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，从社会中榨取数十亿美元的医疗保健费用和工资损失，以及对受害者及其家人造成的无法估量的痛苦。最近，静脉注射重组组织型纤溶酶原激活剂（rt-PA）溶栓治疗可改善急性缺血性卒中患者的神经和功能结局，这些患者可在发病3小时内接受治疗。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。一种新的第二代血栓溶解药物TNK-TPA已经被特异性工程化为比rt-PA更具纤维蛋白特异性，并且已经在血栓形成的实验模型中显示出比rt-PA更有效和更快地起作用。在实验性中风中，脑血管凝块溶解更快，颅内出血的发生率降低。在心肌梗死的人体研究中，该药耐受性良好，治疗并发颅内出血的发生率并不高，可能低于rt-PA。该提案描述了一项在3小时内可接受治疗的急性缺血性卒中患者中开展的TNK-TPA多中心、开放标签、初步剂量递增安全性试验。待检验的主要假设是TNK-TPA可以安全地给予急性缺血性卒中患者，其剂量可能与神经学结局的改善相关。本研究的主要终点是治疗后36小时内症状性颅内出血的发生率。设计安全性监测和样本量计算，以便如果观察到的颅内出血率超过rt-PA治疗卒中报告的颅内出血率，则停止入组。药物活性将通过具有重大早期神经系统改善的患者比例来衡量，如通过在卒中发作后24小时在国立卫生研究院卒中量表上的8分或以上改善或0分的完美评分来确定。将使用Barthel指数、改良兰金销售和全球结局统计评估3个月时的结局，以便于后续研究的样本量计算。将入组60至100例患者，每个剂量层最多25例患者。

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.