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.
It is becoming increasingly difficult to conduct clinical trials in patients with drug-resistant epilepsy. High placebo response rates jeopardize the successful assessment of new therapies. The proposed study will help understand these factors and will inform the design of more rigorous studies in a population of patients at significant need for new and effective therapies.