Strategy for Improving Stroke Treatment Response (SISTER) Trial

改善中风治疗反应策略 (SISTER) 试验

• 批准号: 10595947
• 负责人: Jordan J. Elm
• 金额: $ 511.03万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595947
• 关键词: Acute; Advanced Development; Advisory Committees; Alteplase; Antibody Therapy; Antiplasmin; Apoptosis; Basic Science; Biometry; Blinded; Blood - brain barrier anatomy; Blood Vessels; Blood coagulation; Blood flow; Brain; Brain Infarction; Brain Injuries; Brain Ischemia; Brain hemorrhage; Cardiology; Caring; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Cyclic GMP; Data; Development; Disabled Persons; Dose; Eligibility Determination; Failure; Fibrin fragment D; Fibrinolysis; Funding; Future; Gelatinase B; Hemorrhage; Hour; Human; Impairment; Infarction; Inflammation; Intracranial Hemorrhages; Ischemia; Ischemic Stroke; Laboratories; Left; Link; Measures; Mediating; Medical; Modeling; Molecular; Monoclonal Antibodies; National Institute of Neurological Disorders and Stroke; Neurologic; Neurological outcome; Neurology; Neutrophil Infiltration; Outcome Measure; Patients; Persons; Phase; Placebo Control; Placebos; Plasminogen Activator; Play; Pre-Clinical Model; Probability; Process; Property; Randomized; Recombinants; Relative Risks; Reperfusion Therapy; Reproducibility; Research; Research Support; Risk; Role; Safety; Site; Stroke; StrokeNet trials; Swelling; Symptoms; Tenecteplase; Testing; Therapeutic; Thrombosis; Thrombus; Time; Tissues; Toxic effect; Toxicology; Treatment Failure; United States National Institutes of Health; artery occlusion; brain tissue; cost; disability; effective therapy; efficacious treatment; endovascular thrombectomy; healthy volunteer; improved; innovation; manufacture; mortality; neurotoxic; neurotoxicity; neutrophil; perfusion imaging; pharmacologic; phase I trial; phase II trial; post stroke; pre-clinical; prevent; primary outcome; protective effect; stability testing; standard of care; stroke model; stroke outcome; stroke patient; stroke therapy; study population; thromboembolic stroke; tool; translational medicine; treatment response; trial design

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.

25年前重组组织纤溶酶原激活剂（r-tPA，阿替普酶）的引入，以及血管内治疗（EVT）的最新发展，显著降低了缺血性卒中患者的神经功能障碍。尽管如此，在美国只有20%的中风患者有资格接受这些治疗，70%的治疗者致残。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小时接受治疗而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，以减轻缺血性卒中后残疾的痛苦和巨大成本。NINDS资助的研究表明，α 2-抗纤溶酶（α 2 AP）是一种在急性缺血性卒中中起关键有害作用的分子。高a2 AP水平与临床上r-tPA失败的风险增加有关，并且a2 AP在临床前模型中以剂量依赖性方式增加脑损伤。a2 AP阻断由r-tPA引发的血栓溶解并增加微血管血栓形成。α 2 AP促进中性粒细胞募集和基质金属蛋白酶-9（MMP-9）表达，这促进血脑屏障破坏，从而引起颅内出血。相反，与r-tPA或无治疗相比，α 2 AP缺陷或使α 2 AP失活的单克隆抗体（α 2 AP-1）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，a2 AP-I具有比r-tPA长几倍的治疗窗口。与r-tPA相比，a2 AP-I显著降低了临床前卒中中的脑梗死、脑出血、残疾和死亡率。来自多个实验室的稳健研究，使用不同的模型和工具，显示出一致的效果。总之，这些数据表明单独的a2 AP-I具有安全治疗人缺血性中风的非凡潜力，特别是在延长的缺血时间窗中。在NIH/NINDS研究支持下开发了单克隆抗体α 2 AP-1，TS 23。在健康志愿者的I期试验中，TS 23诱导剂量相关的a2 AP失活，放大内源性血栓溶解，并且耐受性良好。在NIH StrokeNet中进行的一项随机、安慰剂对照、盲法、贝叶斯、剂量探索、II期SISTER试验将检验中心假设，即与标准医疗相比，TS 23将安全地改善无完全梗死的长期缺血患者的神经功能结局。将在300例症状发作后4.5-24小时出现灌注成像良好的急性缺血性卒中患者中比较TS 23与安慰剂。如果TS 23被证明是安全和潜在有效的，基于神经功能缺损的减少，将计划未来的关键临床试验。