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.

摘要 镰状细胞性贫血（SCA）是世界上最常见的遗传性血液病之一，可导致严重的发病率和早期死亡。 mortality. SCA在撒哈拉以南非洲非常流行，每年影响超过30万例新生儿，估计增长30% 在下一代。为了解决非洲SCA的负担，需要进行新生儿筛查，以建立适当的 诊断，和羟基脲治疗需要改善发病率和降低死亡率。羟基脲的列出方式 世界卫生组织作为SCA儿童的基本药物，代表了唯一现实和负担得起的 在这种情况下的疾病修饰疗法。直到最近，对羟基脲的研究主要集中在高收入国家， 几乎没有关于其在非洲安全有效使用的数据。为了满足这一关键的未满足需求，我们设计了 并推出了REACH（用羟基脲实现跨洲有效性，NCT 01966731），这是一项前瞻性开放标签研究， 在撒哈拉以南非洲患有SCA幼儿中使用羟基脲的研究。在目前的资助期间，四个国家的606名儿童 非洲国家接受了递增至最大耐受剂量（MTD）的羟基脲。尽管有COVID，我们的研究团队在 安哥拉、刚果民主共和国、肯尼亚和乌干达收集了前所未有的关于安全性、可行性和 在非洲使用羟基脲治疗SCA的益处，治疗时间>3000患者-年。我们记录了镰状细胞的减少- 相关的临床事件，并发现疟疾，输血和死亡的意外减少。我们进行了整个外显子组 测序以研究患者间变异性，包括羟基脲药代动力学、药效学和 药物基因组学在更新中，我们将通过将羟基脲治疗扩展到这一点来做出额外的贡献。 一个独特的队列，他们的平均年龄现在是11岁，很快进入青春期，使用持续供应的羟基脲 由布里斯托迈尔斯施贵宝捐赠。虽然我们的初步结果是令人鼓舞的，REACH没有安慰剂对照 cohort比较因此，我们将在所有四个研究中心招募一组年龄匹配的SCA儿童， 治疗前数据与我们的治疗队列进行比较。在第一个具体目标中，我们将评估 在MTD时使用羟基脲可改善SCA相关临床并发症并保护器官功能（尤其是脑功能， 还有肾、脾和眼）。我们将获得关于MTD时的羟基脲对身体健康的影响的纵向数据。 生长，性发育和整体生殖健康，并收集系列DNA以测试克隆的出现。 造血在第二个目标中，我们将研究羟基脲减少疟疾感染的机制， 将流行病学数据与体外寄生虫侵入测定和保护性遗传学的不可知性搜索相结合， 多态性在第三个目标中，我们将使用新的和创新的方法简化和优化羟基脲治疗。 方法，通过在新患者队列中测试基于药代动力学的给药算法的可行性和安全性 最大限度地减少剂量调整和实验室监测，然后通过验证我们新发现的遗传多态性， 预测HbF治疗反应。REACH将扩大非洲的羟基脲治疗范围，建设当地能力，并 为未来的合作建立强大的研究基础设施，包括计划中的NIH治疗性疗法。REACH是 该公司已做好独特的准备，可以阐明延长羟脲的益处和风险，从而在非洲实现安全且基于证据的给药。