Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease in Children

卒中、无症状性脑梗死（SCI）、短暂性脑缺血发作（TIA）和认知障碍累积为 儿童镰状细胞病（SCD）的常见和高度病态并发症。目前，预防和 SCD神经系统并发症的治疗包括经颅多普勒超声（TCD）筛查， 识别中风风险增加的儿童，然后进行慢性输血。羟基脲（HU）可降低 疼痛危象、急性胸部综合征和输血的频率，并可能对中枢神经系统产生有益影响。 神经系统（CNS）并发症。NIH赞助的一项III期试验显示了HU在婴儿中的安全性 和儿童HU用于输血后TCD异常的二级预防是有效的，但其 SCD CNS并发症的一级预防价值尚不清楚， 低我们的初步数据表明，CNS并发症减少50%将导致≥ 90%的儿童 血液学家给所有患有SCD的幼儿开HU。该项目的目标是计划一个明确的 一级预防试验，以证明HU的神经保护作用。在预备R34赠款中，我们同意- 进行了一项可行性试验，显示了随机化的可接受性和脑MRI镇静的安全性， 患有SCD的儿童我们建立了领导层，中心网络和必要的程序，以确定- 阳性III期研究（HU预防）。我们的R34和随后的RO 1提交使用了传统的随机， 双盲、安慰剂对照研究设计。对《规则》的审查1引起了对平衡的关注， 安慰剂将是可行的或提供信息的，因为NHLBI指南可能导致难以说服医生 患者接受随机化。基于这些批评，我们重新设计了我们的研究作为一个混合试验， 将一个较小的随机试验与一个非随机（观察）队列相结合。描述了一个草案方案， 在这个提议中。主要结局是卒中、SCI、TIA、 条件性和异常TCD。次要结果是认知功能（IQ）和健康相关质量。 生活统计因果推断方法，包括倾向评分匹配，用于联合收割机患者 从随机试验和非随机队列中，使用ad- 先进的回归模型。随后的综述质疑是否有非随机化组 可能会使随机化变得困难，并产生偏倚，对推断和脱落的影响产生不利影响 考虑到HU的可用性和最近FDA批准的年龄≥ 2岁的HU， 和问题的重要性，我们认为，全面重新评估研究设计，包括新颖的，非传统的， 常规设计是为了克服孤儿病的样本量问题，与随机相关的问题， 化和安慰剂，实施最佳对照组的困难和交叉的可能性。通知 设计，我们将使用额外的电子表型数据来完善纳入和排除标准，评估当前的 HU的使用和执行一个完整的社区参与评估，内部和外部我们的研究财团。

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.