NC-758 for Prevention of Recurrent Cerebral Hemorrhage

描述(由申请人提供)：目前还没有已知的治疗脑淀粉样血管病(CAA)的方法，CAA是老年人出血性中风和其他临床症状的重要原因。CAA相关卒中的病理基础是淀粉样蛋白B-肽(AB)在脑血管中沉积，导致血管壁变性。我们建议进行一项多中心、II期先导性研究，研究NC-758二级预防CAA相关性脑出血的安全性、耐受性和初步疗效。NC-758是一种小分子，旨在与糖胺聚糖竞争结合AB。初步研究表明，这种化合物可以渗透到中枢神经系统，抑制AB纤维的形成和AB诱导的细胞毒性，并在没有主要内在毒性证据的情况下，降低转基因小鼠模型中CAA的严重程度。拟议的试验是基于首席调查员在CAA的诊断和分期方面取得的进展。参与者将是大叶出血性中风的幸存者，根据基线梯度回波MRI扫描或载脂蛋白-E基因被认为是复发的高危人群。预计将在20个参与地点对280名患者进行筛查，210名患者随机接受低剂量NC-758、高剂量NC-758或安慰剂治疗。患者将接受为期16个月的治疗，并对不良临床事件、实验室异常、反复中风或认知、功能或神经状态下降进行跟踪。在8个月和16个月的治疗中，受试者将接受后续的MRI扫描，以确定治疗期间新的出血性病变的出现。建议的样本量被计算为有很高的可能性检测到与NC-758相关的主要不良反应，并检测到新的有症状和无症状出血的出现减少了50%。除了测试一种有希望用于CAA的药物外，拟议的研究还将产生组织和试点数据，作为未来新兴抗淀粉样蛋白治疗试验的跳板。

DESCRIPTION (provided by the applicant): There is no known therapy for Cerebral Amyloid Angiopathy (CAA), an important cause of hemorrhagic stroke and other clinical syndromes in the elderly. The pathologic basis of CAA-related stroke is deposition of the Amyloid B-peptide (AB) in cerebral vessels, and resultant degeneration of the vessel wall. We propose a multi-center, phase II pilot study of the safety, tolerability, and preliminary efficacy of NC-758 for secondary prevention of recurrent CAA-related intracerebral hemorrhage. NC-758 is a small molecule designed to compete with glycosaminoglycans for binding to AB. Preliminary studies have demonstrated that this compound penetrates to the CNS, inhibits AB fibril formation and AB-induced cellular toxicity, and reduces severity of CAA in a transgenic mouse model without evidence for major intrinsic toxicity. The proposed trial builds on progress by the Principal Investigator in the diagnosis and staging of CAA. Participants will be survivors of lobar hemorrhagic stroke, considered at high-risk for recurrence based on baseline gradient-echo MRI scan, or apolipoprotein-E genotype. An anticipated 280 patients will be screened at 20 participating sites, and 210 patients randomized to receive low-dose NC-758, high-dose NC-758, or placebo. Patients will be treated for a 16-month period, and followed for adverse clinical events, laboratory abnormalities, and recurrent stroke or decline in cognitive, functional, or neurologic status. At 8 and 16 months of treatment, subjects will undergo follow-up MRI scans to determine the appearance of new hemorrhagic lesions during treatment. The proposed sample size is calculated to have high likelihood of detecting major adverse effects associated with NC-758, and for detecting a 50% reduction in appearance of new symptomatic and asymptomatic hemorrhages. In addition to testing a promising agent for CAA, the proposed study will generate the organization and pilot data to serve as a springboard for future trials of emerging anti-amyloid treatments.