BACKGROUND Phase III trials often require large sample sizes, leading to high costs and delays in clinical decision-making. Group sequential designs can improve trial efficiency by allowing for early stopping for efficacy and/or futility and thus may decrease the sample size, trial duration and associated costs. Bayesian approaches may offer additional benefits by incorporating previous information into the analyses and using decision criteria that are more practically relevant than those used in frequentist approaches. Frequentist group sequential designs have often been used for phase III studies, but the use of Bayesian group sequential designs is less common. The aim of this work was to explore how Bayesian group sequential designs could be constructed for phase III trials conducted in emergency medicine. METHODS The PARAMEDIC2 trial was a phase III randomised controlled trial that compared the use of adrenaline to placebo in out-of-hospital cardiac arrest patients on 30-day survival rates. It used a frequentist group sequential design to allow early stopping for efficacy or harm. We constructed several alternative Bayesian group sequential designs and studied their operating characteristics via simulation. We then virtually re-executed the trial by applying the Bayesian designs to the PARAMEDIC2 data to demonstrate what might have happened if these designs had been used in practice. RESULTS We produced three alternative Bayesian group sequential designs, each of which had greater than 90% power to detect the target treatment effect. A Bayesian design which performed interim analyses every 500 patients recruited produced the lowest average sample size. Using the alternative designs, the PARAMEDIC2 trial could have declared adrenaline superior for 30-day survival with approximately 1500 fewer patients. CONCLUSIONS Using the PARAMEDIC2 trial as a case study, we demonstrated how Bayesian group sequential designs can be constructed for phase III emergency medicine trials. The Bayesian framework enabled us to obtain efficient designs using decision criteria based on the probability of benefit or harm. It also enabled us to incorporate information from previous studies on the treatment effect via the prior distributions. We recommend the wider use of Bayesian approaches in phase III clinical trials. TRIAL REGISTRATION PARAMEDIC2 Trial registration ISRCTN, ISRCTN73485024. Registered 13 March 2014, http://www.isrctn.com/ISRCTN73485024.

中文翻译：

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III 期急诊医学试验的贝叶斯组序贯设计：使用 PARAMEDIC2 试验的案例研究。

背景 III 期试验通常需要大样本量，导致高成本和临床决策延迟。组序设计可以通过允许提前停止有效性和/或无效性来提高试验效率，从而可以减少样本量、试验持续时间和相关成本。贝叶斯方法可以通过将先前的信息纳入分析并使用比频率论方法中使用的更实际相关的决策标准来提供额外的好处。频繁组序列设计经常用于 III 期研究，但贝叶斯组序列设计的使用不太常见。这项工作的目的是探索如何为急诊医学中进行的 III 期试验构建贝叶斯组序贯设计。方法 PARAMEDIC2 试验是一项 III 期随机对照试验，比较了在院外心脏骤停患者中使用肾上腺素与安慰剂对 30 天生存率的影响。它使用了常客群体顺序设计，以允许提前停止以提高疗效或伤害。我们构建了几个备选的贝叶斯群序列设计，并通过仿真研究了它们的操作特性。然后，我们通过将贝叶斯设计应用于 PARAMEDIC2 数据来虚拟地重新执行试验，以证明如果这些设计在实践中使用可能会发生什么。结果 我们产生了三种可供选择的贝叶斯组序贯设计，每一种都具有大于 90% 的功效来检测目标治疗效果。每招募 500 名患者进行中期分析的贝叶斯设计产生的平均样本量最低。使用替代设计，PARAMEDIC2 试验可以宣布肾上腺素在 30 天的生存期中具有优势，大约减少了 1500 名患者。结论 使用 PARAMEDIC2 试验作为案例研究，我们展示了如何为 III 期急诊医学试验构建贝叶斯组序贯设计。贝叶斯框架使我们能够使用基于受益或伤害概率的决策标准来获得有效的设计。它还使我们能够通过先前的分布整合来自先前研究的关于治疗效果的信息。我们建议在 III 期临床试验中更广泛地使用贝叶斯方法。TRIAL REGISTRATION PARAMEDIC2 试用注册 ISRCTN，ISRCTN73485024。