Phase 2B Study of TNK in Acute Stroke

TNK 治疗急性中风的 2B 期研究

• 批准号: 6776137
• 负责人: Elliott CLARKE HALEY
• 金额: $ 111.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776137
• 关键词: behavior test; cardiovascular disorder chemotherapy; cerebral hemorrhage; cerebral ischemia /hypoxia; clinical research; clinical trial phase II; computed axial tomography; dosage; drug adverse effect; drug screening /evaluation; electrocardiography; fibrin; human subject; human therapy evaluation; intravenous administration; myocardial infarction; outcomes research; patient oriented research; pharmacokinetics; plasminogen activator; plasminogen activator inhibitors; stroke; transient ischemic attack

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.

描述(申请人提供)：中风是美国第三大致死原因和成人残疾的主要原因。到目前为止，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中风患者有效的治疗方法。尽管rt-PA已被证实有效，但它在中风治疗中的使用一直受到限制。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其使用相关的6.4%的症状性颅内出血。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的发病率和护理成本。替替普酶(TNK)是一种半衰期更长、纤维蛋白特异性更强、对纤溶酶原激活物抑制物-I(PAI-I)抵抗增加的改良rt-PA，已被批准用于急性心肌梗死(MI)患者。在心肌梗塞患者中，TNK与RT-PA相比全身出血较少，在缺血性卒中动物模型中，TNK可能与较RT-PA更少的颅内出血有关。2000年6月，申请者开始了一项由美国国立卫生研究院资助的TNK在急性缺血性中风患者中的试点剂量递增安全性研究。从选择与批准的rt-PA治疗中风剂量生物等效的初始剂量开始，连续3次递增剂量的TNK在0.1 mg/kg到0.4 mg/kg之间进行测试，没有观察到任何症状性颅内出血。三个月的结果数据表明，与秋明疗法相关的严重残疾和死亡可能会相应减少。这些有希望的结果值得进一步检测TNK在急性缺血性卒中中的应用。本文概述的方案描述了一项大型、多中心、随机对照临床试验，比较了TNK和rt-PA在发病3小时内接受治疗的急性缺血性中风患者的疗效。整个试验中嵌入的是一项规模较小的2B期试验，该试验将a)选择适当剂量的秋水仙素进行进一步研究；b)提供进一步证据，证明与同时治疗的rt-PA人群相比，秋水仙素是安全的；以及c)证实与rt PA相比，秋水仙素在减少急性缺血性中风后不良结局方面的前景。