BACKGROUND/AIMS Showing "similar efficacy" of a less intensive treatment typically requires a non-inferiority trial. Yet such trials may be challenging to design and conduct. In acute promyelocytic leukemia, great progress has been achieved with the introduction of targeted therapies, but toxicity remains a major clinical issue. There is a pressing need to show the favorable benefit/risk of less intensive treatment regimens. METHODS We designed a clinical trial that uses generalized pairwise comparisons of five prioritized outcomes (alive and event-free at 2 years, grade 3/4 documented infections, differentiation syndrome, hepatotoxicity, and neuropathy) to confirm a favorable benefit/risk of a less intensive treatment regimen. We conducted simulations based on historical data and assumptions about the differences expected between the standard of care and the less intensive treatment regimen to calculate the sample size required to have high power to show a positive Net Treatment Benefit in favor of the less intensive treatment regimen. RESULTS Across 10,000 simulations, average sample sizes of 260 to 300 patients are required for a trial using generalized pairwise comparisons to detect typical Net Treatment Benefits of 0.19 (interquartile range 0.14-0.23 for a sample size of 280). The Net Treatment Benefit is interpreted as a difference between the probability of doing better on the less intensive treatment regimen than on the standard of care, minus the probability of the opposite situation. A Net Treatment Benefit of 0.19 translates to a number needed to treat of about 5.3 patients (1/0.19 ≃ 5.3). CONCLUSION Generalized pairwise comparisons allow for simultaneous assessment of efficacy and safety, with priority given to the former. The sample size required would be of the order of 300 patients, as compared with more than 700 patients for a non-inferiority trial using a margin of 4% against the less intensive treatment regimen for the absolute difference in event-free survival at 2 years, as considered here.

中文翻译：

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使用广义配对比较设计临床试验来测试强度较低的治疗方案。

背景/目的 显示较低强度治疗的“相似功效”通常需要非劣效性试验。然而，此类试验的设计和实施可能具有挑战性。在急性早幼粒细胞白血病中，随着靶向治疗的引入，已经取得了巨大进展，但毒性仍然是一个主要的临床问题。迫切需要证明强度较低的治疗方案的有利益处/风险。方法 我们设计了一项临床试验，对五种优先结果（2 年内存活且无事件、3/4 级记录的感染、分化综合征、肝毒性和神经病变）进行广义配对比较，以确认较小的治疗方案的有利获益/风险。强化治疗方案。我们根据历史数据和关于标准护理和较低强度治疗方案之间预期差异的假设进行了模拟，以计算具有高功效以显示有利于较低强度治疗方案的正净治疗效益所需的样本量。结果 在 10,000 次模拟中，使用广义配对比较的试验需要平均样本量为 260 至 300 名患者，以检测 0.19 的典型净治疗效益（样本量为 280 时四分位数范围为 0.14-0.23）。净治疗效益被解释为强度较低的治疗方案比标准护理效果更好的概率之间的差异，减去相反情况的概率。0.19 的净治疗效益意味着需要治疗约 5.3 名患者 (1/0.19 ≃ 5.3)。结论 广义配对比较可以同时评估疗效和安全性，并优先考虑前者。所需样本量约为 300 名患者，而非劣效性试验则需要 700 多名患者，相对于强度较低的治疗方案，2 年无事件生存期的绝对差异使用 4% 的裕度，如此处所考虑的。