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大的国家。SCD是儿童中风的最常见原因，并导致受影响儿童的相当高的发病率。由于供应稀缺、成本和高血源性感染率，目前对卒中高危儿童（通过经颅多普勒测量确定）进行定期每月输血治疗的一级预防方法在低收入国家（如尼日利亚）不可行。在美国，羟基脲（HU）是成人SCD患者的标准治疗，可能是治疗高危儿童原发性卒中的常规输血的合理预防替代方案。考虑到尼日利亚SCD患者的绝对数量较大，最初可能无法对所有SCD患者进行HU治疗;然而，将HU用于卒中一级预防的靶向策略是高危患者标准治疗（观察）的替代方案。因此，我们提出了一项可行性研究，以确定随机化HU与安慰剂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申办的多中心III期试验做准备。我们将建立在临床试验环境中使用HU的安全性方案，并完成确定性III期试验的必要准备工作。为了实现这些目标，我们组建了一个强大的多学科团队，代表范德比尔特大学和两个主要的国内机构：阿米努卡诺教学医院，尼日利亚，和全球健康之友，尼日利亚。最终试验的完成不仅将使撒哈拉以南非洲的SCA儿童受益，因为世界上大多数SCA儿童都生活在那里，而且可以为输血治疗的替代方案提供合理的证据，用于美国卒中的一级预防。据我们所知，这将是尼日利亚的第一个卒中预防试验，并可能建立一个先例，扩大到SCA儿童和成人的二级卒中预防，遗憾的是，在资源贫乏的国家，没有治疗方法可以预防这些高危患者的复发性卒中。 公共卫生相关性：镰状细胞病是儿童中风的最常见原因，导致受影响儿童的发病率相当高。尼日利亚是世界上中风负担最重的国家，但这些高危儿童中风一级预防的标准治疗（反复输血）并不容易获得。在镰状细胞病中风的一级预防中，对羟基脲的可行性试验可以为世界上安全血液服务不容易获得的地区的反复输血的替代方法提供证据。

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.