SCREENING AND TREATMENT OF SILENT INFARCTS FOR CHILDREN WITH SICKLE CELL DISE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。无症状性脑梗塞(SCI)是严重神经系统疾病的最常见原因，在患有镰状细胞性贫血的儿童中，22%的儿童在18岁之前发生。这项试验的总体目标是确定输血治疗是否将进一步降低无症状脑梗塞儿童的神经发病率，如果是，则确定这一益处的幅度。我们提出了一项包含22个临床地点的多中心随机试验，一个临床协调中心和一个统计协调中心(参见随附的R01--Pi Michael Terrin，医学博士，公共卫生硕士)，以检验以下假设：根据大脑MRI的定义，对无症状脑梗塞的儿童进行预防性输血治疗将导致随后显性中风或新发脑梗塞的发生率至少降低86%。干预是输血治疗与观察，目的是使输血患者的最高血红蛋白-S浓度保持在30%以下。大约3,020名患有镰状细胞性贫血的儿童，年龄大于6岁，小于13岁，将有资格接受筛查评估。在这组符合条件的患者中，大约1,880名儿童将被要求参加，并将接受脑部核磁共振检查。在这一组中，我们估计376名儿童(20%)将会有无症状脑梗塞，其中38名儿童(10%)的TCD测量将升高(200厘米/秒)。不会有资格参加这项研究。其余338名儿童将有资格随机分配到观察组或输血治疗组。基于60%的父母和无症状脑梗塞儿童的儿童接受率，203名参与者(每个治疗任务至少101名)的研究规模确保了90%的能力来检测使输血疗法值得推荐所需的效果(减少86%)，考虑了10%的辍学率和20%的交叉率。试验的标准化将在前6个月进行，登记24个月，干预36个月。登记12个月后，每个患者都将接受核磁共振和TCD检查。每个研究参与者将在研究结束时(注册后36个月)接受核磁共振和认知评估。这项试验的主要目的是确定输血疗法对预防中风或通过脑部核磁共振评估的新的无症状脑梗塞的有效性。这项试验的次要目标是确定：1)预防性输血疗法是否将限制一般智力的进一步下降；2)在正式的风险-收益分析中，输血疗法对无症状脑梗塞的总体益处大于与这种疗法相关的风险。我们预计这项研究的结果可能会导致对同时患有镰状细胞病和无症状脑梗塞的儿童的标准护理做法的改变。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Silent Cerebral Infarct (SCI) is the most common cause of severe neurological disease in children with sickle cell anemia, occurring in 22% of this population prior to their 18th birthday. The overall goal of this trial is to determine whether blood transfusion therapy will decrease further neurologic morbidity in children with Silent Cerebral Infarcts and, if so, the magnitude of this benefit. We propose a multi-center, randomized trial with 22 Clinical Sites, a Clinical Coordinating Center, and a Statistical Coordinating Center (see accompanying R01--PI Michael Terrin, MD, MPH) to test the following hypothesis: Prophylactic blood transfusion therapy in children with Silent Cerebral Infarcts will result in at least an 86% reduction in the rate of subsequent overt strokes or new cerebral infarcts, as defined by the MRI of the brain. The intervention is blood transfusion therapy vs. observation, with a goal to keep the maximum hemoglobin-S concentration less than 30% in the transfused patients. Approximately 3,020 children with Sickle Cell Anemia, greater than 6 years of age and less than 13 years of age, will be eligible for screening evaluations. Among this group of eligible patients, approximately 1,880 children will be asked to participate and will receive MRIs of the brain. In this group, we estimate that 376 children (20%) will have Silent Cerebral Infarcts, among whom 38 children (10%) will have an elevated TCD measurement (200 cm./sec. and will not be eligible for the study. The remaining 338 children will be eligible for random allocation to either observation or blood transfusion therapy. Based on a 60% parent, and a child acceptance rate among children with Silent Cerebral Infarcts, a study size of 203 participants (at least 101 in each treatment assignment) ensures 90% power to detect the effect necessary to make transfusion therapy worth recommending (86% reduction), after accounting for 10% drop-out and 20% crossover rates. The standardization of the trial will occur during the first six months, enrollment for 24 months, and the intervention for 36 months. Twelve months after enrollment, each patient will receive a MRI and TCD. Each study participant will receive MRI and cognitive assessment at study exit (month 36 after enrollment). The primary aim of this trial is to determine the effectiveness of blood transfusion therapy for the prevention of stroke, or new Silent Cerebral Infarct assessed by the MRI of the brain. The secondary aims of this trial are determining whether: 1) prophylactic blood transfusion therapy will limit further decline in general in general intellectual abilities; and 2) the overall benefits of blood transfusion therapy for Silent Cerebral Infarcts outweigh risks associated with this therapy in a formal risk-benefit analysis. We anticipate results of this study could lead to a change in standard care practices for children affected with both sickle cell Disease and silent cerebral Infarcts.