PILOT STUDY OF TNK-TPA IN ACUTE ISCHEMIC STROKE

缺血性中风仍然是一个主要的公共卫生问题，造成数十亿美元的医疗费用和工资损失，并给受害者及其家属造成难以估量的痛苦。最近，静脉溶栓治疗重组组织型纤溶酶原激活剂（rt-PA）被证明可以改善急性缺血性卒中患者的神经和功能预后，这些患者可以在发病3小时内治疗。然而，rt-PA治疗并发症状性颅内出血的风险为6.4%，39%的患者在治疗后死亡或严重残疾。一种新的第二代溶栓药物TNK-TPA经过特异性设计，比rt-PA更具纤维蛋白特异性，并且在血栓形成的实验模型中显示，它比rt-PA更有效，活性更快。在实验性脑卒中中，脑血管凝块溶解更快，颅内出血发生率降低。在心肌梗死的人体研究中，该药耐受性良好，颅内出血并发治疗的发生率并不大于rt-PA，甚至可能小于rt-PA。该提案描述了一项多中心、开放标签、剂量递增安全性试验，在急性缺血性脑卒中患者中使用TNK-TPA，该患者可在3小时内接受治疗。需要验证的主要假设是，TNK-TPA可以安全地用于急性缺血性卒中患者，其剂量可能与神经预后的改善有关。该研究的主要终点将是治疗后36小时内症状性颅内出血的发生率。安全监测和样本量计算的目的是，如果观察到颅内出血率超过rt-PA治疗脑卒中的报告，将停止入组。药物活性将通过患者早期主要神经系统改善的比例来衡量，该比例由美国国立卫生研究院卒中量表改善8分或以上或卒中发作后24小时满分0分确定。3个月时的结果将通过Barthel指数、修改后的Rankin Sale和全球结果统计来评估，以方便后续研究的样本量计算。60至100名患者将被纳入剂量级别，每个剂量级别最多25名患者。

Ischemic stroke continues to be a major public health problem exacting billions of dollars from society in medical care costs and lost wages, as well as incalculable suffering to victims and their families. Recently, thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) was shown to improve neurological and functional outcome in patients with acute ischemic stroke who could be treated with 3 hours of onset. However, the risk of symptomatic intracranial hemorrhage complicating rt-PA treatment was 6.4%, and 39% of patients either died or were severely disabled despite treatment. A novel, second generation thrombolytic drug, TNK-TPA, has been specificity engineered to be more fibrin specific than rt-PA, and has been shown in experimental models of thrombosis to be more potent and active more quickly than rt- PA. In experimental stroke, cerebrovascular clots were lysed more quickly, and the incidence of intracranial hemorrhage was reduced. In human studies of myocardial infarction, the drug is well tolerated, and the incidence of intracranial hemorrhage complicating treatment is not greater, and may be less than that with rt-PA. This proposal describes a multi-center, open-label, pilot dose-escalation safety trial of TNK-TPA in patients with acute ischemic stroke who can be treated within 3 hours. The primary hypothesis to be tested is that TNK-TPA may be safely administered to patients with acute ischemic stroke at doses which may be associated with improvement in neurological outcome. The primary endpoint of the study will be the incidence of symptomatic intracranial hemorrhage within 36 hours of treatment. Safety monitoring and sample size calculations are designed so that enrollment will cease if the observed intracranial hemorrhage rate exceeds that reported with rt-PA treatment of stroke. Drug activity will be gauged by the proportion of patients with major early neurological improvement as determined by an 8 or more point improvement on the National Institutes of Health Stroke Scale or a perfect score of 0 at 24 hours after stroke onset. Outcome at 3 months will be assessed with the Barthel Index, the modified Rankin Sale, and a global outcome statistic to facilitate sample size calculations for subsequent studies. Sixty to 100 patients will be enrolled in dosage tiers of up to 25 patients each.