Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (-0.80 vs. -0.84 T40, -0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.

中文翻译：

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高剂量他莫昔芬和肌酸治疗肌萎缩性侧索硬化症的选择设计II期试验。

目的：使用分级和选择范式进行II期试验，在该试验中，将多种治疗方法与有限的样本量进行比较，然后选择最佳方法进行后续疗效试验（与安慰剂相比）。与对安慰剂进行较大试验的传统策略相比，该策略可以更快地找到有效的治疗方法。方法：将60名肌萎缩性侧索硬化症（ALS）参与者按1：1：1的比例随机分配至肌酸30克/天（CRE），他莫昔芬40毫克/天（T40）或他莫昔芬80毫克/天（T80），并配以安慰剂。主要结果是修订的ALS功能评定量表（ALSFRS-R）发生了38周的变化，并通过重复测量方差分析进行了分析。次要结果包括缓慢的肺活量（SVC），定量肌肉力量，早期停药（EDD），不良事件（AEs）和生存期。结果：CRE参与者经历了较高的药物相关AEs（82％比43％T40，47％T80）和EDD（50％比24％T40，29％T80）。T80参与者的ALSFRS-R调整后平均下降点/月（-0.80对-0.84 T40，-0.85 CRE）和定量肌力较慢，但SVC却没有，死亡率更高。结论：就ALSFRS-R下降而言，T80的疗效在数值上优于CRE和T40。遵循选择范例，将选择T80进行安慰剂测试。该方法并非旨在区分几乎相同有效或无效的治疗方法。如果处理是等效的，则在该范式下，选择哪种处理都没有关系。新型的提高试验效率的方法，包括自适应平台试验设计，