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Perampanel Pivotal

Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304

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Year of Publication: 2012

Authors: French JA, Krauss GL, Biton V, ..., Rogawski MA

Journal: Neurology

Citation: Neurology 2012;79(6):589-596

Link: https://doi.org/10.1212/WNL.0b013e3182635735

PDF: https://www.neurology.org/doi/pdf/10.121...b013e3182635735

Clinical Question

Is adjunctive perampanel effective for 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

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: Mid/late 2000s

Follow-up Duration: 6-week titration + 13-week maintenance + follow-up or open-label extension

Centers: Multicenter, international

Sample Size: 388

Analyzed: 387

Analysis: Intention-to-treat; median % change analyzed non-parametrically

Inclusion Criteria

  • Age ≥12 years
  • Refractory partial-onset seizures (with/without secondary generalization)
  • On 1-3 stable concomitant AEDs for ≥30 days
  • ≥5 seizures during 6-week prospective baseline
  • No single seizure-free period >25 days during baseline

Exclusion Criteria

  • Primary generalized epilepsy
  • Status epilepticus within 12 months
  • Progressive neurologic disease
  • Psychiatric disorder limiting evaluation
  • Previous treatment with perampanel

Arms

FieldControlPerampanel 8 mgPerampanel 12 mg
N136129121
InterventionMatching placebo once dailyPerampanel titrated to 8 mg once daily over 6 weeks, then maintenancePerampanel titrated to 12 mg once daily over 6 weeks, then maintenance
Duration19 weeks (titration + maintenance)19 weeks19 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Median percent change from baseline in seizure frequency per 28 days during 13-week maintenance phasePrimary-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)
≥50% responder rate (8 mg vs placebo)Secondary~26% (placebo)~33% (8 mg)p=0.0760 (not statistically significant)
≥50% responder rate (12 mg vs placebo)Secondary~26% (placebo)~34% (12 mg)p=0.0914 (not statistically significant)
Seizure-free status during maintenanceSecondaryVery low in all armsVery low in all armsNot discriminative
Median % change in secondarily generalized seizures (post-hoc)SecondarySmaller reductionLarger reduction with 12 mgNominally favorable
Any adverse event (treatment emergent)Adverse~67%~83% (8 mg); ~90% (12 mg)Dose-dependent
DizzinessAdverse~9%~32% (8 mg); ~43% (12 mg)Dose-dependent
SomnolenceAdverse~7%~15% (8 mg); ~18% (12 mg)Dose-dependent
FatigueAdverse~5%~8% (8 mg); ~12% (12 mg)Dose-dependent
IrritabilityAdverse~3%~5% (8 mg); ~12% (12 mg)Dose-dependent; relevant for psychiatric boxed warning
HeadacheAdverse~11%~11% (8 mg); ~14% (12 mg)Similar
Gait disturbance / fallsAdverse~2%~4% (8 mg); ~9% (12 mg)Dose-dependent
Aggression / hostility (psychiatric)AdverseUncommonHigher at 12 mg — contributed to later boxed warningDose-dependent
Discontinuation due to AEs (all arms, overall)Adverse~6%~17.5% overall (higher at 12 mg)Dose-dependent

Subgroup Analysis

Benefit on seizure frequency reduction was consistent across subgroups defined by baseline seizure frequency, number of concomitant AEDs, age, and sex. Tolerability concerns predominated at 12 mg, particularly CNS (dizziness, somnolence, falls) and psychiatric (irritability, aggression) AEs — later reflected in the FDA boxed warning for neuropsychiatric reactions.

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

Funding

Eisai Inc. (manufacturer of perampanel)

Based on: Perampanel Pivotal (Neurology, 2012)

Authors: French JA, Krauss GL, Biton V, ..., Rogawski MA

Citation: Neurology 2012;79(6):589-596

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