Authors :
Presenting Author: Lavanya Biju, BS – University of Pittsburgh Neurology
Katherine McFarlane, MS – University of Pittsburgh Department of Neurology
Advith Reddy, BS – University of Pittsburgh Neurology
Neo Kok, BS – University of Pittsburgh Department of Neurology
Jacqueline French, MD – Department of Neurology and Comprehensive Epilepsy Center, New York University Grossman School of Medicine, NYU Langone Health
Wesley Kerr, MD, PhD – University of Pittsburgh Neurology
Rationale:
Placebo-controlled randomized clinical trials for antiseizure medications for generalized tonic-clonic seizures typically evaluate efficacy in a 20-week pre-specified maintenance phase. The alternative Time to Pre-randomization monthly Seizure Count (T-PSC) can shorten exposure to placebo and ineffective treatment evaluating efficacy until the participant has the same number of seizures in the maintenance as their average monthly seizure frequency in the pre-randomization baseline. Re-analyses of typically designed trials with the T-PSC design have replicated the efficacy of treatment; but there is limited data demonstrating replication of the evaluation of tolerability and safety.
Methods:
Using data from 3 double-blind placebo-controlled trials of antiseizure medications for generalized-onset epilepsy (lamotrigine extended release NCT00104416, lamotrigine NCT00043901, levetiracetam NCT00160550), we evaluated the proportion of treatment emergent adverse effects (TEAE) that occurred prior to T-PSC compared to the full-length trial. We also used Fisher exact tests and Cox Proportional Hazards to evaluate if the difference in TEAE rate impacted comparisons between active treatment and placebo.
Results:
Of the 428 participants in the 3 trials, 243 (57%) were included in the safety analysis and experienced any TEAE. Of those 243 participants with any TEAE, 208 (86%) occurred prior to T-PSC (95% Confidence Interval 81-90%). Across all 3 trials, 5 of 29 (17%) of serious or severe TEAE occurred after T-PSC (95% Confidence Interval 11-53%). Not observing these TEAE did not change statistical comparisons in TEAE rate between active treatment and placebo. Conclusions:
As compared to the full-length trials, the T-PSC design applied to trials of generalized-onset seizures would have observed almost all TEAE. Similar conclusions regarding the tolerability and safety of these antiseizure medications would have been reached with the T-PSC design. The T-PSC may benefit participants by reducing exposure to placebo and ineffective treatment, which could reduce the risk of serious consequences of ineffective treatment including, but not limited to, serious or severe TEAE.
Funding:
US National Institute for Neurological Disorders and Stroke (NIH K23NS135134, R25NS089450, NIH U24NS107158), the American Epilepsy Society, the Epilepsy Foundation, the American Academy of Neurology, the American Brain Foundation, and the UPMC Competitive Medical Research Grant.