Strategy for Improving Stroke Treatment Response (SISTER) Trial

25年前，重组组织型纤溶酶原激活剂（r-tPA，阿替普酶）的引入，以及最近血管内治疗（EVT）的发展，显著降低了缺血性卒中患者的神经功能障碍。然而，在美国，只有20%的中风患者有资格接受这些治疗，其中70%的治疗后残疾。不幸的是，这些疗法也与脑出血等毒性作用有关。对于许多患者，例如那些在中风后4.5-24小时没有大血管闭塞的患者，没有既定的治疗方法。我们迫切需要开发更安全、更有效的治疗方法，以减轻缺血性中风后残疾的痛苦和巨大成本。ninds资助的研究表明，a2-antiplasmin （a2AP）是一种在急性缺血性中风中起关键有害作用的分子。高a2AP水平与临床上r-tPA衰竭风险增加有关，并且在临床前模型中a2AP以剂量依赖的方式增加脑损伤。a2AP阻断由r-tPA引起的血栓溶解，增加微血管血栓形成。a2AP促进中性粒细胞募集和基质异素蛋白酶-9 （MMP-9）表达，增强血脑屏障破坏，导致颅内出血。相反，与r-tPA或未治疗相比，缺乏a2AP或单克隆抗体灭活a2AP （a2AP- i）可显著减少细胞凋亡、MMP-9表达、微血管血栓形成、出血和肿胀。重要的是，a2ap - 1的治疗窗口期比r-tPA长几倍。与r-tPA相比，a2ap - 1可显著降低临床前脑卒中患者的脑梗死、脑出血、残疾和死亡率。来自多个实验室、使用不同模型和工具的有力研究显示出一致的效果。综上所述，这些数据表明，单独使用a2ap - 1具有非凡的安全治疗人类缺血性卒中的潜力，特别是在延长的缺血时间窗内。单克隆抗体a2ap - 1 （TS23）是在NIH/NINDS的研究支持下开发的。在一项健康志愿者的I期试验中，TS23诱导剂量相关的a2AP失活，放大内源性血栓溶解，并且耐受性良好。美国国立卫生研究院StrokeNet的一项随机、安慰剂对照、盲法、贝叶斯、剂量发现的II期SISTER试验将检验中心假设，即与标准医疗相比，TS23将安全地改善延长缺血患者的神经系统预后，而不会完全梗死。在300例急性缺血性脑卒中患者中，TS23将与安慰剂进行比较，这些患者在症状出现后4.5-24小时出现良好的灌注成像。如果TS23在减少神经损伤方面被证明是安全和潜在有效的，未来将计划进行关键的临床试验。

The introduction of recombinant tissue plasminogenactivators (r-tPA, alteplase) 25 years ago, and the recent development of endovascular therapy (EVT), significantly reduced neurologic disability in patients with ischemic stroke. Still, only 20% of stroke patients in the US are eligible for these therapies and 70% of those treated are left disabled. Unfortunately, these therapies are also associated with toxic effects such as brain hemorrhage. For many patients, such as those who would be treated at 4.5-24 hours after stroke without large vessel occlusion, no established therapy exists. We urgently need to develop safer and more effective treatments that can lessen the suffering and enormous costs of disability after ischemic stroke. NINDS-funded research shows that a2-antiplasmin (a2AP) is a molecule that plays a crucial, deleterious role in acute ischemic stroke. High a2AP levels are linked to an increased risk of r-tPA failure clinically, and a2AP increases brain injury in a dose-dependent fashion in preclinical models. a2AP blocks thrombus dissolution ini- tiated by r-tPA and increases microvascular thrombosis. a2AP promotes neutrophil recruitment and matrix met- alloproteinase-9 (MMP-9) expression, which enhances blood brain barrier breakdown to cause intracranial hem- orrhage. Conversely, a2AP deficiency, or a monoclonal antibody that inactivates a2AP (a2AP-I), profoundly reduces apoptosis, MMP-9 expression, microvascular thrombosis, hemorrhage and swelling by comparison to r-tPA or no treatment. Importantly, an a2AP-I has a several-fold longer therapeutic window than r-tPA. Compared to r-tPA, an a2AP-I significantly decreases brain infarction, brain hemorrhage, disability and mortality in preclinical stroke. Robust studies from multiple labs, using different models and tools, show consistent effects. Taken together, these data suggest that an a2AP-I alone has extraordinary potential for safe treatment of human ischemic stroke, particularly in an extended ischemic time window. The monoclonal antibody a2AP-I, TS23, was developed with NIH/NINDS research support. In a Phase I trial of healthy volunteers TS23 induced dose-related a2AP inactivation, amplified endogenous thrombus disso- lution, and was well-tolerated. A randomized, placebo-controlled, blinded, Bayesian, dose-finding, Phase II SISTER trial within the NIH StrokeNet will test the central hypothesis that, when compared to standard medical care, TS23 will safely improve neurological outcomes in patients with extended ischemia, without completed infarction. TS23 will be compared to placebo in 300 acute ischemic stroke patients presenting 4.5-24 h after symptom onset with favorable perfusion imaging. If TS23 proves be safe and potentially efficacious, based on reduction of neurological impairment, a future, pivotal clinical trial will be planned.