Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.
Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design.
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DOI：
10.1177/1740774511410582
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Haley EC
中科院分区：
文献类型：
--
作者：
Levin B;Thompson JL;Chakraborty B;Levy G;MacArthur R;Haley EC
背景TNK-S2B是一种创新的、随机的、 替奈普酶与rt-PA用于 急性缺血性卒中，在监管批准前因入组缓慢而终止 II期患者在III期的使用。目的（1）审查试验设计和 全面的I类错误率模拟和（2）讨论提出的问题 在监管审查期间，以便于将来批准类似的设计。方法在II期，早期（24小时）的结果和 自适应序贯程序选择三种替奈普酶剂量中的一种用于阶段 与rt-PA比较。将该剂量与rt-PA进行比较的决策规则将 在II期结束时因无效而停药，或继续进入III期。相 III纳入了两个共同主要假设，允许治疗效果为 兰金量表的两端。假设没有提前终止， 对1908例患者进行的四项中期分析和一项最终分析提供了 实验方面的I类错误率<0.05。超过1，000个分布场景，每个场景 涉及40，000次重复，第三阶段的最大I类错误为0.038。 剂量选择引起的膨胀被一半的 检验统计量中的连续性校正。通货膨胀来自重复的中期 临床停止规则的减少超过了分析的抵消 在首次中期分析时无效。限制设计复杂性和不断发展 监管要求延长了审查过程。结论（1）本设计具有创新性， 高效.根据方案，I类错误在共同主要电极中得到良好控制 第三阶段假设检验和实验。(2a)必须留出时间 从第一个设计阶段开始与监管审查人员进行沟通。(2b)足够 必须证明I类错误控制。(2c)需要进一步澄清（i） 这是否包括I类错误控制的演示，如果协议是 违反和（ii）是否模拟类型I的错误控制是可接受的。 (2d)监管机构担心，无效停止的方案可能不会 可以通过向他们提交中期分析结果来缓解， 分析发生。
Background TNK-S2B, an innovative, randomized, seamless phase II/III trial of tenecteplase versus rt-PA for acute ischemic stroke, terminated for slow enrollment before regulatory approval of use of phase II patients in phase III. Purpose (1) To review the trial design and comprehensive type I error rate simulations and (2) to discuss issues raised during regulatory review, to facilitate future approval of similar designs. Methods In phase II, an early (24-h) outcome and adaptive sequential procedure selected one of three tenecteplase doses for phase III comparison with rt-PA. Decision rules comparing this dose to rt-PA would cause stopping for futility at phase II end, or continuation to phase III. Phase III incorporated two co-primary hypotheses, allowing for a treatment effect at either end of the trichotomized Rankin scale. Assuming no early termination, four interim analyses and one final analysis of 1908 patients provided an experiment-wise type I error rate of <0.05. Results Over 1,000 distribution scenarios, each involving 40,000 replications, the maximum type I error in phase III was 0.038. Inflation from the dose selection was more than offset by the one-half continuity correction in the test statistics. Inflation from repeated interim analyses was more than offset by the reduction from the clinical stopping rules for futility at the first interim analysis. Limitations Design complexity and evolving regulatory requirements lengthened the review process. Conclusions (1) The design was innovative and efficient. Per protocol, type I error was well controlled for the co-primary phase III hypothesis tests, and experiment-wise. (2a) Time must be allowed for communications with regulatory reviewers from first design stages. (2b) Adequate type I error control must be demonstrated. (2c) Greater clarity is needed on (i) whether this includes demonstration of type I error control if the protocol is violated and (ii) whether simulations of type I error control are acceptable. (2d) Regulatory agency concerns that protocols for futility stopping may not be followed may be allayed by submitting interim analysis results to them as these analyses occur.
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影响因子：
8.3
作者：
VANSWIETEN, JC;KOUDSTAAL, PJ;VANGIJN, J
通讯作者：
VANGIJN, J
DOI：
10.1073/pnas.78.8.4663
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-PHYSICAL SCIENCES
影响因子：
--
作者：
LEVIN, B;ROBBINS, H
通讯作者：
ROBBINS, H
影响因子：
8.3
作者：
Haley, EC;Lyden, PD;Hemmen, TM
通讯作者：
Hemmen, TM
影响因子：
8.3
作者：
Graham, GD
通讯作者：
Graham, GD
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