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: 10223406
• 负责人: Russell E Ware
• 金额: $ 67.58万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223406
• 关键词: 10 year old; 5 year old; Address; Adherence; Affect; Africa; Africa South of the Sahara; African; Angola; Bacterial Infections; Birth; Blood; Blood specimen; Caring; Characteristics; Child; Child Mortality; Clinic Visits; Clinical; Clinical and Translational Science Awards; Collaborations; Collection; Country; Data; Database Management Systems; Databases; Developed Countries; Development; Diagnosis; Disease; Dose; Drug Kinetics; Education; Effectiveness; Enrollment; Europe; Event; Family; Fetal Hemoglobin; Frequencies; Future; Genetic; Goals; Growth; Health; Healthcare; Hematological Disease; Hematology; Hemoglobinopathies; Immunization; Infant; Infection; Inherited; Intervention; Investigation; Kenya; Laboratories; Lead; Life; Location; Maintenance; Malaria; Malnutrition; Maximum Tolerated Dose; Measures; Medical; Medicine; Monitor; Morbidity - disease rate; Multicenter Trials; Multilingualism; Neonatal Screening; Newborn Infant; Nutritional status; Oral; Outcomes Research; Participant; Patients; Penicillins; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phase; Physicians; Pilot Projects; Process; Prophylactic treatment; Prospective Studies; Protocols documentation; Publishing; Renal function; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Role; Safety; Savings; Science; Severities; Sickle Cell Anemia; Sickle Cell Trait; Site; Standardization; Sustainable Development; Talents; Testing; Toxic effect; Training; Uganda; United States; World Health Organization; burden of illness; clinical research site; cohort; comorbidity; cost effective; design; evidence base; exome; exome sequencing; experience; genetic variant; genome sequencing; hydroxyurea; individual patient; infancy; innovation; insight; interpatient variability; investigator training; malaria infection; mortality; next generation; next generation sequencing; novel; patient variability; preventable death; programs; research study; response; safety and feasibility; safety testing; screening; screening program; sickling; trait; treatment guidelines; treatment program; treatment response; virtual

ABSTRACT Sickle cell anemia (SCA) is among the world’s most common inherited blood disorders, and causes both morbidity and early mortality. SCA is highly prevalent in Africa, affecting over 300,000 births annually, with projections for an increasing burden in the next generation. In the US, infants with SCA are identified by newborn screening; simple interventions have dramatically reduced morbidity and mortality. In Africa, by contrast, neonatal screening is not available, and most affected infants will die before age 5 years, without proper diagnosis and treatment of SCA. The World Health Organization (WHO) notes SCA contributes substantially to under-5 mortality for many African countries. Several pilot SCA screening programs have begun in sub-Saharan Africa, which document a large burden (10-25% sickle trait and 1-2% SCA). With better screening and early care and treatment programs, more children with SCA in Africa will likely survive, but their medical needs will strain the limited healthcare resources. Accordingly, there is an urgent need to investigate the role of hydroxyurea for children with SCA in Africa, since hydroxyurea is the only realistic and affordable disease-modifying therapy in this setting. To date, hydroxyurea has been studied only in developed countries, with virtually no data available regarding its safe and effective use in Africa. To address this critical unmet need, we developed and launched the REACH (Realizing Effectiveness Across Continents with Hydroxyurea) trial, ClinicalTrials.gov NCT01966731, a prospective study of hydroxyurea designed to gather critical data regarding the safety, feasibility, and benefits of hydroxyurea for young children in sub-Saharan Africa. REACH is also designed to gather important data about why children have different responses to hydroxyurea treatment; using novel and innovative approaches, we will collect data regarding the inter-patient variability by analysis of hydroxyurea pharmacokinetics, pharmacodynamics, and pharmacogenomics. A total of 600 children with SCA between 1-10 years of age will enroll and first receive fixed dose hydroxyurea, then dose escalation to the maximum tolerated dose (MTD), followed by maintenance treatment to a common study termination date. We have obtained all drug supply in donation from Bristol-Myers Squibb, performed a rigorous site selection process to identify sites able to perform high-quality research, and four locations (Luanda Angola, Kinshasa DRC, Kilifi, Kenya; and Mbale, Uganda) are actively enrolling children and providing protocol-directed hydroxyurea treatment. Using an adaptive study design and the REDCap electronic database system through our Clinical & Translational Science Award program, we are collecting data on the safety, feasibility, and benefits of hydroxyurea for SCA within Africa. We will also collect novel information about inter-patient variability by creating a hydroxyurea pharmacokinetics profile for each participant, and then investigate associations with pharmacodynamics parameters like HbF responses. We will also perform Whole Exome Sequencing on this cohort, to allow pharmacogenomics analysis that should yield important insights into the variable treatment responses. Over the long term, the REACH trial will teach local African physicians how to administer hydroxyurea and help establish a robust research infrastructure for future collaborations. REACH data will provide better understanding and characterization of inter-patient variability of hydroxyurea-related toxicities and responses, and will guide future research and evidence-based hydroxyurea treatment guidelines for wider usage in Africa.

抽象的 镰状细胞性贫血 (SCA) 是世界上最常见的遗传性血液疾病之一，会导致发病和早期 SCA 在非洲非常普遍，每年影响超过 300,000 名新生儿，预计该国的负担将日益增加。 在美国，通过简单的干预措施即可发现患有 SCA 的婴儿； 相比之下，非洲的发病率和死亡率较低，无法进行新生儿筛查，而大多数受影响的婴儿将会进行筛查。 世界卫生组织 (WHO) 指出，如果没有正确诊断和治疗 SCA，则在 5 岁之前死亡。 许多非洲国家已开始实施多项 SCA 筛查试点项目。 撒哈拉以南非洲地区的负担很大（10-25% 镰状特征和 1-2% SCA）。 和治疗计划，更多非洲患有 SCA 的儿童可能会存活下来，但他们的医疗需求将使有限的资源捉襟见肘。 因此，迫切需要研究羟基脲对 SCA 儿童的作用。 非洲，因为羟基脲是迄今为止该地区唯一现实且负担得起的疾病缓解疗法。 仅在发达国家进行了研究，几乎没有关于其在非洲安全有效使用的数据。 为了解决这一未满足的关键需求，我们制定并启动了 REACH（在各大洲实现有效性） 羟基脲）试验，ClinicalTrials.gov NCT01966731，一项旨在收集关键数据的羟基脲前瞻性研究 还设计了关于羟基脲对撒哈拉以南非洲幼儿的安全性、可行性和益处的研究。 收集关于为什么儿童对使用新颖和创新的羟基脲治疗有不同反应的重要数据； 方法，我们将通过分析羟基脲药代动力学来收集有关患者间变异性的数据， 总共 600 名 1-10 岁的 SCA 儿童将首先入组。 接受固定剂量羟基脲，然后剂量递增至最大耐受剂量（MTD），然后维持治疗 我们已从百时美施贵宝捐赠了所有药物供应， 进行了严格的选址过程，以确定能够进行高质量研究的地点，以及四个地点（罗安达 安哥拉、刚果民主共和国金沙萨、肯尼亚基利菲和乌干达姆巴莱）正在积极招收儿童并提供礼宾指导 通过我们的临床和治疗，使用适应性研究设计和 REDCap 电子数据库系统。 转化科学奖计划，我们正在收集有关羟基脲用于 SCA 的安全性、可行性和益处的数据 我们还将通过创建羟基脲药代动力学来收集有关患者间差异的新信息。 我们将研究每个参与者的概况，然后研究与 HbF 反应等药效学参数的关联。 还对该队列进行全外显子组测序，以进行药物基因组学分析，从而产生重要的结果 从长远来看，REACH 试验将教会非洲当地医生如何应对不同的治疗反应。 管理羟基脲并帮助为未来的合作建立强大的研究基础设施。 更好地理解和表征羟基脲相关毒性的患者间变异性 反应，并将指导未来的研究和基于证据的羟基脲治疗指南，以在非洲更广泛地使用。