PARP inhibitory therapy of acute ischemic stroke

描述（由申请人提供）：中风激活核酶聚（ADP-核糖）聚合酶（“PARP”），触发细胞发生坏死和炎症。Inotek的超强临床PARP抑制剂（“INO-1001”）在短暂性和永久性缺血性大鼠中风模型中显著减少组织坏死和神经功能障碍。我们的数据与中风小鼠的基因缺失研究一致，该研究表明在MCA闭塞模型中> 80%的神经保护。我们现在提出一项INO-1001的临床研究，以确认急性卒中人群的耐受性、药代动力学和安全性。 基于INO-1001在健康受试者中的临床研究，我们预期INO-1001将是 耐受性良好且安全，并在治疗后24小时内维持治疗药物血药浓度。 单次推注。我们将通过进行一项前瞻性、开放标签、多中心研究来检验这一假设 临床诊断和CT证实为急性非腔隙性脑梗死的n=30例受试者 缺血性中风计划进行剂量递增，以每个剂量水平n=10例受试者的队列进行结构化。 将持续监测和观察受试者的生命体征、体格检查， 心电图、代谢状态、临床生化、血液学和凝血 参数和血浆药物浓度。虽然将记录临床结局，但这不是 旨在作为一项治疗性试验，并且包括能够自己同意的稳定患者 并报告症状，进行更详细的药代动力学和耐受性监测， 在大型多中心疗效研究中具有典型性。在后续的第二阶段SBIR中，我们将 在900名患者中进行了一项INO-1001的关键性研究，以确定其在急性 非腔隙性缺血性中风我们将评估INO-1001对1）脑梗死的影响， 通过MRI定量，和2）神经功能障碍，在基线、4天、1周、2周时评估， a）NIHSS改良兰金和Barthel评分。

DESCRIPTION (provided by applicant): Stroke activates the nuclear enzyme poly (ADP-ribose) polymerase ("PARP"), triggering cells to undergo necrosis and inflammation. Inotek's ultrapotent clinical PARP inhibitor ("INO-1001') profoundly reduces tissue necrosis and neurologic dysfunction in transient and permanent ischemic rat stroke models. Our data are in agreement with genetic deletion studies in stroked mice, which demonstrate > 80% neuroprotection in MCA occlusion models. We now propose a clinical study of INO-1001 to confirm tolerability, pharmacokinetics, and safety in a population with acute stroke. Based on clinical studies of INO-1001 in healthy subjects, we expect that INO-1001 will be Well-tolerated and safe, and maintain therapeutic drug plasma concentrations for 24 hours after a single bolus. We will test this hypothesis by carrying out a prospective, open-label multi-center study of n=30 subjects presenting with a clinical diagnosis and CT confirmation of acute non-lacunar ischemic stroke. A dose-escalation is planned, structured in cohorts of n=10 subjects per dose level. Subjects will be continuously monitored and observed for alterations in vital signs, physical exam, electrocardiogram, metabolic status, and clinical chemistries, hematologic and coagulation parameters, and plasma drug concentration. Whilst clinical outcome will be recorded, this is not intended to be a therapeutic trial, and wall include stable patients, who are able to consent themselves and report symptoms, with more detailed pharmacokinetic and tolerability monitoring than would be typical in a large multi-center investigation of efficacy. In a follow-on Phase 2 SBIR, we will carry out a pivotal study of INO-1001 in 900 patients to establish efficacy in a population with acute non-lacunar ischemic stroke. We will assess the effect of INO-1001 on 1) brain infarction, as quantitated by MRI, and 2) neurologic dysfunction, as assessed at baseline, 4 days, I week, 2 weeks, and I month by (a) NIHSS modified Rankin and Barthel score.