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Clinical Trial
. 2022 Feb;269(2):885-896.
doi: 10.1007/s00415-021-10670-y. Epub 2021 Jun 30.

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis

Hitoshi Aizawa  1 , Haruhisa Kato  2 , Koji Oba  3 , Takuya Kawahara  4 , Yoshihiko Okubo  2 , Tomoko Saito  2 , Makiko Naito  2 , Makoto Urushitani  5 , Akira Tamaoka  6 , Kiyotaka Nakamagoe  6 , Kazuhiro Ishii  6 , Takashi Kanda  7 , Masahisa Katsuno  8 , Naoki Atsuta  8 , Yasushi Maeda  9 , Makiko Nagai  10 , Kazutoshi Nishiyama  10 , Hiroyuki Ishiura  11 , Tatsushi Toda  11 , Akihiro Kawata  12 , Koji Abe  13 , Ichiro Yabe  14 , Ikuko Takahashi-Iwata  14 , Hidenao Sasaki  14 , Hitoshi Warita  15 , Masashi Aoki  15 , Gen Sobue  8 , Hidehiro Mizusawa  16 , Yutaka Matsuyama  3 , Tomohiro Haga  4 , Shin Kwak  2
Affiliations
Clinical Trial

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis

Hitoshi Aizawa et al. J Neurol. 2022 Feb.

Abstract

Objective: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).

Methods: This 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.

Results: One 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).

Conclusions: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Keywords: AMPA receptor; Efficacy; Perampanel; Safety; Sporadic amyotrophic lateral sclerosis.

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Conflict of interest statement

K.O. reports receiving honoraria from Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd, Eisai Co., Ltd, Chugai Pharmaceutical Co, Ltd., and Daiichi Sankyo Co., Ltd., outside the submitted work. M.K. reports receiving grants from AMED, Japan, during the conduct of the study; receiving grants from Mitsubishi Tanabe Pharma, grants from Sanofi, and consulting fees from Eisai, outside the submitted work. N.A. reports receiving grants from the Center for Clinical Trials, Japan Medical Association, during the conduct of the study. H.I. reports receiving speaker fees from Eisai, outside the submitted work. M.A. reports receiving research grants for Research on Nervous and Mental Disorders, Research on Rare and Intractable Diseases, Research on Psychiatric and Neurological Diseases and Mental Health from the Japanese Ministry of Health Labor and Welfare; Grants-in-Aid for Scientific Research, an Intramural Research Grant for Neurological Psychiatric Disorders from National Center of Neurology and Psychiatry (NCNP); Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT); and a grants of Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED); and funding for travel and speaker honoraria from Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd, Sanofi K.K. Novartis Pharma K.K and Dainippon Sumitomo Pharma Co. Ltd. H.M. reports receiving grants from the Japan Agency for Medical Research and Development and grants from the Japanese Ministry of Health, Labor and Welfare, outside the submitted work. The other authors have nothing to report.

Figures

Fig. 1
Fig. 1
Enrolment and randomization of patients. Randomization was stratified according to change in ALS functional rating scale-revised (ALSFRS-R) score during the observation period (− 2 or − 3 vs. − 4 or − 5), sex (male vs. female), age (42 to 64 vs. 65 to 78), and the use of riluzole or edaravone (yes vs. no)
Fig. 2
Fig. 2
Changes in ALSFRS-R score and Kaplan–Meier curve. A Mean change in ALSFRS-R score over time from the baseline in the placebo group, 4 mg perampanel group, and 8 mg perampanel groups. Error bars represent standard deviations (SDs) for the mean values at each timepoint. B Changes in ALSFRS-R score over time from the baseline for each ALS patient. There were wide variations in the changes of ALSFRS-R scores over the treatment period within each group. C The Kaplan–Meier curve for time to death or disease progression. There was no significant difference in dropout rate due to disease progression (inability to walk without assistance, loss of function of both upper limbs, tracheostomy, respirator use, tube feeding, or death) among the three groups. Some patients were followed for 48 weeks after disease progression (6, 4, and 2 patients in placebo, 4 mg, and 8 mg groups, respectively). (D) Changes in ALSFRS-R score suggested by trajectory analysis. Cases were classified into three subgroups; a subgroup with small changes (red line; n = 11 in the placebo group and n = 7 in the perampanel group), a subgroup with intermediate changes (green line; n = 9 in the placebo group and n = 20 in the perampanel group), and a subgroup with large changes (blue line; n = 2 in the placebo group and n = 12 in the perampanel group). Solid lines are estimated curves from the trajectory analysis and dotted lines are the mean of the measured values. Error bars represent 95% CIs for the mean values at each timepoint
Fig. 3
Fig. 3
Changes in MMT grades at 48 weeks from baseline in placebo and perampanel groups. Data are mean (95% CI). MMT manual muscle testing
See this image and copyright information in PMC

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