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，会导致发病率和早期 死亡率。SCA在非洲非常普遍，每年影响30多万名新生儿，预计#年负担将增加。 下一代。在美国，通过新生儿筛查确定患有SCA的婴儿；简单的干预措施显著 降低发病率和死亡率。相比之下，在非洲，新生儿筛查是不可用的，大多数受影响的婴儿会 5岁前死亡，没有正确的诊断和治疗。世界卫生组织(WHO)注意到SCA 这在很大程度上导致了许多非洲国家5岁以下儿童的死亡率。几个SCA筛查试点项目已在#年开始。 撒哈拉以南非洲，记录了很大的负担(10-25%的镰刀状和1-2%的特殊配合力)。通过更好的筛查和早期护理 和治疗计划，更多患有SCA的非洲儿童可能会存活下来，但他们的医疗需求将使有限的 医疗保健资源。因此，迫切需要研究羟基脲在儿童SCA中的作用。 在非洲，因为羟基脲是这种环境下唯一现实和负担得起的疾病修正疗法。迄今为止，羟基脲 仅在发达国家进行了研究，几乎没有关于其在非洲安全和有效使用的数据。至 为了满足这一关键的未得到满足的需求，我们开发并推出了REACH(通过以下各项实现跨大洲的有效性 羟基尿素)试验，临床试验，政府NCT01966731，一项旨在收集关键数据的羟基尿素前瞻性研究 关于羟基尿素对撒哈拉以南非洲幼儿的安全性、可行性和益处。REACH还被设计为 收集有关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的药代动力学来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岁患有SCA的儿童将登记参加，并首先 接受固定剂量的羟基脲，然后剂量增加到最大耐受量(MTD)，然后维持 治疗至一个共同的研究终止日期。我们从百时美施贵宝的捐赠中获得了所有药品供应， 执行了严格的选址流程，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、金沙萨、刚果民主共和国、肯尼亚基里菲和乌干达姆巴莱)正在积极招收儿童，并提供礼宾指导 羟基脲治疗。使用适应性研究设计和RedCap电子数据库系统通过我们的临床和 翻译科学奖计划，我们正在收集羟基脲对SCA的安全性、可行性和益处的数据 在非洲境内。我们还将通过创建羟基脲药代动力学来收集有关患者间可变性的新信息 每个参与者的个人资料，然后调查与HBF反应等药效学参数的关联。我们会 还要对这个队列进行完整的外显子组测序，以便进行药物基因组学分析，这应该会产生重要的 对不同治疗反应的洞察。从长远来看，REACH试验将教会非洲当地医生如何 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。到达数据将 更好地了解和描述羟基脲相关毒性的患者间变异性和 并将指导未来的研究和基于证据的羟基尿素治疗指南，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.