PDF: Perampanel Pivotal
(2012)Objective
To evaluate adjunctive perampanel for refractory partial-onset seizures (Study 304).
Study Summary
• The ≥50% responder rate was not statistically significant at either dose (8 mg p=0.076; 12 mg p=0.091)
• Adverse events were dose-dependent (dizziness, somnolence, irritability/aggression), and ~17.5% of treated patients discontinued for AEs
Intervention
Adjunctive perampanel 8 mg or 12 mg once daily vs placebo, added to 1-3 AEDs; N=388
Inclusion Criteria
Age ≥12 years with refractory partial-onset seizures (±secondary generalization), ≥5 seizures during a 6-week baseline on 1-3 stable AEDs.
Study Design
Arms: Perampanel 12 mg vs Perampanel 8 mg vs Placebo (control)
Patients per Arm: Placebo: 136, Perampanel 8 mg: 129, Perampanel 12 mg: 121
Outcome
• ≥50% responder rate: not significant (8 mg p=0.076; 12 mg p=0.091)
• Dizziness up to ~43% and irritability/aggression rose at 12 mg (later boxed warning)
• Discontinuation for AEs ~17.5% overall, dose-dependent
Clinical Question
Is adjunctive perampanel (a selective non-competitive AMPA receptor antagonist) effective and safe for adults with refractory partial-onset seizures?
Bottom Line
Adjunctive perampanel 8 mg and 12 mg once daily provided statistically significant but modest reductions in partial-onset seizure frequency vs placebo in adults with epilepsy refractory to 1–3 AEDs. 50% responder rates were not significant at either dose. AEs were dose-dependent (dizziness, somnolence, fatigue, irritability). This trial established Class I evidence for perampanel as the first selective AMPA receptor antagonist antiepileptic.
Major Points
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group adjunctive trial (Study 304)
- 388 patients randomized 1:1:1 to placebo, perampanel 8 mg/day, or perampanel 12 mg/day
- Included adults and adolescents ≥12 years with ≥5 partial-onset seizures during a 6-week baseline despite 1–3 AEDs at stable doses
- 6-week titration (2 mg/week increments) followed by 13-week maintenance; concomitant AEDs held stable
- Classification of evidence: Class I
- Primary endpoint: median % change in seizure frequency per 28 days during maintenance vs baseline
- Results: −21.0% (placebo), −26.3% (8 mg; p=0.0261), −34.5% (12 mg; p=0.0158)
- Secondary 50% responder rate: not significant at 8 mg (p=0.0760) or 12 mg (p=0.0914)
- 17.5% of all treated patients discontinued due to AEs; discontinuation rate dose-dependent
- Most common AEs: dizziness, somnolence, fatigue, irritability, falls — all dose-dependent and higher in 12-mg arm
- Psychiatric AEs including aggression and hostility were observed, particularly at 12 mg — subsequent labeling included boxed warning
- Trial supported FDA approval of perampanel in 2012 for adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 388
- Follow-up
- 6-week titration + 13-week maintenance + follow-up or open-label extension
- Centers
- Multicenter, international
Primary Outcome
Definition: Median percent change from baseline in seizure frequency per 28 days during 13-week maintenance phase
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -21.0% (placebo) | -26.3% (perampanel 8 mg); -34.5% (perampanel 12 mg) | - | p=0.0261 (8 mg vs placebo); p=0.0158 (12 mg vs placebo) |
Limitations & Criticisms
- Modest effect size on % change relative to typical adjunctive AED trials
- 50% responder rate did not reach statistical significance at either dose
- Dose-dependent psychiatric AEs (aggression) led to boxed warning later
- 6-week titration period may be long in clinical practice
- Long half-life (>100 h) makes dose changes slow
- No comparator AED; only placebo-controlled
Citation
Neurology 2012;79(6):589-596