Hydroxyurea to Prevent the Central Nervous System 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: 9810412
• 负责人: James F Casella
• 金额: $ 16.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810412
• 关键词: Affect; Age; Age-Months; Blood Transfusion; Brain; Brain Injuries; Cerebral Infarction; Child; Chronic; Clinical Research; Clinical Trials; Clinical and Translational Science Awards; Cognition; Communities; Control Groups; Data; Development; Doppler Ultrasound; Double-Blind Method; Drops; Duct (organ) structure; Enrollment; Equipoise; Erythrocyte Transfusion; Exclusion Criteria; Family health status; Frequencies; Goals; Grant; Guidelines; Health Personnel; Healthcare Systems; Hybrids; Immunization; Impaired cognition; Impaired health; Impairment; Infant; Infarction; Injury; Institution; Intelligence; Lead; Leadership; Life; Light; Measures; Medical; Methods; Modeling; National Heart, Lung, and Blood Institute; Neuraxis; Neurologic; Nursery Schools; Outcome; Pain; Participant; Patients; Pediatric Hematologist; Penicillins; Performance; Pharmaceutical Preparations; Phase; Phenotype; Physicians; Placebos; Prevention; Prevention trial; Preventive measure; Primary Prevention; Procedures; Protocols documentation; Provider; Publishing; Quality of life; Randomized; Rare Diseases; Recommendation; Research Design; Resources; Risk; Safety; Sample Size; School-Age Population; Secondary Prevention; Sedation procedure; Sickle Cell Anemia; Sickle Hemoglobin; Stroke; Stroke prevention; Testing; Thalassemia; Time; Transfusion; Transient Ischemic Attack; United States National Institutes of Health; acute chest syndrome; arm; base; central nervous system injury; cognitive function; cohort; cost; design; feasibility trial; health related quality of life; hydroxyurea; improved; inclusion criteria; innovation; novel; phase 3 study; phase III trial; phenotypic data; placebo controlled study; prevent; primary outcome; programs; prophylactic; randomized placebo controlled trial; randomized trial; recruit; screening; secondary outcome; simulation; stroke risk; treatment effect; working group

Stroke, silent cerebral infarct (SCI), transient ischemic attack (TIA) and cognitive impairment cumulatively are frequent and highly morbid complications of sickle cell disease (SCD) in children. Currently, the prevention and treatment of neurological complications of SCD include screening by transcranial Doppler ultrasound (TCD) to identify children at increased risk for strokes, followed by chronic transfusions. 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. A NIH-sponsored phase III trial showed the safety of HU in infants and children. HU for secondary prevention of abnormal TCDs after a period of transfusion is efficacious, but its value in primary prevention of CNS complications of SCD remains unclear, and usage rates early in life remain low. Our preliminary data indicate that a 50% reduction of CNS complications would cause ≥ 90% of pediatric hematologists to prescribe HU to all young children with SCD. The goal of this project is to plan a definitive primary prevention trial to demonstrate the neuroprotective effect of HU. In a preparatory R34 grant, we con- ducted a feasibility trial showing the acceptability of randomization and the safety of sedation for brain MRIs in young children with SCD. We created the leadership, network of centers and procedures necessary for a defin- itive phase III study (HU Prevent). Our R34 and subsequent RO1 submission used a traditional randomized, double-blind, placebo-controlled study design. Reviews of the RO1 raised concerns about equipoise and whether a placebo would be feasible or informative, as NHLBI guidelines could lead to difficulty convincing physicians and patients to accept randomization. Based on these criticisms, we redesigned our study as a hybrid trial, combining a smaller randomized trial with a non-randomized (observational) cohort. A draft protocol is described in this proposal. The primary outcome is a composite of the weighted risk of impairment due to stroke, SCI, TIA, conditional and abnormal TCD. Secondary outcomes are cognitive function (IQ) and Health Related Quality of Life. Statistical causal inference methods, including propensity score matching, are used to combine patients from the randomized trial and the non-randomized cohort to estimate the overall HU treatment effect using ad- vanced regression models. Subsequent reviews questioned whether the availability of a non-randomized arm could make randomization difficult and create bias, adversely affecting inferences, and the effects of drop-outs or crossovers, given the availability of HU and recent FDA approval of HU for age ≥ 2 yrs. Given these concerns and the importance of the problem, we feel that a full reassessment of study design, including novel, non-tradi- tional designs is in order, to overcome the issues of sample size in an orphan disease, issues related to random- ization and placebos, difficulty of implementing an optimal control group and potential for crossovers. To inform design, we will use additional electronic phenotype data to refine inclusion and exclusion criteria, assess current HU usage and perform a full community engagement assessment, internal and external to our study consortium.

中风、无症状性脑梗塞（SCI）、短暂性脑缺血发作（TIA）和认知障碍累计为 儿童镰状细胞病（SCD）的常见且高发病率的并发症。目前，预防和 SCD 神经系统并发症的治疗包括通过经颅多普勒超声 (TCD) 进行筛查 识别中风风险增加的儿童，然后进行长期输血。羟基脲 (HU) 降低 疼痛危象、急性胸部综合征和输血的频率，可能对中枢神经系统产生有益影响 SCD 的神经系统 (CNS) 并发症。 NIH 资助的 III 期试验显示 HU 对婴儿的安全性 和孩子们。 HU对于输血一段时间后异常TCD的二级预防是有效的，但其 SCD 中枢神经系统并发症一级预防的价值仍不清楚，生命早期的使用率仍然存在 低的。我们的初步数据表明，中枢神经系统并发症减少 50% 将导致 ≥ 90% 的儿科并发症 血液学家为所有患有 SCD 的幼儿开 HU 处方。该项目的目标是规划一个明确的 一级预防试验证明 HU 的神经保护作用。在预备性 R34 拨款中，我们同意 进行了一项可行性试验，显示脑 MRI 随机化的可接受性和镇静的安全性 患有 SCD 的幼儿。我们创建了领导层、中心网络和定义所需的程序 积极的 III 期研究（HU Prevent）。我们的 R34 和随后的 RO1 提交使用了传统的随机、 双盲、安慰剂对照研究设计。对 RO1 的审查引起了人们对平衡以及是否 安慰剂是可行的或提供信息的，因为 NHLBI 指南可能会导致难以说服医生 和患者接受随机分组。基于这些批评，我们将我们的研究重新设计为混合试验， 将较小规模的随机试验与非随机（观察）队列相结合。描述了协议草案 在此提案中。主要结局是由中风、SCI、TIA、 有条件和异常 TCD。次要结果是认知功能 (IQ) 和健康相关质量 生活。使用统计因果推断方法（包括倾向评分匹配）来组合患者 从随机试验和非随机队列中使用 ad- 来估计整体 HU 治疗效果 高级回归模型。随后的评论质疑非随机组的可用性是否 可能会使随机化变得困难并产生偏差，对推论以及退出的影响产生不利影响 或交叉，考虑到 HU 的可用性以及最近 FDA 批准 HU 适合年龄 ≥ 2 岁的患者。鉴于这些担忧 以及该问题的重要性，我们认为对研究设计进行全面重新评估，包括新颖的、非传统的 合理的设计是为了克服孤儿疾病的样本量问题、与随机相关的问题 化和安慰剂、实施最佳对照组的难度以及交叉的可能性。告知 设计中，我们将使用额外的电子表型数据来完善纳入和排除标准，评估当前 HU 的使用并对我们的研究联盟内部和外部进行全面的社区参与评估。