Stroke with Transfusions Changing to Hydroxyurea

描述（由申请人提供）： 10%的镰状细胞性贫血（SCA）儿童会发生中风，如果不进行治疗，复发的风险非常高。受影响的儿童接受慢性红细胞输注，以防止继发性中风，这是有效的，但由于传染性病原体的传播，红细胞同种抗体和自身抗体的形成，以及铁过载，长期效用有限。对于SCA和卒中的年轻患者，输血获得性铁过载具有发病率和死亡率，包括慢性器官损伤伴肝纤维化和肝硬化、生长发育不良、心律失常和早期猝死。去铁胺（Desferal（r））螯合疗法难以耐受，并导致不依从性，显然需要一种替代输血的二级预防中风的方法，这也解决了输血获得性铁过载的问题。羟基脲可以预防SCA的急性血管闭塞事件，但其对脑血管疾病的效用，特别是预防SCA继发性卒中的效用尚未得到证实。我们的试验数据表明，羟基脲可以预防SCA儿童卒中复发，停止输血后，连续放血可降低铁负荷。我们提出了一个III期随机临床试验的儿童与SCA称为中风与输血改为羟基脲（SWITCH）。我们假设，羟基脲和静脉切开术可以维持可接受的卒中复发，并显着降低肝脏铁负荷。主要目的是比较标准治疗（输血和螯合）与替代治疗（羟基脲和静脉切开术）预防继发性卒中和管理铁超载。其他目的包括比较生长和发育、非卒中神经系统和其他镰刀相关事件的频率以及生活质量。使用羟基脲进行二级卒中预防，再加上通过静脉切开术去除多余的铁，将代表SCA和卒中患者管理的显著改善。如果羟基脲对预防继发性卒中有效，它也可能对其他患有SCA和脑血管疾病的儿童有益，包括那些有原发性卒中风险的儿童。

DESCRIPTION (provided by applicant): Stroke occurs in 10% of children with sickle cell anemia (SCA) and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload has morbidity and mortality for young patients with SCA and stroke, including chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death. Deferoxamine (Desferal(r)) chelation therapy is difficult to tolerate and leads to non-compliance an alternative to transfusions for secondary stroke prevention is clearly needed, which also addresses the issue of transfusion acquired iron overload. Hydroxyurea can prevent acute vaso-occlusive events in SCA, but its utility for cerebrovascular disease and specifically for the prevention of secondary stroke in SCA, is not proven. Our pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA, and after transfusions are discontinued, serial phlebotomy reduces iron burden. We propose a Phase III randomized clinical trial for children with SCA termed Stroke with Transfusions Changing to Hydroxyurea (SWiTCH). We hypothesize that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence and significantly reduce the hepatic iron burden. The primary aim is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload. Additional aims include comparisons of growth and development, frequency of non-stroke neurological and other sickle-related events, and quality of life. The use of hydroxyurea for secondary stroke prevention, coupled with removal of excess iron by phlebotomy, would represent a significant improvement in the management of patients with SCA and stroke. If hydroxyurea has efficacy for prevention of secondary stroke, it may also be beneficial for other children with SCA and cerebrovascular disease including those at risk for primary stroke.