Hulshof Tessa A, Zuidema Sytse U, Janus Sarah I M, Luijendijk Hendrika J
University Medical Center Groningen, Department of General Practice, University of Groningen, Groningen, Netherlands.
Front Pharmacol. 2020 Feb 21;10:1701. doi: 10.3389/fphar.2019.01701. eCollection 2019.
A typical antipsychotics for neuropsychiatric symptoms in dementia have been tested in much larger trials than the older conventional drugs. The advantage of larger sample sizes is that negative findings become less likely and the effect estimates more precise. However, as sample sizes increase, the trials also get more expensive and time consuming while exposing more patients to drugs with unknown safety profiles. Moreover, a large sample size might yield a statistically significant effect that is not necessarily clinically relevant.
To assess (1) the variation in sample size and sample size calculations of antipsychotic trials in dementia, (2) the size of reported treatment effects and related statistical significance, and (3) general study characteristics that might be related to sample size.
We performed a meta-epidemiological study of randomized trials that tested antipsychotics for neuropsychiatric symptoms in dementia. The trials compared conventional or atypical antipsychotics with placebo or another antipsychotic. Two reviewers independently extracted sample size, sample size calculations, reported treatment effects with p-values, and general study characteristics (drug type, trial duration, type of funding). We calculated a reference sample size of 83 and 433 per study group for the placebo-controlled and head-to-head trials respectively.
We identified 33 placebo-controlled trials, and 18 head-to-head trials. Only 14 (42%) and 2 (11%), respectively, reported a sample size calculation. The average sample size per arm was 34 (range 6-179) in placebo-controlled trials testing conventional drugs, 107 (8-237) in such trials testing atypical drugs, and 104 (95-115) in such trials testing both drug types; it was 31 (10-88) in head-to-head trials. Thirteen out of 18 trials with sample sizes larger than required (72%) reported a statistically significant treatment effect, of which two (15%) were clinically relevant. None of the head-to-head trials reported a statistically significant treatment effect, even though some suggested non-inferiority. In placebo-controlled trials of atypical drugs, longer trial duration (>6 weeks) and commercial funding were associated with higher sample size.
Sample size calculations were poorly reported in antipsychotic trials for dementia. Placebo-controlled trials of atypical antipsychotics showed large sample size fallacy while head-to-head trials were massively underpowered.
用于治疗痴呆症神经精神症状的典型抗精神病药物已在比传统老药规模大得多的试验中进行了测试。更大样本量的优势在于阴性结果出现的可能性降低，效应估计更精确。然而，随着样本量增加，试验成本更高、耗时更长，同时让更多患者暴露于安全性未知的药物之下。此外，大样本量可能产生在统计学上有显著意义但不一定具有临床相关性的效应。
评估（1）痴呆症抗精神病药物试验样本量及样本量计算方法的差异，（2）报告的治疗效应大小及相关统计学显著性，（3）可能与样本量相关的一般研究特征。
我们对测试用于痴呆症神经精神症状的抗精神病药物的随机试验进行了一项元流行病学研究。这些试验将传统或非典型抗精神病药物与安慰剂或另一种抗精神病药物进行比较。两名评审员独立提取样本量、样本量计算方法、报告的治疗效应及P值，以及一般研究特征（药物类型、试验持续时间、资金类型）。我们分别计算出安慰剂对照试验和头对头试验每个研究组的参考样本量为83和433。
我们识别出33项安慰剂对照试验和18项头对头试验。分别只有14项（42%）和2项（11%）报告了样本量计算方法。在测试传统药物的安慰剂对照试验中，每组平均样本量为34（范围6 - 179），在测试非典型药物的此类试验中为107（8 - 237），在测试两种药物类型的此类试验中为104（95 - 115）；在头对头试验中为31（10 - 88）。18项样本量大于所需的试验中有13项（72%）报告了具有统计学显著性的治疗效应，其中两项（15%）具有临床相关性。头对头试验均未报告具有统计学显著性的治疗效应，尽管有些试验显示出非劣效性。在非典型药物的安慰剂对照试验中，试验持续时间较长（>6周）和商业资金支持与较大样本量相关。
痴呆症抗精神病药物试验中样本量计算方法的报告情况不佳。非典型抗精神病药物的安慰剂对照试验显示出大样本量谬误，而头对头试验的效能严重不足。
