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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。无症状性脑梗死（SCI）是镰状细胞性贫血儿童严重神经系统疾病的最常见原因，在18岁之前发生在22%的人群中。本试验的总体目标是确定输血治疗是否会进一步降低无症状脑梗死儿童的神经系统发病率，如果是，这种益处的程度。我们提出了一项多中心随机试验，包括22个临床站点，一个临床协调中心和一个统计协调中心（见相关R01- PI Michael Terrin， MD， MPH）来验证以下假设：根据脑MRI的定义，对无症状脑梗死儿童进行预防性输血治疗将导致随后明显中风或新脑梗死的发生率至少降低86%。干预为输血治疗+观察，目的是使输血患者的最大血红蛋白s浓度保持在30%以下。大约3020名患有镰状细胞性贫血的儿童（大于6岁和小于13岁）将有资格进行筛查评估。在这组符合条件的患者中，大约1880名儿童将被要求参与并接受脑部核磁共振成像。在这一组中，我们估计376名儿童（20%）将出现无症状性脑梗死，其中38名儿童（10%）将出现TCD升高（200cm ./sec）。也不符合参加研究的资格。其余338名儿童将有资格随机分配观察或输血治疗。在考虑到10%的退出率和20%的交叉率后，基于60%的家长和无症状脑梗死儿童的儿童接受率，203名参与者（每个治疗分配至少101名）的研究规模确保了90%的检测能力，使输血治疗值得推荐（减少86%）。试验的标准化将在前6个月进行，入组时间为24个月，干预时间为36个月。入组12个月后，每位患者将接受MRI和TCD检查。每位研究参与者将在研究结束时（入组后第36个月）接受MRI和认知评估。该试验的主要目的是确定输血治疗预防中风或通过脑MRI评估的新发无症状脑梗死的有效性。该试验的次要目的是确定：1)预防性输血治疗是否会限制一般智力的进一步下降；2)在正式的风险-收益分析中，输血治疗无症状性脑梗死的总体获益大于与该治疗相关的风险。我们预计这项研究的结果可能会导致镰状细胞病和无症状性脑梗死患儿的标准护理实践发生变化。

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.