Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis

Hitoshi Aizawa,Takuya Kawahara,Tomoko Saito,Akira Tamaoka,Hidenao Sasaki,Makiko Nagai,Takashi Kanda,Koji Oba,Kōji Abe ,Makoto Urushitani,Kazutoshi Nishiyama,Haruhisa Kato,Kiyotaka Nakamagoe,Hiroyuki Ishiura,Akihiro Kawata,Yasushi Maeda,Yutaka Matsuyama,Hidehiro Mizusawa,Ichiro Yabe,Masahisa Katsuno,Gen Sobue,Naoki Atsuta,Ikuko Takahashi-Iwata,Yoshihiko Okubo,Kazuhiro Ishii,Hitoshi Warita,Makiko Naito,Tomohiro Haga,Tatsushi Toda,Masashi Akiyama ,Shin Kwak

doi:10.1007/s00415-021-10670-y

Abstract

ObjectiveTo evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).MethodsThis randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment.ResultsOne patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [− 8.4 (95% CI − 13.9 to − 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483).ConclusionsPerampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by degeneration of upper and lower motor neurons in the CNS
The discontinuation rate of the trial increased in a dosedependent manner, with 18 of 22 patients (82%) in the placebo group, 14 of 22 patients (64%) in the 4 mg perampanel group, and 7 of 21 patients (33%) in the 8 mg perampanel group completing the 48-week trial
Of the 26 patients who did not complete the trial, one patient died of ALS, 11 had Adverse events (AEs), 11 declined to participate further, and 3 did not meet continuation criteria (Fig. 1)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterized by degeneration of upper and lower motor neurons in the CNS. Its onset features progressive focal weakness and atrophy, spreading to involve most skeletal muscles, resulting in respiratory failure within 3–5 years of onset [1]. The incidence of ALS is approximately 1–2 per 100,000, and the prevalence is approximately 4–8 per 100,000 [2, 3]. The average age of onset is 58–60 years [4]. More than 90% of patients with ALS have no family history and are classified as sporadic ALS (SALS); the remaining < 10% are familial [4], usually autosomal dominant. At least 25 genes have been associated with half of familial ALS cases and a small proportion of SALS patients [5]. Riluzole and edaravone can modify the course of the disease but are not curative [7, 8]

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