Hydroxyurea to Prevent CNS Complications of Sickle Cell Disease in Children

羟基脲预防儿童镰状细胞病中枢神经系统并发症

• 批准号: 8144680
• 负责人: James F Casella
• 金额: $ 36.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144680
• 关键词: Adherence; Adverse reactions; Age-Months; Alabama; Blood Flow Velocity; Blood Transfusion; Brain; Brain Injuries; Case Report Form; Cephalic; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Chronic; Clinical; Cognition; Data; Development; Doppler Ultrasound; Enrollment; Erythrocyte Transfusion; Exclusion; Family health status; Frequencies; Funding; Goals; Grant; Healthcare Systems; Hematologist; Impaired cognition; Impairment; Infant; Infarction; Injury; Institutional Review Boards; Intervention; Intervention Studies; Lead; Leadership; Magnetic Resonance Imaging; Manuals; Measurement; Measures; Monitor; Morbidity - disease rate; Multicenter Trials; Neuraxis; Neurocognitive; Neurologic; Neurologist; Pain; Participant; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Philadelphia; Pilot Projects; Placebos; Preparation; Prevention; Prevention approach; Primary Prevention; Procedures; Protocols documentation; Randomized; Research Infrastructure; Resources; Risk; Safety; Sampling; Screening procedure; Sedation procedure; Sickle Cell Anemia; Site; Stroke; Thalassemia; Transfusion; United States National Institutes of Health; Universities; Washington; acute chest syndrome; clinical practice; cost; experience; follow-up; hydroxyurea; operation; prevent; randomized trial; sickling

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. PUBLIC HEALTH RELEVANCE: Children with sickle cell disease are at increased risk for stroke and other injury to the brain. Chronic, usually monthly, transfusions are often necessary for these problems. This study will provide the necessary information to plan a study that would show whether hydroxyurea, a drug that prevents other complications of sickle cell disease, can also prevent brain injury and reduce the need for transfusions.

描述（由申请人提供）：中风，沉默的脑梗塞（SCI）和认知障碍是儿童镰状细胞病（SCD）的频繁且病态的并发症。当前的预防和治疗SCD神经系统并发症的方法包括经颅多普勒超声（TCD）筛查，以确定患有脑流速升高的儿童，他们的中风风险增加了；然后，这些孩子通常会无限期地用慢性输血治疗。羟基脲（HU）降低了痛苦的危机，急性胸部综合征和输血的频率，并且可能对中枢神经系统（CNS）并发症产生有益的影响。最近在NIH赞助的III期试验中证明了HU在婴儿和儿童中的安全性；但是，在儿童中使用HU的确切指示尚不清楚，以及它在防止CNS并发症的功效。我们的初步数据表明，如果异常TCD，SCI和中风的累积频率可以降低50％，则大多数儿科血液学家会向所有SCD的年幼儿童开出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，并扩大儿童HU的适应症。该提案的目标是：1）进行可行性试验，证明了HU随机试验可接受的可接受性，以减少SCD的中枢神经系统并发症； 2）证明，可以使用标准化方案安全地在患有SCD的幼儿中安全地进行MRIS的镇静； 3）建立领导，临床中心网络以及进行确定的III期试验所需的其他程序，证明了HU对SCD神经系统并发症的一级预防的疗效。可行性和确定性III期试验的主要终点将是TCD，SCI或中风异常的发展。为了开始可行性试验，我们在约翰·霍普金斯和华盛顿大学获得了CTSA支持的CTSA支持。在接下来的两年中，这些站点将筛选40名参与者12-48个月大，并随机分配并关注20名参与者两年。在R34的过程中，将开始入学两个中心（费城儿童医院和阿拉巴马大学，伯明翰大学）将开始入学（20名患者和10名参与者每个站点随机分配），以提供80名参与者，40名随机分配的参与者，至少有70名参与者的随访年。参与者必须具有远低于没有SCI证据的输血和MRI阈值的TCD测量。试点研究的参与者将继续进行拟议的R34和III期试验，以完成HU或安慰剂的3年。可行性试验中的信息对于证明确定性III期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预防SCD的中枢神经系统并发症，包括异常TCD，SCI，神经认知障碍和中风。这样，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。 公共卫生相关性：患有镰状细胞疾病的儿童中风的风险增加和大脑其他伤害。慢性（通常每月一次）通常需要输血。这项研究将提供必要的信息来计划一项研究，该研究将表明羟基脲（一种阻止其他并发症的药物）是否也可以防止脑损伤并减少输血的需求。