Khan Arif, Fahl Mar Kaysee, Schilling Joshua, Brown Walter A
Northwest Clinical Research Center, Bellevue, WA, USA; Department of Psychiatry, Duke University School of Medicine, Durham, NC, USA.
Northwest Clinical Research Center, Bellevue, WA, USA.
Contemp Clin Trials. 2018 Jan;64:95-100. doi: 10.1016/j.cct.2017.10.017. Epub 2017 Oct 31.
This study aimed to replicate and extend the findings of previous investigations looking at treatment responses in antiepileptic clinical trials over time and to examine the effects of subject age and duration of treatment. To address the potential biases of published literature, we examined the reported data from 14 investigational antiepileptic drugs (AEDs) (34 trials, 59 treatment arms, 10,783 patients) reviewed and approved by the US FDA (1996-2016). For each treatment arm, we recorded drug and placebo response (percent reduction in seizure frequency), calculated effect sizes, and examined these measures over time. Regression analysis showed that placebo response has increased significantly over time (R=0.292, p=0.001) from 5% to 20% reduction in seizure frequency in 20years. Response to drug treatment appears to have increased in parallel but the trend was not statistically significant (p=0.143). Effect sizes have remained stable over time (p=0.084). Treatment duration was not related to treatment response or outcomes. Including younger patients in trials appeared to predict lower drug response (β=1.44, p=0.012) and effect size (β=0.014, p=0.047) but not placebo response (p=0.141). These FDA-reviewed and source-verified data support and extend prior findings from published literature that response to placebo treatment is noticeably increasing over time, nearly quadrupling in magnitude, while AED efficacy remains the same due to a parallel increase in drug response. The rise in placebo response appears to be an ongoing phenomenon rather than a mere historical artifact. Future design and interpretation of data from clinical trials of investigational antiepileptic drugs can be informed by these observations.
本研究旨在复制并扩展以往关于抗癫痫临床试验中治疗反应随时间变化的研究结果，并探讨受试者年龄和治疗持续时间的影响。为解决已发表文献的潜在偏差，我们研究了美国食品药品监督管理局（FDA）（1996 - 2016年）审查并批准的14种抗癫痫药物（AEDs）（34项试验，59个治疗组，10783名患者）的报告数据。对于每个治疗组，我们记录了药物和安慰剂反应（癫痫发作频率降低的百分比），计算了效应大小，并随时间检查这些指标。回归分析表明，安慰剂反应随时间显著增加（R = 0.292，p = 0.001），在20年中癫痫发作频率从降低5%增加到降低20%。药物治疗反应似乎也平行增加，但趋势无统计学意义（p = 0.143）。效应大小随时间保持稳定（p = 0.084）。治疗持续时间与治疗反应或结果无关。在试验中纳入年轻患者似乎预示着较低的药物反应（β = 1.44，p = 0.012）和效应大小（β = 0.014，p = 0.047），但与安慰剂反应无关（p = 0.141）。这些经FDA审查和来源验证的数据支持并扩展了已发表文献中的先前发现，即随着时间推移，安慰剂治疗反应显著增加，幅度几乎增加了四倍，而由于药物反应的平行增加，AED疗效保持不变。安慰剂反应的增加似乎是一个持续的现象，而不仅仅是一个历史假象。这些观察结果可为未来抗癫痫药物临床试验数据的设计和解释提供参考。
