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

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.