Adjunctive Perampanel Effective and Safe for the Treatment of Uncontrolled Partial-onset Seizures

11 Nov, 21

Introduction

Perampanel, a highly selective, noncompetitive ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–type glutamate receptor antagonist, blocks excessive neuronal activation and is a potential pharmacological treatment for seizures. Phase II studies have already demonstrated preliminary safety and tolerability of perampanel as an adjunctive therapy for uncontrolled partial onset seizures.

Aim

To evaluate the efficacy and safety of various perampanel dose regimens added to 1–3 concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.

Patient Profile

Patients with uncontrolled partial-onset seizures while receiving 1–3 AEDs (age ≥12 years)

Methods

Study Design

Phase III, double-blind, placebo-controlled, randomized, multicenter, dose-response trial conducted across 24 countries of Europe, Asia and Australia

Treatment Strategy

The trial was initiated with a 6-week baseline phase, followed by a 19-week treatment phase that comprised 6-week titration and 13-week maintenance phase.
Patients were randomized 1:1:1:1 to receive either placebo, or 2, 4 or 8 mg/day perampanel
Patients with persisting seizures on 1–3 AEDs were randomized to perampanel 2, 4, and 8 mg/day or placebo following a 6-week baseline phase. Perampanel was titrated weekly by 2 mg/day and maintained at the dose achieved for 13 weeks.

Outcomes

Primary Efficacy Outcomes

Median percent change in seizure frequency
50% responder rate (50% or greater reduction in seizure frequency)

Secondary Efficacy Outcomes

Percent change in the frequency of complex partial seizures plus secondarily generalized seizures
A dose-response analysis of the percent change in seizure frequency

Safety Outcomes

Incidence of adverse events (AEs)
Withdrawals due to AEs

Results

Of the 706 patients who were randomized to the trial medication, 623 completed the trial.
Mean years since epilepsy diagnosis was 19.1 years. Of the entire study population, 14.7% were on 1 AED and 85.3% were on 2 or 3 AEDs. The median seizure frequency ranged from 9.3 to 10.9 seizures per 28 days for the treatment groups during the 6-week baseline phase.
The Median percent change in seizure frequency was significantly greater for all the perampanel doses vs. placebo, with the same being highest for perampanel 8 mg/day (Fig.1).

Fig. 1: Median percent change in seizure frequency during the study

The corresponding 50% responder rates were also significantly higher for perampanel 4 mg/day and 8 mg/day, compared with placebo (Fig. 2)

Fig. 2: 50% responder rate during the study

The median percent change in frequency of complex partial seizures plus secondarily generalized seizures during the double-blind phase was significantly greater for perampanel 4 mg/day and 8 mg/day regimen, compared with placebo (Table 1).

Table 1: Median percent change of complex partial seizures plus secondarily generalized seizure frequency

Study Group	% Change in Seizure Frequency	*P value vs.* placebo**
Placebo	-17.6%	-
Perampanel 2 mg/day	-20.5%	-
Perampanel 4 mg/day	-31.2%	0.007
Perampanel 8 mg/day	-38.7%	<0.001

The percentages of patients who achieved seizure-free status during the maintenance period was 1.2%, 1.9%, 4.4%, and 4.8% in placebo, 2 mg/day, 4 mg/day, and 8 mg/day groups, respectively.
Majority of the treatment-emergent AEs (TEAEs) were of mild to moderate severity. Dizziness and somnolence appeared to be the most frequent TEAEs associated with dose reduction of perampanel.
Discontinuation of treatment due to TEAEs occurred in 3.8% patients in the placebo group, 6.7% patients in the 2 mg/day group, 2.9% patients in the 4 mg/day group, and 7.1% patients in the 8 mg/day group.

Conclusions

Adjunctive perampanel 4 and 8 mg/day effectively reduced seizure frequency, compared with placebo and exhibited a favorable tolerability profile in patients aged ≥12 years with partial-onset seizures (with or without secondary generalization).
Adjunctive treatment of uncontrolled partial-onset seizure with perampanel seems to be promising, given the treatment-resistant nature of the study population.

Neurology. 2012;78:1408–1415.