Time to exceed pre-randomization monthly seizure count for perampanel in participants with primary generalized tonic-clonic seizures: A potential clinical end point

Abstract

Objective: To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy.

Methods: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial.

Results: The exploratory end point of median T-PSC on placebo was 43 days and >120 days on perampanel (log-rank p < .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel.

Significance: The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

Keywords: clinical trials; epilepsy; genetic generalized epilepsy; perampanel; primary generalized tonic-clonic seizures; time to event.

Conflict of interest statement

Dr. Kerr writes review articles for Medlink Neurology and has acted as a consultant for SK Life Science. Dr. Brandt has honoraria as a speaker or for consulting from Arvelle Therapeutics/Angelini Pharma, Desitin, Eisai, Equilibre Biopharmaceuticals, GW Pharmaceuticals, Idorsia, Janssen‐Cilag GmbH, Marinus Pharmaceuticals, UCB, Xenon Pharmaceuticals, and Zogenix. Drs. Ngo, Patten, Cheng, and Kramer are employees of Eisai, Inc or Eisai, Ltd. Dr. French receives salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Angelini Pharma S.p.A, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Camp4 Therapeutics Corporation, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Eisai, Eliem Therapeutics, Encoded Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc., Equilibre BioPharmaceuticals, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Phamaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Marck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuroelectives USA Corporation, Neuronetics Inc., Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Paladin Labs, Passage Bio, Pfizer, Praxis, Pure Tech LTY Inc., Rafa Laboratories Ltd, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Inc., Ventus Therapeutics, Xenon, Xeris, Zogenix, and Zynerba. Dr. French also has received research support from the Epilepsy Study Consortium (Funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, and Vogelstein Foundation), the Epilepsy Study Consortium/Epilepsy Foundation (Funded by UCB), GW/FACES, and the National Institute of Neurological Disorders and Stroke (NINDS). She is on the editorial board of Lancet Neurology and Neurology Today. She is Chief Medical/Innovation Officer of the Epilepsy Foundation. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Angelini Pharma S.p.A., Clinical Education Alliance, NeuCyte, Inc., Neurocrine, Praxis, and Xenon.

© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Kaplan–Meier time to end point curves with censoring starting with titration or maintenance for the time to first, second, or exceeding pre‐randomization monthly seizure count (PSC). + represents a censored observation. Abbreviation: PGTC, primary generalized tonic–clonic

FIGURE 2

Primary efficacy outcomes calculated at each of the time‐to‐event end points. Median percent reduction in seizure frequency (MPC) was calculated during titration and maintenance; 50% responder rate (50RR) was calculated during maintenance only. For MPC and 50RR during both treatment periods, see Figure S1. Error bars reflect 95% confidence intervals. Abbreviations: PBO, placebo; PER, perampanel; PGTC Sz, primary generalized tonic–clonic seizure

FIGURE 3

Individual level correspondence of 50% responder rate (50RR) using Cohen's kappa and median percent reduction in seizure frequency (MPC) using Spearman's rho when calculated at each of the time‐to‐event end points compared to the full‐length trial. Analogous to Figure S2. Abbreviations: PBO, placebo; PER, perampanel; PGTC Sz, primary generalized tonic–clonic seizure