Factors determining placebo response in drug-resistant focal epilepsy

描述(由申请人提供)：临床试验构成了研究的黄金标准，为癫痫的治疗和药物审批过程提供了信息。不正确的试验设计或基于不正确假设的设计可能会导致错误的结论，并可能导致药物的滥用。在过去的20年里，辅助疗法AED试验的设计和进行的背景发生了深刻的变化。与这些变化相关的是观察到的应答率在研究期间和研究内的变异性增加，特别是观察到对安慰剂的反应增加，峰值高达40%。最近对辅助性抗癫痫药的随机对照试验的分析表明，随着时间的推移，对安慰剂的反应显著增加。高于假设的安慰剂应答率可能会混淆真实的治疗效果大小，可能导致研究中的AED未能 显示出效力。该项目的目标是在成人和儿童局灶性癫痫的AEDs的辅助随机临床试验中，确定与接受安慰剂随机治疗的患者的反应相关的因素。在与NINDS的合作下，国际抗癫痫联盟已经与一些制药公司达成了一项协议，这些公司已经表示对这个项目感兴趣，并愿意分享他们的试验信息。先前荟萃分析表明，多种因素可能是安慰剂应答率增加的原因。这些因素在不同程度上起到了作用。我们将探索三大类变量。在目标1中，我们将关注与患者相关的因素，在目标2中，我们将专注于特定于试验的因素，在目标3中，我们将关注与现场相关的因素。这个 进行癫痫临床试验的背景随着时间的推移而改变。为了设计最有效和最成功的试验，必须了解在设计阶段和进行试验时需要考虑哪些因素。这项拟议的研究将有助于了解这些因素，并将为设计新的耐药癫痫患者研究提供参考。

DESCRIPTION (provided by applicant): Clinical trials constitute the gold standard of research that informs treatment of epilepsy as well as the drug approval process. Improper trial design or a design based on incorrect assumptions could lead to the wrong conclusions and, potentially, to a misuse of the drug. The context in which adjunctive-therapy AED trials are designed and conducted has profoundly changed over the past 20 years. Associated with these changes is an observed increased variability in the responder rate both across and within studies and, in particular, an observed increased response to placebo with peaks as high as 40%. Recent analysis of randomized controlled trials of adjunctive AEDs showed that response to placebo has increased significantly over time. Higher than hypothesized placebo response rates can confound the true treatment effect size potentially resulting in failure of investigational AEDs to show efficacy. The goal of this project is to determine factors associated with response in patients randomized to placebo in adjunctive randomized clinical trials of AEDs in adults and children with focal epilepsy. In collaboration with the NINDS, the International League against Epilepsy has reached an agreement with a number of pharmaceutical companies who have expressed interest in this project and willingness to share information about their trials. Previou meta-analysis have suggested that multiple factors may be responsible for the increasing placebo response rates. These factors contribute at different levels. We will be exploring three major categories of variables. In Aim 1 we will be looking at patient-related factors, in Aim 2 we will focus on trial-specific factors and in Aim 3 we will be looking at site- related factors. The context in which clinical trials in epilepsy are conducted has changed over time. In order to design the most efficient and most successful trials it is essential to understand what factors need to be taken into consideration during the design phase and the conduct of the trial. The proposed study will help understand these factors and will inform the design of new studies in patients with drug resistant epilepsy.