Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease

描述（由申请人提供）：镰状细胞病（SCD）是世界上最常见的遗传性疾病。每年约有15万尼日利亚儿童出生时患有SCD，使其成为世界上镰状细胞病负担最重的国家。SCD是儿童中风的最常见原因，在受影响的儿童中导致相当大的发病率。目前的初级预防方法是对中风高危儿童（经颅多普勒测量升高确定）每月定期输血治疗，由于供应短缺、成本高和血源性感染率高，在尼日利亚等低收入国家是不可行的。在美国，羟基脲（HU）是成人SCD的标准治疗方法，可能是治疗高危儿童原发性卒中的一种合理的预防选择，而不是常规输血。鉴于尼日利亚SCD患者的绝对数量巨大，HU治疗最初可能并不适用于所有SCD患者；然而，对于高危人群来说，将HU用于卒中一级预防是标准治疗（观察）之外的另一种选择。因此，我们提出了一项可行性研究，以确定HU与安慰剂随机化对尼日利亚镰状细胞性贫血（SCA）儿童卒中一级预防的可接受性，为NIH赞助的多中心III期试验做准备。我们将建立在临床试验环境中使用HU的安全方案，并为最终的III期试验完成必要的准备工作。为了实现这些目标，我们组建了一支强大的多学科团队，代表范德比尔特大学和两家主要的国内机构：尼日利亚Aminu Kano教学医院和尼日利亚全球健康之友。完成一项明确的试验不仅将使撒哈拉以南非洲的SCA儿童受益，世界上大多数SCA儿童生活在那里，而且可以为输血治疗替代美国中风一级预防提供合理的证据。据我们所知，这将是尼日利亚的第一个中风预防试验，并可能建立一个先例，扩大到患有SCA的儿童和成人的二级中风预防，因为遗憾的是，在资源贫乏的国家，没有可用的治疗方法来预防这些高风险患者复发性中风。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is the most common genetic disease in the world. Approximately 150,000 Nigerian children are born each year with SCD, making it the country with the largest burden of sickle cell disease in the world. SCD is the most common cause of stroke in children and results in considerable morbidity in affected children. The current primary prevention approach of regular monthly blood transfusion therapy of children at high risk of stroke (identified by elevated transcranial Doppler measurements) is not feasible in a low income country such as Nigeria due to scarcity of supply, cost, and high rate of blood borne infections. In the United States, hydroxyurea (HU) is standard therapy for adults with SCD and may be a reasonable prevention alternative to regular blood transfusion for treatment of primary stroke in high-risk children. Given large absolute numbers of individuals with SCD in Nigeria, HU therapy for all individuals with SCD may not be initially feasible; however, a targeted strategy of HU use for primary prevention of strokes is an alternative to the standard therapy (observation) for high-risk individuals. We therefore propose a feasibility study to determine the acceptability of randomization to HU vs. placebo for primary prevention of strokes in Nigerian children with sickle cell anemia (SCA) in preparation for a NIH sponsored multicenter, phase III Trial. We will establish a safety protocol for using HU in a clinical trial setting and complete the necessary preparations for a definitive phase III trial. To accomplish these aims we have assembled a strong multidisciplinary team representing Vanderbilt University and two premier in-country institutions: Aminu Kano Teaching Hospital, Nigeria, and Friends in Global Health-Nigeria. Completion of a definitive trial will not only benefit children wth SCA in sub-Saharan Africa, where the majority of children with SCA live in the world, but could provide reasonable evidence for an alternative to blood transfusion therapy for the primary prevention of strokes in the US. To our knowledge this would be the first stroke prevention trial in Nigeria and could establish a precedent to expand to secondary stroke prevention for children and adults with SCA, as regrettably, no therapy is available to prevent recurrent stroke in these high-risk patients in resource-poor nations. PUBLIC HEALTH RELEVANCE: Sickle cell disease is the most common cause of stroke in children, resulting in considerable morbidity among affected children. Nigeria has the largest burden of the disease in the world, but the standard therapy for primary prevention of stroke in these high-risk children (recurrent transfusions) is not readily available. A feasibility trial of hydroxyurea for primary prevention of stroke in sickle cell disease could provide evidence for an alternative approach to recurrent transfusions in a part of the world where safe blood services are not readily accessible.