Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.
Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.
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DOI：
10.1161/strokeaha.109.572040
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发表时间：
2010-04
期刊：
影响因子：
8.3
通讯作者：
Tenecteplase in Stroke Investigators
中科院分区：
文献类型：
--
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
静脉注射阿尔替普酶(rt-PA)仍然是唯一被批准的治疗急性缺血性中风的药物，但其使用仍然有限。在之前的一项试验性剂量递增研究中，静脉注射替替普利显示出作为一种潜在的更安全的替代方案的前景。因此，开始了一项IIB期临床试验，以a)选择最佳剂量的替替普酶继续进行，以及b)为进一步测试替替普酶与rt-PA的前景或徒劳提供证据。如果Promise成立，那么该试验将继续进行III期疗效试验，比较选定的替替普酶剂量和标准rt-PA。这项试验最初是一项小型、多中心、随机、双盲、对照临床试验，比较0.1、0.25和0.4 mg/kg替替普酶与标准0.9 mg/kg rt-PA对发病3小时内的急性中风患者的疗效。一项适应性序贯设计采用了早期(24小时)对主要神经功能改善与症状性颅内出血(ICH)发生率的评估，以选择“最佳”剂量的替替普酶继续使用。一旦确定了“最佳”剂量，试验将继续进行，直到至少100对选定的替替普酶剂量与标准rt-PA在中期分析中使用改良的Rankin分级法进行3个月的结果比较。制定决策规则是为了给出一个明确的建议，要么停止治疗，要么继续进入第三阶段。2006年至2008年，在8个临床中心只随机抽取了112名患者后，这项试验因招募缓慢而提前终止。在只有73名患者被随机选择后，0.4 mg/kg剂量被视为次要剂量，但在试验停止时，选择程序仍然无法区分0.1 mg/kg和0.25 mg/kg作为有利剂量。在其余替替普利组和rt-PA之间，3个月的结果没有统计学上有说服力的差异。丢弃替替普酶0.4 mg/kg组症状性脑出血发生率最高，0.1 mg/kg组最低(0/31)。既没有希望，也没有徒劳。这项过早终止的试验证明了一种新设计在为未来研究新的急性卒中溶栓剂选择有利剂量方面的潜在效率。考虑到试验的截短，对于未来替替普酶在急性卒中中的研究前景，还没有令人信服的结论。
Intravenous alteplase (rt-PA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to a) choose a best dose of tenecteplase to carry forward, and b) to provide evidence for either promise or futility of further testing of tenecteplase versus rt-PA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rt-PA. The trial began as a small, multi-center, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rt-PA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24 hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage (ICH) to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rt-PA could be compared by 3 month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4 mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3 month outcomes between the remaining tenecteplase groups and rt-PA. Symptomatic ICH rates were highest in the discarded 0.4 mg/kg tenecteplase group and lowest (0/31) in the 0.1 mg/kg tenecteplase group. Neither promise nor futility could be established. This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.