PILOT STUDY OF TNK-TPA IN ACUTE ISCHEMIC STROKE

缺血性中风仍然是一个重大的公共卫生问题，给社会造成了数十亿美元的医疗费用和工资损失，并给受害者及其家人带来了无法估量的痛苦。近年来，重组组织型纤溶酶原激活剂(rt-PA)静脉溶栓治疗可以改善发病3h的急性缺血性卒中患者的神经功能预后。然而，rt-PA治疗并发症状性颅内出血的风险为6.4%，39%的患者在接受治疗后死亡或严重残疾。一种新的第二代溶栓药物TNK-TPA已经被特异性地设计为比rt-PA更具纤维蛋白特异性，并且在血栓形成的实验模型中被证明比rt-PA更有效和更快地起作用。在实验性卒中中，脑血管血栓溶解更快，颅内出血的发生率降低。在心肌梗死的人体研究中，该药物耐受性良好，治疗过程中并发颅内出血的发生率并不高于rt-PA，而且可能低于rt-PA。这项建议描述了一项多中心、开放标签、试点剂量递增的TNK-TPA在急性缺血性中风患者中的安全性试验，这些患者可以在3小时内得到治疗。需要检验的主要假设是，TNK-TPA可以安全地应用于急性缺血性中风患者，剂量可能与改善神经预后有关。这项研究的主要终点将是治疗36小时内出现症状性颅内出血的发生率。安全性监测和样本量计算的设计使得，如果观察到的颅内出血率超过报道的rt-PA治疗中风的比率，登记将停止。药物活性将通过早期神经功能有重大改善的患者的比例来衡量，这一比例由美国国立卫生研究院中风评分标准中改善8分或更多分或中风发病后24小时满分为0来确定。3个月后的结果将使用Barthel指数、修正的Rankin Sale和全球结果统计进行评估，以便于后续研究的样本量计算。60至100名患者将参加每个最多25名患者的剂量层级。

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.