Phase 2B Study of TNK in Acute Stroke

TNK 治疗急性中风的 2B 期研究

• 批准号: 7228595
• 负责人: Elliott CLARKE HALEY
• 金额: $ 66.09万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228595
• 关键词: Acute; Acute myocardial infarction; Adult; Alteplase; Animal Model; Caring; Cause of Death; Cessation of life; Controlled Clinical Trials; Data; Dose; Fibrin; Fibrinolytic Agents; Funding; Goals; Half-Life; Hemorrhage; Hour; Intracranial Hemorrhages; Intravenous; Ischemic Stroke; Morbidity - disease rate; Myocardial Infarction; Outcome; Patients; Phase; Phase III Clinical Trials; Plasminogen Inactivators; Population; Randomized; Rate; Research; Resistance; Safety; Site; Specificity; Stroke; Symptoms; Tenecteplase; Testing; Thrombolytic Therapy; United States; United States National Institutes of Health; acute stroke; cost; design; disability; improved; trial comparing

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（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卒中患者有效的治疗方法。尽管其有效性已得到证实，但rt-PA用于中风治疗的应用仍受到限制.虽然许多因素可能导致不愿意使用rt-PA治疗卒中，但rt-PA的一个潜在主要限制是与其使用相关的症状性颅内出血发生率为6.4%。一种出血率降低、疗效提高的更安全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。替奈普酶（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，已获批用于急性心肌梗死（MI）患者。在MI患者中，TNK与RT PA相比全身出血较少相关，并且在缺血性卒中的动物模型中，其可能与RT PA相比颅内出血较少相关。2000年6月，申请人开始了一项由美国国立卫生研究院资助的TNK在急性缺血性卒中患者中的剂量递增安全性试验研究。从选择与批准的rt-PA用于卒中的剂量具有生物等效性的初始剂量开始，在0.1 mg/kg和0.4 mg/kg之间测试了3个连续递增剂量的TNK，未观察到任何症状性颅内损害。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会相应减少。这些有希望的结果保证了进一步测试TNK在急性缺血性中风。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，在发病3小时内治疗的急性缺血性卒中患者中比较TNK与rt-PA。在整个试验中包含一项较小的II期B试验，该试验将a）选择适当剂量的TNK进行进一步研究; B）提供TNK与同期接受rt-PA治疗的人群相比的安全性的进一步证据;以及c）证实TNK与rt PA相比在减少急性缺血性卒中后不良结局方面的前景。

项目成果

Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.

• DOI: 10.1177/1740774511410582
• 发表时间: 2011-08
• 期刊: Clinical trials (London, England)
• 作者: Levin B;Thompson JL;Chakraborty B;Levy G;MacArthur R;Haley EC
• 通讯作者: Haley EC

Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.

• DOI: 10.1161/strokeaha.109.572040
• 发表时间: 2010-04
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Haley EC Jr;Thompson JL;Grotta JC;Lyden PD;Hemmen TG;Brown DL;Fanale C;Libman R;Kwiatkowski TG;Llinas RH;Levine SR;Johnston KC;Buchsbaum R;Levy G;Levin B;Tenecteplase in Stroke Investigators
• 通讯作者: Tenecteplase in Stroke Investigators