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.

Time‐to‐event clinical trial designs: Existing evidence and remaining concerns

“…When this time‐to‐PSC design was used, sufficient seizures were observed so that the efficacy conclusions were unchanged, despite shortening observation duration. When comparing percent reduction in seizure frequency and 50% responder rate at time‐to‐PSC to the full‐length trial, there was more than 90% and 80% correspondence on an individual participant level, respectively 29 . Using simulated data, the time‐to‐PSC outcome had similar power and total trial cost to the percent reduction in seizure frequency, and both approaches were superior to 50% responder rate 33 …”

“…In traditionally designed trials, more than 80% of participants opted for open‐label extension; therefore the risk of withdrawing effective treatment is low 15–28 . Treatment efficacy can be measured using Cox‐proportional hazards models, proportion of failures, and the traditional primary efficacy endpoints of percent reduction in seizure frequency and 50% responder rate 29 . These latter primary efficacy endpoints are calculated to the “event” of interest, similar to the last observation carried forward method for addressing missing data that is used within trials commonly.…”

“…The evidence supporting time‐to‐Nth trials focuses on re‐analysis of traditionally designed trials for adjunctive ASMs plus the trial of lacosamide that used the endpoint of time‐to‐second primary generalized tonic–clonic (PGTC) seizure 14,29–31 . Most retrospective evidence supports the time‐to‐PSC design, where each participant is observed until their seizure count post‐randomization exceeds their individual baseline average monthly seizure count (Figure 2).…”

“…In pediatric epilepsies like the application of time‐to‐PSC used to evaluate the efficacy of fenfluramine for Dravet syndrome, baseline seizure frequencies were high enough that numerous seizures were observed prior to the TTE endpoint (median 26/month) 32 . In contrast, the perampanel trial for primary generalized tonic–clonic seizures included seizure frequencies as low as 1 per month (median 2.6/month) and the TTE reanalysis re‐demonstrated efficacy 29 . These two applications reflect epilepsies that are particularly suitable for a TTE design because of the high risk of SUDEP, clearly identifiable clinical correlate of myoclonic or generalized tonic–clonic seizures, and sufficient baseline seizure frequency.…”

“…[15][16][17][18][19][20][21][22][23][24][25][26][27][28] can be measured using Cox-proportional hazards models, proportion of failures, and the traditional primary efficacy endpoints of percent reduction in seizure frequency and 50% responder rate. 29 These latter primary efficacy endpoints are calculated to the "event" of interest, similar to the last observation carried forward method for addressing missing data that is used within trials commonly.…”