Inserm U1153 Team METHODS, University Paris Descartes, Service Hospitalo-Universitaire de Psychiatrie, Centre Hospitalier Sainte-Anne, Paris, France.
Meta-research Innovation Center (METRICS), Stanford University, Palo Alto, California.
Int J Methods Psychiatr Res. 2019 Sep;28(3):e1779. doi: 10.1002/mpr.1779. Epub 2019 Apr 17.
To evaluate the impact of controllable design factors on the power of antidepressants trials.
Using clinical trial simulation (CTS), we analyzed the combined impact on the power of trials of controllable design factors (sample size, outcome metrics, and disease severity at inclusion) and uncontrollable parameters (heterogeneity of diseases labeled "depression" in the source population and selective effects of drugs on items of the Hamilton Depression Rating Scale [HDRS], the most used outcome measurement tool). We elaborated 3,840 scenarios calibrated with real data, particularly the publication bias-corrected effect size.
For an effect size of 0.26, simulations revealed that in trials with ≤650 participants, power was less than 80%. Among the tested outcome metrics, the "remission" outcome provided more robustness for sample heterogeneity, whereas the continuous outcome "HDRS changes" provided more robustness when investigating drugs with a selective effect on the HDRS items. For the "remission" outcome, the power of trials increased with increasing HDRS threshold at inclusion but decreased with the outcomes "response" and "HDRS changes. Drugs with a selective effect on the HDRS items could not reach the same power as for the reference drug.
Our study allows for drawing recommendations to avoid underpowered trials of antidepressants.
评估可控设计因素对抗抑郁药试验效力的影响。
采用临床试验模拟（CTS），我们分析了可控设计因素（样本量、结局指标和纳入时疾病严重程度）和不可控参数（源人群中被标记为“抑郁”的疾病异质性以及药物对汉密尔顿抑郁评定量表[HDRS]项的选择性作用，这是最常用的结局测量工具）对试验效力的综合影响。我们详细阐述了 3840 个基于真实数据校准的情景，特别是发表偏倚校正的效应量。
对于 0.26 的效应量，模拟显示，在≤650 名参与者的试验中，效力小于 80%。在测试的结局指标中，“缓解”结局对样本异质性提供了更高的稳健性，而“HDRS 变化”的连续结局在研究对 HDRS 项具有选择性作用的药物时提供了更高的稳健性。对于“缓解”结局，随着纳入时 HDRS 阈值的升高，试验的效力增加，但随着结局“反应”和“HDRS 变化”的增加而降低。对 HDRS 项具有选择性作用的药物无法达到与参比药物相同的效力。
我们的研究可以为避免抗抑郁药试验效力不足提供建议。
