Hydroxyurea to Prevent CNS Complications of Sickle Cell Disease in Children

描述(申请人提供)：中风、无症状性脑梗塞(SCI)和认知障碍是儿童镰状细胞病(SCD)常见且高度病态的并发症。目前预防和治疗SCD神经系统并发症的方法包括经颅多普勒超声(TCD)筛查，以确定脑血流速度升高的儿童中风的风险增加；然后，这些儿童通常接受无限期的慢性输血治疗。羟基脲(HU)可减少SCD的疼痛危象、急性胸部综合征和输血的频率，并可能对SCD的中枢神经系统(CNS)并发症产生有利影响。HU在婴儿和儿童中的安全性最近在NIH赞助的III期试验中得到证实；然而，HU在儿童中使用的确切适应症仍然不清楚，以及它在预防SCD的中枢神经系统并发症方面的有效性。我们的初步数据表明，如果TCD、SCI和卒中的累积异常频率能够减少50%，大多数儿科血液学家会给所有患有SCD的幼儿开HU。该项目的长期目标是进行一项初级预防试验，以证明HU的神经保护作用，并拓宽HU在儿童中的适应症。这项建议的目标是：1)进行一项可行性试验，证明HU用于减少SCD的中枢神经系统并发症的随机试验的可接受性；2)证明可以使用标准化的方案在SCD的幼儿中安全地对MRI进行镇静；以及3)建立领导层、临床中心网络和其他必要的程序，以进行最终的III期试验，展示HU对SCD神经系统并发症的一级预防的有效性。可行性和决定性的III期试验的主要终点将是出现异常的经颅多普勒、脊髓损伤或中风。为了开始可行性试验，我们已经在约翰·霍普金斯大学和华盛顿大学获得了CTSA对试点研究的支持；在接下来的两年里，这些网站将筛选40名12-48个月大的参与者，并随机分配并跟踪20名参与者两年。另外两个中心(费城儿童医院和阿拉巴马大学伯明翰分校)将在R34期间开始注册(每个站点筛选20名患者和随机分配10名参与者)，以提供总共80名筛查的参与者、40名随机分配的参与者和至少70年的参与者随访。参与者必须有远低于输血门槛的TCD测量和没有SCI证据的磁共振成像。试验性研究的参与者将继续进行拟议的R34和第三阶段试验，完成3年的HU或安慰剂治疗。可行性试验的信息对于证明最终的第三阶段试验的安全性和实用性是必要的。这些研究的结果可能导致真正的初级预防SCD的中枢神经系统并发症，包括TCD异常、SCI、神经认知障碍和中风。通过这样做，这项研究还可以通过扩大HU的适应症来减轻慢性输血的负担并改变临床实践。

DESCRIPTION (provided by applicant): Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly morbid complications of sickle cell disease (SCD) in children. Current approaches to the prevention and treatment of neurological complications of SCD include screening by transcranial Doppler ultrasound (TCD) to identify children with elevated cerebral blood flow velocity who are at increased risk for strokes; these children are then typically treated with chronic transfusions indefinitely. Hydroxyurea (HU) reduces the frequency of painful crisis, acute chest syndrome and transfusion and may have beneficial effects on central nervous system (CNS) complications of SCD. The safety of HU in infants and children has been demonstrated recently in a NIH-sponsored phase III trial; however, the exact indications for the use of HU in children remain unclear, as well as its efficacy in preventing CNS complications of SCD. Our preliminary data suggest that, if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%, the majority of pediatric hematologists would prescribe HU to all young children with SCD. The long term goal of this project is to perform a primary prevention trial to demonstrate the neuroprotective effect of HU and broaden the indications for HU in children. The goals of this proposal are to: 1) conduct a feasibility trial demonstrating the acceptability of a randomized trial of HU to reduce the CNS complications of SCD; 2) demonstrate that sedation for MRIs can be safely performed in young children with SCD using a standardized protocol; and 3) create the leadership, network of clinical centers and other procedures necessary to conduct a definitive phase III trial demonstrating the efficacy of HU for primary prevention of neurological complications of SCD. The primary endpoint for the feasibility and definitive phase III trials will be the development of abnormal TCD, SCI or stroke. To begin the feasibility trial, we have obtained CTSA support for pilot studies at Johns Hopkins and Washington University; over the next two years, these sites will screen 40 participants 12-48 months of age and randomly assign and follow 20 participants for two years. Two additional centers (Children's Hospital of Philadelphia and the University of Alabama, Birmingham) will begin enrollment during the course of the R34 (20 patients screened and 10 participants randomly assigned per site), to provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70 participant years of follow-up. Participants must have TCD measurements that are well below the threshold for transfusion and MRIs that are without evidence of SCI. Participants in the pilot studies will continue into the proposed R34 and phase III trials, to complete 3 years on HU or placebo. The information from the feasibility trial is necessary to demonstrate the safety and practicality of a definitive phase III trial. The results of these studies could lead to true primary prevention of CNS complications of SCD, including abnormal TCD, SCI, neurocognitive impairment and stroke. In doing so, this study could also reduce the burden of chronic transfusions and change clinical practice by broadening the indications for HU.