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: 8865963
• 负责人: James F Casella
• 金额: $ 37.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865963
• 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; 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; screening; 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.

描述（由申请人提供）：中风、无症状性脑梗死（SCI）和认知障碍是儿童镰状细胞病（SCD）常见且高度发病的并发症。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，以识别脑血流速度升高的儿童卒中风险增加；然后，这些儿童通常接受无限期的长期输血治疗。羟基脲（HU）减少疼痛危象、急性胸综合征和输血的频率，并可能对SCD的中枢神经系统（CNS）并发症有有益的影响。最近，美国国立卫生研究院（nih）资助的一项III期临床试验证实了HU在婴幼儿中的安全性；然而，在儿童中使用HU的确切适应症以及其预防SCD的中枢神经系统并发症的有效性仍不清楚。我们的初步数据表明，如果异常TCD、SCI和卒中的累积频率可以降低50%，大多数儿科血液学家会给所有SCD患儿开HU。该项目的长期目标是开展一项初级预防试验，以证明胡芦胡的神经保护作用，并扩大胡芦胡在儿童中的适应症。本提案的目标是：1)进行可行性试验，证明HU随机试验减少SCD的中枢神经系统并发症的可接受性；2)证明使用标准化方案对SCD幼儿进行mri镇静是安全的；3)建立领导、临床中心网络和其他必要的程序，以开展明确的III期试验，证明HU对SCD神经系统并发症的一级预防效果。可行性和最终III期试验的主要终点将是异常TCD、SCI或卒中的发展。为了开始可行性试验，我们已获得CTSA对约翰霍普金斯大学和华盛顿大学试点研究的支持；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，并随机分配和跟踪20名参与者两年。另外两个中心（费城儿童医院和伯明翰阿拉巴马大学）将在R34的过程中开始招募（筛选20名患者，每个地点随机分配10名参与者），总共提供筛选80名参与者，随机分配40名参与者，以及至少70名参与者年的随访。参与者的TCD测量值必须远低于输血的阈值，核磁共振成像也必须没有脊髓损伤的证据。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3年的胡塞酮或安慰剂治疗。可行性试验的信息对于证明确定的III期试验的安全性和实用性是必要的。这些研究结果可能导致SCD中枢神经系统并发症的真正一级预防，包括异常TCD、SCI、神经认知障碍和卒中。这样，本研究还可以通过扩大HU的适应症来减轻慢性输血负担并改变临床实践。

项目成果

Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease.

为患有镰状细胞病的幼儿进行羟基脲试验，开发基于风险的复合神经学结果。

• DOI: 10.1177/1740774518807160
• 发表时间: 2019
• 期刊: Clinical trials (London, England)
• 作者: Casella,JamesF;Adams,RobertJ;Brambilla,DonaldJ;Strouse,JohnJ;Maier,Pia;Dlugash,Rachel;Avadhani,Radhika;Vermillion,Krista;Tonascia,James;Voeks,JeniferH;Hanley,DanielF;Thompson,RichardE;Lehmann,HaroldP
• 通讯作者: Lehmann,HaroldP

Is low dose hydroxyurea the solution to the global epidemic of sickle cell disease?

低剂量羟基脲是全球镰状细胞病流行的解决方案吗？

• DOI: 10.1002/pbc.25471
• 发表时间: 2015
• 期刊: Pediatric blood & cancer
• 影响因子: 3.2
• 作者: Strouse,JohnJ