Authors :
Presenting Author: Leock Y Ngo, PhD – Pharma Industry
Presenting Author: Leock Y Ngo, PhD – Pharma Industry
Presenting Author: Leock Y Ngo, PhD – Pharma Industry
Presenting Author: Leock Y Ngo, PhD – Pharma Industry
Liang Zhu, PhD – Biostatistics – Eisai; Anna Patten, PhD – Biostatistics – Eisai; Jocelyn Cheng, MD – Neurology – Eisai; Jacqueline French, MD – Neurology – New York University Grossman School of Medicine; Wesley kerr, MD, PhD – Neurology – University of Pittsburgh
Rationale:
Parallel‑group randomized clinical trials (RCTs) are the mainstay to evaluate the efficacy of novel treatments for epilepsy, but their design has not changed in decades. Static assignment of participants to placebo or ineffective treatment confers risk, including an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). In the alternative Time to Pre-randomization monthly Seizure Count (T-PSC) design, participants’ response to blinded treatment is measured until they either have the same or more seizures than their average pre-randomization monthly seizure count (PSC) or reach the standard 12-week maintenance period, whichever happens first. This T-PSC design has shown promise to replicate the efficacy conclusions of numerous RCTs. We evaluated if this T-PSC design could also replicate the safety conclusions of a trial by analyzing how often treatment-emergent adverse events (TEAEs) occurred before T-PSC.
Methods:
We retrospectively applied the T-PSC design to analyze TEAEs from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The Safety Analysis Set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs (regardless of causality), treatment-related TEAEs, and serious TEAEs that occurred before T-PSC relative to those observed during the full-length trial.
Results:
Of the 67 participants who experienced TEAEs in the perampanel arm during full-length trial, 66 (99%) participants experienced TEAEs with onset occurring before T-PSC. Similarly, of the 59 participants experienced TEAEs in the placebo arm during full-length trial, 54 (92%) participants reported TEAEs with onset occurring before T-PSC (Table 1). When limited to treatment-related TEAEs, 32/37 (86%) and 55/56 (98%) of participants reported treatment-related TEAEs that occurred before T-PSC in placebo and perampanel arms, respectively. Treatment-related TEAEs were more likely to occur before T-PSC for perampanel relative to placebo (odds ratio 8.6, p=0.035). Serious TEAEs occurred before T-PSC in 6/7 (86%) and 4/6 (67%) of participants receiving placebo and perampanel, respectively. Two deaths occurred in the full-length trial; both events occurred before T-PSC. TEAEs leading to study drug adjustments (mainly study drug withdrawal or dose reduction) occurred before T-PSC in 8/10 (80%) and 15/16 (94%) participants in the placebo and perampanel arms, respectively.
Conclusions: Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may either be due to a shorter T-PSC or delayed time to TEAE for placebo. This analysis suggests the T-PSC design was sufficient to evaluate the safety of perampanel.
Funding: Eisai, the American Epilepsy Society, the Epilepsy Foundation, the American Academy of Neurology, the American Brain Foundation.