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: 10444370
• 负责人: Russell E Ware
• 金额: $ 154.51万
• 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/10444370
• 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; 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; 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; base; 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.

抽象的 镰状细胞贫血（SCA）是世界上最常见的血液疾病之一，并引起严重的发病率和早期 死亡。 SCA在撒哈拉以南非洲高度普遍，每年影响30万以上的出生，估计增加了30％ 在下一代。为了解决非洲境内SCA的伯宁，需要进行新生儿筛查以建立适当的 需要诊断和羟基脲治疗以改善发病率并降低死亡率。羟基脲列出 世界卫生组织是SCA儿童的重要医学，代表了唯一的现实且负担得起的 在这种情况下进行疾病改良治疗。直到最近，羟基脲一直在研究高收入国家， 几乎没有有关其在非洲安全有效使用的数据。为了满足这种关键的未满足需求，我们设计了 并启动了触及范围（通过羟基脲的大陆实现效果，NCT01966731），这是一个潜在的开放标签 在撒哈拉以南非洲的SCA羟基脲研究。在当前的资金期间，有606名儿童四个 非洲国家接受羟基脲升级为最大耐受剂量（MTD）。尽管Covid，我们的研究团队 安哥拉，刚果民主共和国，肯尼亚和乌干达收集了有关安全性，可行性和 非洲羟基脲对SCA的好处，> 3000例患者年治疗。我们记录了镰刀的减少 相关的临床事件，发现疟疾，输血和死亡的意外减少。我们执行了整个外显子公司 测序以研究患者间的变异性，包括羟基脲药代动力学，药效学和 药物基因组学。在续签中，我们将通过将羟基脲处理为此做出其他贡献 独特的队列，他们的平均年龄现在已经11岁了，很快进入青春期，使用羟基脲的供应 由Bristol Myers Squibb捐赠。尽管我们的最初结果令人鼓舞，但触及范围没有安慰剂对照 比较队列。彼此之间，我们将在所有四个站点上注册一个新的与SCA年龄匹配的儿童，以提供 预处理数据，以与我们处理过的队列进行比较。在第一个特定目的中，我们将评估 MTD的羟基脲可改善SCA相关的临床并发症并保留器官功能（尤其是大脑，但） 还有肾脏，脾和眼睛）。我们将获得有关MTD羟基脲对物理影响的纵向数据 生长，性发育和整体复制健康，并收集串行DNA以测试克隆的出现 造血。在第二个目标中，我们将研究羟基脲降低疟疾感染的机制， 将流行病学数据与体外寄生虫入侵测定和对保护性通用的不可知论者相结合 多态性。在第三个目标中，我们将使用新颖和创新的方法简化并优化羟基脲处理 方法，通过测试新患者队列中基于药代动力学的剂量算法的可行性和安全性 最大程度地减少剂量调整和实验室监测，然后通过验证我们新鉴定的遗传多态性 这可以预测HBF治疗反应。覆盖范围将扩大非洲的羟基脲治疗，建立地方能力，并 为未来的合作建立强大的研究基础设施，包括计划的NIH治疗疗法。到达 独特的中毒，以阐明扩展羟基脲的福利和风险，从而使非洲的安全和基于证据的给药。