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Randomized Controlled Trial
. 2025 Sep;66(9):3207-3218.
doi: 10.1111/epi.18460. Epub 2025 May 15.

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of focal seizures

Wesley T Kerr  1   2 , Leock Y Ngo  3   4 , Liang Zhu  5 , Anna Patten  6 , Jocelyn Y Cheng  5 , Lavanya Biju  1 , Jacqueline A French  7
Affiliations
Randomized Controlled Trial

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of focal seizures

Wesley T Kerr et al. Epilepsia. 2025 Sep.

Abstract

Objective: In traditionally designed randomized clinical trials of antiseizure medications, participants take a blinded treatment for a prespecified number of weeks, irrespective of continued seizures. The alternative design time to prerandomization monthly seizure count (T-PSC) allows participants to end the blinded treatment after an individually prespecified number of seizures, which shortens exposure to placebo and ineffective treatment. Previous reanalyses have shown that T-PSC replicated the efficacy conclusions of trials; therefore, we evaluated whether T-PSC also could replicate tolerability and safety conclusions.

Methods: We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from three blinded, placebo-controlled trials of perampanel for focal onset seizures (NCT00699972, NCT00699582, NCT00700310). We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs that prompted medication adjustment compared to those observed during the full-length trial.

Results: Of the 1480 participants in the three trials, 1093 experienced any TEAE, of whom 1006 (92%) had onset prior to T-PSC. When evaluating the differences in each type of TEAE for each dose of perampanel from placebo within each trial, there was no consistent pattern of under- or overestimation. Across the three studies, 23 of 79 (29%) serious TEAEs, most requiring hospitalization, occurred after T-PSC.

Significance: Almost all TEAEs occurred before T-PSC. Similar conclusions regarding the tolerability and safety of perampanel would have been reached if the T-PSC design had been used. This suggests that the T-PSC design may potentially benefit participants by allowing earlier change from an ineffective treatment to an alternate treatment, which could reduce the risk of serious consequences of ineffective treatment, such as hospitalization.

Keywords: clinical trials; epilepsy; survival analysis; time to event; trial design.

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Conflict of interest statement

W.T.K. has received compensation as Associate Editor of Epilepsia; writes review articles for Medlink Neurology; is a paid consultant for SK Life Sciences, the Epilepsy Study Consortium, UCB Pharmaceuticals, Cerebral Therapeutics, Jazz Pharmaceuticals, Neurelis, Ventus, Harmony, Epygenix, EpiTel, Neurona Therapeutics, and Biohaven Pharmaceuticals; and has collaborative or data use agreements with Eisai, Janssen, Johnson & Johnson, Radius Health, Glaxo‐Smith‐Kline, and Praxis. L.Y.N., L.Z., A.P., and J.Y.C. were employees of Eisai when this analysis was performed. J.A.F. 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, Arvelle Therapeutics, Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical, BioXcel Therapeutics, Bloom Science, BridgeBio Pharma, 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, Equilibre BioPharmaceuticals, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Phamaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Marck, NeuCyte, Neumirna Therapeutics, Neurocrine, Neuroelectives USA Corporation, Neuronetics, Neuropace, NxGen Medicine, Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics, Paladin Labs, Passage Bio, Pfizer, Praxis, PureTech LTY, Rafa Laboratories, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB, Ventus Therapeutics, Xenon, Xeris, Zogenix, and Zynerba. J.A.F. 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 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, Clinical Education Alliance, NeuCyte, Neurocrine, Praxis, and Xenon. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
The rate of any and of any treatment‐related treatment‐emergent adverse events (TEAEs) observed before time to exceed prerandomization monthly seizure count (T‐PSC; darker overlay) was comparable to the full‐length trial (colors). Symbols (*, +) denote statistical significance between perampanel and placebo groups based on Fisher exact tests (p < .05); + indicates significance using data prior to T‐PSC only, and * indicates significance using full‐length trial data.
FIGURE 2
FIGURE 2
The rate of serious or severe treatment‐emergent adverse events (TEAEs) observed before time to exceed prerandomization monthly seizure count (T‐PSC; darker overlay) was comparable to the full‐length trial (colors). Symbols (*, +) denote statistical significance between perampanel and placebo groups based on Fisher exact tests (p < .05); + indicates significance using data prior to T‐PSC only, and * indicates significance using full‐length trial data.
FIGURE 3
FIGURE 3
The rate of each specific treatment‐emergent adverse events (TEAEs) observed before time to exceed prerandomization monthly seizure count (T‐PSC; darker overlay) was comparable to the full‐length trial (colors). Symbols (*, +) denote statistical significance between perampanel and placebo groups based on Fisher exact tests (p < .05); + indicates significance using data prior to T‐PSC only, and * indicates significance using full‐length trial data.
FIGURE 4
FIGURE 4
The time to any treatment‐emergent adverse events (TEAEs) after the first treatment dose showing the almost identical results from the full‐length trial data as compared to TEAE data censored, or truncated, at the time to exceed prerandomization monthly seizure count (T‐PSC). The large vertical dashed line reflects the transition between titration (first 6 weeks) and maintenance treatment periods. Smaller vertical lines reflect when data were censored from this time to TEAE analysis. Smaller vertical lines reflect when data were censored from this time to TEAE analysis. Each small vertical line reflects one participant, and some overlap. Black censoring lines indicate study withdrawal unrelated to T‐PSC or TEAE. Colors reflect censoring of TEAE information due to simulated truncation at T‐PSC, where green indicates no TEAE occurred after T‐PSC and red indicates a TEAE started after T‐PSC.
See this image and copyright information in PMC

References

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