Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

BACKGROUND AND OBJECTIVES: Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS: A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS: The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION: These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Increasing challenges to trial recruitment and conduct over time.

OBJECTIVE: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time. METHODS: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability. RESULTS: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20). SIGNIFICANCE: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.