Phase 2B Study of TNK in Acute Stroke

描述（由申请人提供）：中风是美国第三大死亡原因和成人残疾的主要原因。迄今为止，重组组织型纤溶酶原激活剂（rt-PA）静脉溶栓治疗是唯一被证明对缺血性脑卒中患者有效的治疗方法。尽管其疗效已被证实，但rt- PA在中风治疗中的应用仍受到限制。虽然许多因素可能导致不愿使用rt-PA治疗中风，但rt-PA的一个潜在主要限制是与使用相关的6.4%的症状性颅内出血率。一种更安全、出血率更低、疗效更好的药物可能会得到更广泛的使用，从而进一步降低患者发病率和护理成本。Tenecteplase （TNK）是一种改良的rt-PA，半衰期更长，纤维蛋白特异性更强，对纤溶酶原激活物抑制剂-I （PAI-I）的耐药性增加，已被批准用于急性心肌梗死（MI）患者。在心肌梗死患者中，TNK比rt PA与更少的全身性出血相关，在缺血性卒中动物模型中，TNK可能比rt PA与更少的颅内出血相关。2000年6月，申请人开始了一项由美国国立卫生研究院（National Institutes of health）资助的秋明明在急性缺血性卒中患者中的剂量递增安全性试验研究。从选择的初始剂量与脑卒中的批准剂量rt- pa生物等效开始，在0.1 mg/kg和0.4 mg/kg之间测试了3次连续递增剂量的TNK，未观察到任何症状性颅内出血。三个月的结果数据表明，与TNK治疗相关的严重残疾和死亡可能相应减少。这些有希望的结果为进一步测试TNK在急性缺血性卒中中的作用提供了依据。本文概述的提案描述了一项大型，多中心，随机对照临床试验，比较TNK和rt-PA在发病3小时内治疗的急性缺血性卒中患者中的疗效。在整个试验中包含一个较小的2B期试验，该试验将a)选择适当剂量的TNK进行进一步研究；b)与同时治疗的rt-PA人群相比，提供进一步的证据证明TNK的安全性；c)与rt PA相比，确认TNK在减少急性缺血性卒中后不良预后方面的前景。

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and leading cause of adult disability in the United States. To date, intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is the only treatment proven to be effective for patients with ischemic stroke. Despite its proven efficacy, the use of rt- PA for stroke treatment has been limited. While many factors may contribute to the reluctance to use rt-PA for stroke treatment, one potentially major limitation of rt-PA is the 6.4% rate of symptomatic intracranial hemorrhage associated with its use. A safer agent with a reduced rate of hemorrhage and with improved efficacy might enjoy more widespread use, with resulting further reductions in patient morbidity and costs of care. Tenecteplase (TNK) is a modified rt-PA with a longer half-life, greater fibrin specificity, and increased resistance to plasminogen activator inhibitor - I (PAI-I) that has been approved for use in patients with acute myocardial infarction (MI). In MI patients, TNK is associated with less systemic bleeding than rt PA, and in an animal model of schemic stroke, it may be associated with less intracranial bleeding than rt PA. In June, 2000, the applicants began a National Institutes of Health-funded pilot dose escalation safety study of TNK in patients with acute ischemic stroke. Beginning with an initial dose chosen to be bioequivalent to the approved dose ofrt-PA for stroke, 3 sequential escalating doses of TNK were tested between 0.1 mg/kg and 0.4 mg/kg without any symptomatic intracranial hemorrhages being observed. Three month outcome data suggest that there may be a corresponding reduction in severe disability and death associated with TNK treatment. These promising results warrant further testing of TNK in acute ischemic stroke. The proposal outlined herein describes a large, multi-center, randomized controlled clinical trial comparing TNK to rt-PA in patients with acute ischemic stroke treated within 3 hours of onset. Embedded within the overall trial is a smaller, Phase 2B trial that will a) select the proper dose of TNK to carry forward for further study; b) provide further evidence of the safety of TNK compared to a contemporaneously treated rt-PA population; and c) confirm the promise of TNK compared to rt PA in reducing poor outcomes following acute ischemic stroke.