Time-to-Event Design in Clinical Trials and Efficacy of Anti-Epileptic Drugs at Group and Individual Levels

Background

The significance of anti-epileptic drugs (ASM) in treating refractory epilepsy cannot be ignored. However, the current parallel assignment, randomized, placebo-controlled trial (RCT) designs have been in use for many years, requiring participants to undergo a maintenance period of 3 to 5 months. This can pose significant risks, including prolonged exposure to placebo or ineffective treatments, potentially increasing the incidence of adverse events and even death. Therefore, developing a trial design that can reduce participant exposure time is a pressing issue.

Study Source

This paper is authored by Wesley T. Kerr, MD, PhD, and his team, including Neo Kok, BS, Advith S. Reddy, BS, Katherine N. McFarlane, MS, John M. Stern, MD, Page B. Pennell, MD, William Stacey, MD, PhD, and Jacqueline French, MD. The research team is affiliated with the University of Pittsburgh, University of Michigan, University of California, Los Angeles, and New York University Grossman School of Medicine. This study was published in the August 2024 issue of Neurology.

Research Methods

The study selected 11 double-blind, placebo-controlled anti-epileptic drug trials, including levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine. These trials primarily involved patients with focal seizures and generalized seizures.

Workflow

The study included the following steps:

1. Trial Selection: Eleven previously completed double-blind, placebo-controlled trials were re-analyzed, involving a total of 3,619 patients.
2. Testing Method: Time to Pre-Randomization Monthly Seizure Count (T-PSC) was used as the primary endpoint to evaluate the time taken for each patient to reach their individual baseline seizure frequency.
3. Experimental Method: A mixed-effects Cox proportional hazards model was used to analyze the data, including median percent reduction (MPR), 50% response rate (50RR), and time to first and second seizure.

Data Analysis Methods

The study used SAS and R software for data analysis, primarily employing Cox regression analysis to assess treatment effects, combined with analysis of variance (ANCOVA), Fisher’s exact test, and Cochran-Mantel-Haenszel test methods. The raw data from each trial were obtained and de-identified.

Study Results

Main Results

Of the 11 trials, 10 had their primary efficacy results consistent with traditional trial designs when using the T-PSC design (the only exception being the lamotrigine trial with a high placebo response rate). The advantage of the T-PSC design was evident in reducing the total treatment time by 40% while only decreasing the MPR by 10% and the 50RR by 15%.

Data Support

• Median Percent Reduction (MPR): 90% of the MPR was observed at the T-PSC endpoint (95% confidence interval of 73%-113%), and further analysis of individual trial data supported this conclusion.
• 50% Response Rate (50RR): 85% of the 50RR was observed under the T-PSC design (95% confidence interval of 65%-110%).
• Time Reduction: Blinded treatment time was reduced by at least 312 participant years, equivalent to a 60% reduction in total seizure counts.

Individual-Level Efficacy Analysis

Spearman correlation analysis (Spearman ρ) and Cohen’s kappa coefficient were used to analyze individual-level data, showing that in most cases (over 80%), the T-PSC endpoint correlated with efficacy results throughout the trial period.

Study Conclusions

The new time-to-event (TTE) trial design, particularly the T-PSC endpoint, demonstrated that reducing treatment time to an appropriate efficacy observation can effectively lower treatment risks while maintaining high efficacy. Although the overall efficacy size did not significantly decrease for the 3,619 participants covered, the new trial design significantly reduced exposure to placebo and ineffective treatments, enhancing participant safety and trial recruitment potential. Further research is needed to determine whether the T-PSC design can achieve safety conclusions consistent with traditional designs regarding adverse events.

Study Highlights

• Innovative Design: The T-PSC design reduced the total exposure time of trial participants and, in most cases, maintained efficacy evaluation consistency with traditional designs.
• Addressing Pain Points: Significantly reduced placebo exposure and ineffective treatment time, facilitating participant recruitment.
• Data Support: Provided strong evidence through re-analysis of 11 RCTs, showing that the T-PSC design can effectively maintain efficacy evaluation consistency in most cases.

Significance

This study provides a new option for future clinical trial designs for anti-epileptic drugs, preserving the accuracy of efficacy evaluations while significantly reducing participant risks. It is expected to improve the recruitment and success rates of clinical trials. This research has important scientific and clinical applications and has far-reaching implications for improving the design of anti-epileptic drug trials.