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

摘要 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，并且引起发病率和早期贫血。 mortality. SCA在非洲非常普遍，每年影响30多万例新生儿，预计2010年的负担将不断增加。 下一代在美国，患有SCA的婴儿是通过新生儿筛查确定的;简单的干预措施 降低发病率和死亡率。相比之下，非洲没有新生儿筛查，大多数受影响的婴儿将 5岁前死亡，没有正确的诊断和治疗SCA。世界卫生组织（WHO）指出， 这是许多非洲国家5岁以下儿童死亡率的主要原因。几个试验性的SCA筛选计划已于2004年开始实施。 撒哈拉以南非洲，该地区有很大负担（10-25%的镰状性状和1-2%的SCA）。通过更好的筛查和早期护理 和治疗计划，更多的儿童与SCA在非洲可能会生存，但他们的医疗需求将紧张有限的 医疗资源。因此，迫切需要研究羟基脲在SCA患儿中的作用， 非洲，因为在这种情况下，羟基脲是唯一现实和负担得起的疾病缓解疗法。迄今为止， 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。到 为了解决这一关键的未满足的需求，我们制定并推出了REACH（实现跨洲有效性， 羟基脲）试验，ClinicalTrials.gov NCT 01966731，一项旨在收集关键数据的羟基脲前瞻性研究 安全性，可行性，和对撒哈拉以南非洲幼儿的好处。REACH还设计了 收集关于为什么儿童对羟基脲治疗有不同反应的重要数据;使用新颖和创新的方法， 方法，我们将通过分析羟基脲药代动力学收集关于患者间变异性的数据， 药效学和药物基因组学。共有600名1-10岁的SCA儿童将报名参加， 接受固定剂量的羟基脲，然后剂量递增至最大耐受剂量（MTD），然后维持治疗 治疗至共同研究终止日期。我们从百时美施贵宝公司获得了所有捐赠的药物供应， 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，并确定了四个地点（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，并提供方案指导的 羟基脲处理使用自适应研究设计和REDCap电子数据库系统，通过我们的临床& 转化科学奖计划，我们正在收集有关用于SCA的羟基脲的安全性，可行性和益处的数据 在非洲。我们还将通过创建一个羟基脲药代动力学模型，收集关于患者间变异性的新信息。 每个参与者的特征，然后研究与药效学参数如HbF反应的相关性。我们将 我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， 对不同治疗反应的深入了解。从长远来看，REACH试验将教会当地的非洲医生如何 管理羟基脲，并帮助建立一个强大的研究基础设施，为未来的合作。REACH数据将 更好地理解和表征患者间的羟基脲相关毒性变异性， 这将为今后的研究和基于证据的羟基脲治疗指南提供指导，以便在非洲更广泛地使用。

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.