Zeenat Qureshi Stroke Institutes and Department of Neurology, University of Missouri, One Hospital Dr. CE507, Columbia, MO, 65212, USA.
Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH, USA.
Neurocrit Care. 2022 Apr;36(2):662-681. doi: 10.1007/s12028-021-01372-4. Epub 2021 Dec 23.
One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.
将新的治疗药物（自尼莫地平以来）引入治疗与动脉瘤性蛛网膜下腔出血（aSAH）相关的脑缺血面临的挑战之一是，在 II 期和随后的 III 期临床试验中观察到的治疗益处不一致。因此，有必要确定改进方法和解释结果的领域，以提高 II 期试验的价值。我们对继续进行 III 期试验的 II 期试验进行了系统评价，评估了一种治疗与 aSAH 相关的脑缺血的治疗药物。我们遵循系统评价和荟萃分析的首选报告项目指南进行了系统评价，该评价基于同行评审的方案（国际前瞻性注册系统评价号 222965）。共有 9 项涉及 7088 名患者的 III 期试验是基于 8 项涉及 1558 名患者的 II 期试验进行的。在选定的 II 期和 III 期试验中评估了以下治疗药物：静脉注射替拉扎特、静脉注射尼卡地平、静脉注射克拉生坦、静脉注射镁、口服他汀类药物和脑室注射尼莫地平。在 II 期 aSAH 试验中确定了几个设计要素的缺陷，这可能解释了 II 期和 III 期试验结果之间的不一致。我们建议考虑以下策略来改进 II 期设计：更加关注疗效替代标志物的选择、选择最佳剂量和干预时机、调整样本量计算中治疗效果的夸大估计、使用无效设计预设的是/否标准、使用多中心设计、丰富研究人群、使用同期对照或安慰剂组以及使用创新的试验设计，如无缝 II 期至 III 期设计。基于从以前的 II 期和 III 期试验组合中吸取的经验教训修改 II 期试验的设计，对于计划更有效的 III 期试验是必要的。
