Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Oki R ，Izumi Y ，Fujita K ，Miyamoto R ，Nodera H ，Sato Y ，Sakaguchi S ，Nokihara H ，Kanai K ，Tsunemi T ，Hattori N ，Hatanaka Y ，Sonoo M ，Atsuta N ，Sobue G ，Shimizu T ，Shibuya K ，Ikeda K ，Kano O ，Nishinaka K ，Kojima Y ，Oda M ，Komai K ，Kikuchi H ，Kohara N ，Urushitani M ，Nakayama Y ，Ito H ，Nagai M ，Nishiyama K ，Kuzume D ，Shimohama S ，Shimohata T ，Abe K ，Ishihara T ，Onodera O ，Isose S ，Araki N ，Morita M ，Noda K ，Toda T ，Maruyama H ，Furuya H ，Teramukai S ，Kagimura T ，Noma K ，Yanagawa H ，Kuwabara S ，Kaji R ，Japan Early-Stage Trial of Ultrahigh-Dose Methylcobalamin for ALS (JETALS) Collaborators ... -  《-》

Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.

In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study population. We aimed to substantiate this post-hoc result and assess safety and efficacy of edaravone in a phase 3 trial that focused on patients with early stage ALS who met the post-hoc analysis inclusion criteria. In this phase 3, randomised, double-blind, parallel-group study, patients aged 20-75 years with ALS of grade 1 or 2 in the Japan ALS Severity Classification, scores of at least 2 points on all 12 items of ALSFRS-R, forced vital capacity of 80% or more, definite or probable ALS according to the revised El Escorial criteria, and disease duration of 2 years or less were recruited from 31 hospitals in Japan. Eligible patients also had a decrease of 1-4 points in the ALSFRS-R score during a 12-week observation period before randomisation. Patients meeting all criteria were then randomly assigned 1:1 to receive 60 mg intravenous edaravone or intravenous saline placebo for 6 cycles (4 weeks per cycle with 2 weeks on, 2 weeks off) for a total treatment duration of 24 weeks. In cycle 1, the study drug or placebo was administered once per day for 14 days within a 14 day period, followed by the drug-free period. In cycle 2 and thereafter, the study drug or placebo was administered for 10 days within a 14 day period, followed by a 2 week drug-free period. Participants and investigators, including those assessing outcomes, were masked to treatment allocation. The primary efficacy outcome was the change in ALSFRS-R score from the baseline to 24 weeks (or at discontinuation if this was after the third cycle) after randomisation. The primary outcome was assessed in all patients who had received at least one treatment infusion, had at least one assessment post-baseline, and reached the end of cycle 3. For patients with missing values at the end of cycle 6, data were imputed by the last observation carried forward (LOCF) method, provided the patients had completed at least cycle 3. Safety was assessed in all patients who had received at least one treatment infusion and had at least one assessment post-baseline. This trial is registered with ClinicalTrials.gov, NCT01492686. Between Nov 28, 2011, and Sept 3, 2014, we screened 213 patients, and enrolled 192 as potential participants. Of these, 137 patients completed the observation period: 69 were randomly assigned to receive edaravone, and 68 were randomly assigned to receive placebo. 68 patients taking edaravone and 66 taking placebo were included in the primary efficacy analysis. For the primary outcome, the change in ALSFRS-R score was -5·01 (SE 0·64) in the edavarone group and -7·50 (0·66) in the placebo group. The least-squares mean difference between groups was 2·49 (SE 0·76, 95% CI 0·99-3·98; p=0·0013) in favour of edaravone. Treatment-emergent adverse events were reported in 58 (84%) patients receiving edaravone and 57 (84%) patients receiving placebo. 11 (16%) patients taking edaravone and 16 (24%) taking placebo had serious adverse events, and one (1%) patient receiving edaravone and four (6%) patients receiving placebo had adverse events (one dysphagia in edaravone group and one dyspnoea, two respiratory disorder, and one rash in the placebo group) that led to withdrawal. Edaravone showed efficacy in a small subset of people with ALS who met criteria identified in post-hoc analysis of a previous phase 3 study, showing a significantly smaller decline of ALSFRS-R score compared with placebo. There is no indication that edaravone might be effective in a wider population of patients with ALS who do not meet the criteria. Mitsubishi Tanabe Pharma Corporation.

Writing Group ，Edaravone (MCI-186) ALS 19 Study Group 《-》

[JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS].

Izumi Y ，Oki R ，Kuwabara S ，Kaji R ... -  《-》

The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). PRR1-10.2196/12046.

Oki R ，Izumi Y ，Nodera H ，Sato Y ，Nokihara H ，Kanai K ，Sonoo M ，Urushitani M ，Nishinaka K ，Atsuta N ，Kohara N ，Shimizu T ，Kikuchi H ，Oda M ，Ikeda K ，Nagai M ，Komai K ，Kojima Y ，Kuzume D ，Isose S ，Shimohama S ，Abe K ，Ito H ，Noda K ，Ishihara T ，Morita M ，Shimohata T ，Teramukai S ，Kagimura T ，Noma K ，Yanagawa H ，Kuwabara S ，Kaji R ，JETALS ... -  《JMIR Research Protocols》

Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Genge A ，van den Berg LH ，Frick G ，Han S ，Abikoff C ，Simmons A ，Lin Q ，Patra K ，Kupperman E ，Berry JD ... -  《-》