SILENT CEREBRAL INFARCT MULTI-CENTER CLINICAL TRIAL

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。理论基础：中枢神经系统(CNS)并发症，包括中风和认知障碍，在镰状细胞病(SCD)患者中会导致显著的发病率和死亡率。经颅多普勒(TCD)测量大脑主要动脉的定时平均平均最大血流速度(TAMV)可以确定儿童有明显卒中的风险。然而，20%的SCD儿童有临床上无症状的脑缺血，TCD没有发现这种情况。这些“沉默的”脑梗塞与严重的认知障碍有关，这种损害可以通过每月输注镰刀状阴性血来预防。建议：无症状性脑梗塞输血(SIT)试验是第三阶段随机对照试验，比较每月输注镰刀阴性血与常规治疗SCD和无症状性脑梗塞儿童的疗效。我们假设预防性输血治疗将导致临床明显中风或新发或进展性无症状脑梗塞患者的比例至少降低86%。我们将评估输血对这一人群的一般智能能力的影响以及输血治疗的总体好处和风险。此外，我们将为SCD的遗传学研究开发一个储存库。方法：我们将从23个中心筛查1880名6岁及13岁的镰状细胞性贫血(HbSS)或镰状细胞缺失型地中海贫血(HbSB0)患者。所有患者(约翰霍普金斯大学约148名儿童)将接受包括T1、T2、弥散加权、液体衰减反转恢复(FLAIR)图像和飞行时间磁共振血管成像(MRA)在内的脑MRI筛查；为遗传库提供静脉血；并完成详细的人口统计学和表型表格。我们将在MRI上识别大约375名有缺血性变化的患者(霍普金斯大学的25名患者)。这些儿童将接受确定的输血指征(明显的中风、异常的TCD)的评估，并接受关于试验干预部分的进一步教育。我们计划将102名儿童随机分配到每一组(为期3年的每月输液与常规护理相比)。所有儿童都将在随机分组前立即进行另一次核磁共振检查和重点神经心理评估。12~18个月和3年后复查神经心理评估，3年后复查MRI。所有的核磁共振成像都将由3名研究放射科医生中的至少2名进行集中审查，以在随机化之前识别梗死样病变，并确定研究终点。父母和医疗提供者将在研究开始和结束时填写问卷，以评估各种健康结果的价值。这项研究将回答有关SCD儿童输血治疗的几个重要问题。它将提供对输血预防患有SCD和无症状脑梗塞的儿童新的或进展性无症状脑梗塞的疗效的准确估计。我们还将能够检测到两组儿童一般智力的变化。SIT试验将严格评估SCD儿童输血的益处和风险。

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. Rationale: Central nervous systems (CNS) complications including stroke and cognitive impairment cause significant morbidity and mortality in patients with sickle cell disease (SCD). Measurement of timed -averaged mean maximum blood flow velocity (TAMV) in the major cerebral arteries by transcranial Doppler (TCD) can identify children at risk for overt stroke. However, 20% of children with SCD have clinically silent cerebral ischemia that is not identified by TCD. These "silent" cerebral infarcts are associated with significant cognitive impairment that may be prevented by monthly transfusions of sickle negative blood. Proposal: The Silent Infarct Transfusion (SIT) Trial is Phase III randomized controlled trial comparing monthly transfusions of sickle negative blood to usual care for children with SCD and silent infarct. We hypothesize that prophylactic transfusion therapy will result in at least 86% reduction in the proportion of patients with clinically evident strokes or new or progressive silent cerebral infarcts. We will evaluate the effect of transfusion on general intellectual abilities and the overall benefits and risks of transfusion therapy in this population. In addition, we will develop a repository for genetic studies of SCD. Methods: We will screen 1880 patients =6 and <13 years of age with sickle cell anemia (HbSS) or sickle ?-null thalassemia (HbSB0) from 23 centers. All patients (approximately 148 children at Johns Hopkins) will be screened by brain MRI including T1, T2, and diffusion weighted, and fluid attenuated inversion recovery (FLAIR) images, and time of flight magnetic resonance angiography (MRA); provide venous blood for the genetic repository; and complete a detailed demographic and phenotype form. We will identify about 375 patients with ischemic changes on MRI (25 at Hopkins). These children will be evaluated for established indications for transfusion (overt stroke, abnormal TCD), and receive further education about the intervention portion of the trial. We plan to randomize 102 children to each arm (monthly transfusion for 3 years versus routine care). All children will have another MRI and focused neuropsychological assessment immediately before randomization. The neuropsychological assessment will be repeated 12 to 18 months and 3 years later; the MRI will be repeated 3 years later. All MRIs will be reviewed centrally by at least 2 of the 3 study radiologists, both to identify infarct-like lesions prior to randomization and for study endpoints. Parents and medical providers will complete questionnaires to estimate the value of various health outcomes at the beginning and end of the study. Implications: This study will answer several important questions about transfusion therapy in children with SCD. It will provide a precise estimate of the efficacy of transfusion to prevent new or progressive silent infarct in children with SCD and silent infarct. We will also be able to detect changes in general intellectual abilities between the two groups The SIT trial will rigorously evaluate the benefits and risks of transfusion in children with SCD.