Time to Prerandomization Seizure Count Demonstrated Efficacy of Levetiracetam, Lacosamide, Lamotrigine, and Brivaracetam with Less Placebo Exposure
Abstract number :
1.287
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2023
Submission ID :
391
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Wesley Kerr, MD, PhD – University of Pittsburgh
Neo Kok, BA – University of Michigan; Advith Reddy, BA – University of Michigan; William Stacey, MD, PhD – University of Michigan; John Stern, MD – University of California Los Angeles; Page Pennell, MD – University of Pittsburgh; Jacqueline French, MD – New York University
Rationale: Parallel assignment randomized clinical trials (RCTs) are the mainstay to evaluate the efficacy of novel treatments for epilepsy, but their design has not changed in decades. Static assignment of participants to placebo or ineffective treatment confers risk, including an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). We evaluated if the modern Time to Pre-randomization Seizure Count (T-PSC) design could replicate the efficacy conclusions of numerous RCTs while also reducing exposure to placebo and ineffective treatment.
Methods:
We applied the T-PSC design to nine double-blind RCTs of adjunctive antiseizure medications (ASMs) for epilepsy including levetiracetam, brivaracetam, lacosamide, and lamotrigine for either focal- or generalized-onset epilepsy. For each trial and in a meta-analysis across trials, we re-calculated the primary efficacy endpoints of median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC compared to the full-length trial. We compared the individual-participant level correspondence of efficacy at T-PSC to the full-length trial using Spearman’s Rho and Cohen’s Kappa.
Results:
For each trial and ASM dose, using a T-PSC design re-demonstrated efficacy of active treatment. Overall, 89% and 92% of the group-level effect size of MPR and 50RR, respectively, were reproduced at T-PSC (95% confidence intervals: MPR 61-117%, 50RR 60-124%). Individual participant efficacy also corresponded at T-PSC (Cohen’s Kappa 83%, Spearman’s Rho 82%). These trials would have been 41% shorter with a T-PSC design.
Conclusions:
This re-analysis of nine RCTs with 3,422 combined participants demonstrated that observation until T-PSC was sufficient to demonstrate both group-level and individual-level treatment efficacy, while also improving participant safety by reducing exposure to placebo and ineffective treatment. Across all nine trials, the T-PSC design would have shortened observation by 300 participant-years, which if included switching participants from placebo to active treatment, would be expected to avoid 1.8 cases of SUDEP.
Funding: National Institute for Neurological Disorders and Stroke (NIH R25NS089450, NIH U24NS107158), the American Epilepsy Society, the Epilepsy Foundation, the American Academy of Neurology, the American Brain Foundation.
Anti-seizure Medications