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(2025)Objective
Perampanel - To assess the long-term efficacy and safety of perampanel monotherapy in adolescent and adult patients (12-74 years) with newly diagnosed or currently untreated recurrent focal-onset seizures, with or without focal to bilateral tonic-clonic seizures
Study Summary
• Cumulative probability of seizure recurrence at 52 weeks was 28.9% at 4-8 mg/day
• Safety profile was consistent with known perampanel tolerability; dizziness (38.2%) was the most common TEAE
Intervention
Perampanel monotherapy 4-8 mg/day
Inclusion Criteria
Age 12-74 years with newly diagnosed or recurrent untreated focal-onset seizures (≥2 years after completing most recent ASM treatment), with or without FBTCS
Study Design
Arms: Single-arm: Perampanel 4 mg/day with optional up-titration to 8 mg/day
Patients per Arm: 89 (Safety Analysis Set); 73 (mITT); 46 entered Extension
Outcome
• Cumulative probability of seizure recurrence at 52 weeks: 28.9% (4-8 mg/day)
• TEAEs in 83.1%; discontinuation due to TEAEs in 10.1%
Bottom Line
Perampanel monotherapy at 4-8 mg/day can maintain seizure freedom for up to 52-104 weeks in patients with untreated focal-onset seizures, with 67.4% of patients entering the Extension phase remaining seizure-free at 52 weeks. The tolerability profile was manageable with dizziness being the most common adverse event.
Major Points
- 52-week seizure-freedom rate was 52.2% at 4 mg/day and 67.4% at 4-8 mg/day among patients entering the Extension phase
- 47.2% (42/89) of all patients had cumulative perampanel exposure for ≥52 weeks
- Cumulative probability of seizure recurrence at 52 weeks was 28.9% at 4-8 mg/day
- Cumulative probability of study withdrawal at 52 weeks was 43.8%
- Seizure-freedom rates were similar across FOS subtypes (FBTCS, FIAS, FIAS plus FBTCS)
- ≥27.4% of patients remained seizure-free for ≤104 weeks, independent of FOS type
- Dizziness (38.2%) was the most common TEAE; most events occurred in first 1-3 months
- Symptomatic epilepsy syndrome was identified as a potential prognostic factor for long-term seizure freedom
- Median daily dose was 4 mg/day throughout the study
Study Design
- Study Type
- Prospective, multicenter, single-arm, open-label, phase 3 study with extension phase
- Randomization
- No
- Blinding
- Open-label; no blinding
- Sample Size
- 89
- Follow-up
- Core Study: 32 weeks (4 mg/day) or up to 62 weeks (8 mg/day regimen); Extension: up to 104 weeks total
- Countries
- Japan, Republic of Korea
Primary Outcome
Definition: Seizure-freedom rate during the 4-mg/day Core Study Maintenance Period (26 weeks)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | 74.0% (previously reported in Core Study publication) | - |
Limitations & Criticisms
- Open-label, single-arm design without a control group limits ability to draw comparative efficacy conclusions
- No randomization or blinding introduces potential for bias
- Small sample size (89 patients in Safety Analysis Set, 46 in Extension)
- Selection bias: Only patients responding well to perampanel during Core Study likely continued into Extension
- Restrictive inclusion/exclusion criteria may have contributed to less heterogeneous study population
- Results summarized descriptively with nominal p-values; no adjustment for multiplicity across subgroups
- Low number of patients joining Extension (46/89) limits generalizability of long-term findings
- Post hoc nature of prognostic factor analysis limits strength of conclusions
- Small sample sizes in certain subgroups (e.g., stroke etiology n=2) limit interpretation
- Study conducted only in Japan and Korea; may not be generalizable to other populations
- Pregnancy safety not assessed in this study
Citation
Epilepsy Research 210 (2025) 107494