脲治疗镰状细胞性贫血儿童的 I/II 期初步研究

• 批准号: 10679001
• 负责人: Russell E Ware
• 金额: $ 143.14万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679001
• 关键词: 11 year old; Acute; Address; Affect; Africa; Africa South of the Sahara; African; Age; Algorithms; Angola; Benefits and Risks; Biological Assay; Birth; Blood; Blood specimen; Brain; Cephalic; Cessation of life; Child; Chronic; Clinical; Collaborations; Country; DNA; Data; Databases; Democratic Republic of the Congo; Development; Diagnosis; Disease; Dose; Dose Limiting; Drug Kinetics; Dysmyelopoietic Syndromes; Effectiveness; Endothelium; Enrollment; Epidemiology; Erythrocytes; Event; Eye; Fetal Hemoglobin; Funding; Future; Genetic; Genetic Polymorphism; Genomic DNA; Genomic approach; Growth; Growth and Development function; Hematological Disease; Hematopoiesis; In Vitro; Incidence; Income; Inflammation; Inherited; Kenya; Kidney; Laboratories; Lead; Leukocytes; Long-Term Effects; Malaria; Maximum Tolerated Dose; Measures; Medical; Medicine; Methodology; Monitor; Morbidity - disease rate; Multilingualism; Mutation; Myeloid Leukemia; National Heart, Lung, and Blood Institute; Neonatal Screening; Oral; Organ; Organ Preservation; Parasitemia; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phase; Physical assessment; Pilot Projects; Placebo Control; Predisposition; Prevention; Puberty; Reproductive Health; Research; Research Infrastructure; Research Personnel; Risk; Safety; Sexual Development; Sickle Cell Anemia; Single Nucleotide Polymorphism; Site; Spleen; Talents; Testing; Toxic effect; Training; Transfusion; Uganda; United States National Institutes of Health; World Health Organization; burden of illness; clinical research site; cohort; coronavirus disease; curative treatments; design; epidemiologic data; evidence base; exome sequencing; experience; feasibility testing; genome wide association study; hydroxyurea; improved; in vitro Assay; innovation; interpatient variability; malaria infection; mortality; neuroprotection; neutrophil; next generation; novel; open label; parasite invasion; prospective; reproductive; research study; safety and feasibility; safety testing; sickling; treatment effect; treatment response; virtual

ABSTRACT Sickle cell anemia (SCA) is among the world’s most common inherited blood disorders, and causes severe morbidity and early mortality. SCA is highly prevalent in sub-Saharan Africa, affecting over 300,000 births annually, with an estimated 30% increase in the next generation. To address the burden of SCA within Africa, neonatal screening is needed to establish the proper diagnosis, and hydroxyurea treatment is needed to ameliorate morbidity and decrease mortality. Hydroxyurea is listed by the World Health Organization as an Essential Medicine for children with SCA, representing the only realistic and affordable disease-modifying therapy in this setting. Until recently, hydroxyurea had been studied primarily in high-income countries, with virtually no data available regarding its safe and effective use in Africa. To address this critical unmet need, we designed and launched REACH (Realizing Effectiveness Across Continents with Hydroxyurea, NCT01966731), a prospective open-label study of hydroxyurea for young children with SCA in sub-Saharan Africa. In the current funding period, 606 children in four African countries received hydroxyurea escalated to maximum tolerated dose (MTD). Despite COVID, our research teams in Angola, Democratic Republic of Congo, Kenya, and Uganda collected unprecedented data on the safety, feasibility, and benefits of hydroxyurea for SCA in Africa, with >3000 patient-years of treatment. We documented reductions in sickle- related clinical events and found unexpected reductions in malaria, transfusions, and death. We performed whole exome sequencing to investigate inter-patient variability including hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics. In the renewal, we will make additional contributions by extending hydroxyurea treatment to this unique cohort, whose average age is now 11 years and soon entering puberty, using a continued supply of hydroxyurea donated by Bristol Myers Squibb. Though our initial results are encouraging, REACH does not have a placebo-controlled cohort for comparison. Accordingly, we will enroll a new cohort of age-matched children with SCA at all four sites, to provide pre-treatment data for comparison to our treated cohort. In the first specific aim, we will assess the long-term effects of hydroxyurea at MTD to ameliorate SCA-related clinical complications and preserve organ function (especially brain but also kidneys, spleen, and eyes). We will obtain longitudinal data on the effects of hydroxyurea at MTD on physical growth, sexual development, and overall reproductive health, and collect serial DNA to test for the emergence of clonal hematopoiesis. In the second aim, we will investigate mechanisms by which hydroxyurea reduces malaria infections, combining epidemiological data with in vitro parasite invasion assays and an agnostic search for protective genetic polymorphisms. In the third aim, we will simplify and optimize hydroxyurea treatment using novel and innovative approaches, by testing the feasibility and safety of a pharmacokinetics-based dosing algorithm in the new patient cohort to minimize dose adjustments and lab monitoring, and then by validating our newly identified genetic polymorphisms that predict HbF treatment responses. REACH will expand hydroxyurea treatment in Africa, build local capacity, and establish a robust research infrastructure for future collaborations, including planned NIH curative therapies. REACH is uniquely poised to elucidate benefits and risks of extended hydroxyurea, allowing safe and evidence-based dosing in Africa.

摘要

项目成果

Effective use of hydroxyurea for sickle cell anemia in low-resource countries.

• DOI: 10.1097/moh.0000000000000582
• 发表时间: 2020-05
• 期刊: CURRENT OPINION IN HEMATOLOGY
• 影响因子: 3.2
• 作者: Power-Hays, Alexandra;Ware, Russell E.
• 通讯作者: Ware, Russell E.