Safety and Efficacy of Perampanel for Sporadic Amyotrophic Lateral Sclerosis: A Multicentre, Double-Blind, Randomised Phase 2 Trial

Background: Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, arrested disease progression in a sporadic ALS (SALS) mouse model, suggesting its potential use in humans.  Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2 study was conducted at 12 sites in Japan. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Using a computerised interactive system with the following minimization factors: change in ALSFRS-R score during the observation period, sex, age, and the use of riluzole or edaravone, patients were randomly assigned in a 1:1:1 ratio to receive placebo, 4 mg perampanel daily, or 8 mg perampanel daily. The primary efficacy outcome was the change in ALSFRS-R scores after 48 weeks of treatment. All patients in the intention-to-treat population were analysed. Patients and investigators were masked to treatment assignment. Findings:  Between April 2017 and January 2020, 65 patients were randomised to perampanel 4 mg (n=22), 8 mg (n=21), or placebo groups (n=22). There was a significant difference (−8·4 [95% confidence interval −13·9–−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 adverse events were significantly more frequent in the perampanel 8 mg group than in the placebo group (p=0·0483). The most common event was dysphagia requiring gastrostomy in two (9·1%) of 22 patients treated with placebo, four (18·2%) of 22 patients treated with 4 mg of perampanel, and six (28·6%) of 21 patients treated with 8 mg of perampanel. Interpretation: Perampanel did not prevent an overall decline of ALSFRS-R score and was linked to worsening of bulbar subscore in the 8 mg group.  Trial Registration: This trial is registered with ClinicalTrials.gov, # NCT03019419.  Funding:  This study received funding from the Japan Agency for Medical Research and Development. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the institutional review board at each study site. Written informed consent was obtained from the patients.