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

ABSTRACT: BACKGROUND: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. OBJECTIVE:This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID):PRR1-10.2196/12046.

SUBMITTER: Oki R

PROVIDER: S-EPMC6320396 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Oki Ryosuke R Izumi Yuishin Y Nodera Hiroyuki H Sato Yasutaka Y Nokihara Hiroshi H Kanai Kazuaki K Sonoo Masahiro M Urushitani Makoto M Nishinaka Kazuto K Atsuta Naoki N Kohara Nobuo N Shimizu Toshio T Kikuchi Hitoshi H Oda Masaya M Ikeda Ken K Nagai Makiko M Komai Kiyonobu K Kojima Yasuhiro Y Kuzume Daisuke D Isose Sagiri S Shimohama Shun S Abe Koji K Ito Hidefumi H Noda Kazuyuki K Ishihara Tomohiko T Morita Mitsuya M Shimohata Takayoshi T Teramukai Satoshi S Kagimura Tatsuo T Noma Kensuke K Yanagawa Hiroaki H Kuwabara Satoshi S Kaji Ryuji R

JMIR research protocols 20181221 12

<h4>Background</h4>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 ...[more]

PMID: 30578206

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Project description:INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a rapid and fatal motor disease marked by progressive physical impairment due to muscle weakness and wasting. It is multidimensional with many patients presenting with cognitive and/or behavioural impairment. Caregivers of patients with ALS, commonly non-paid immediate family members, often take primary responsibility for the complex care needs of patients in non-medicalised setting, and many as a consequence experience caregiver burden, anxiety, and/or depression. METHODS AND ANALYSIS:This randomised controlled trial (RCT) will use randomisation to allocate n=75 caregivers of patients with ALS from the national ALS clinic into three groups with an equal distribution. The RCT consists of two intervention groups and a wait list control (treatment as usual [TAU]) group. The intervention arms of the trial consist of a 'mindfulness-based stress reduction' and 'building better caregivers' manualised group-based intervention, with 9 and 6 weekly sessions, respectively. The TAU group will have access to intervention at the end of the trial period. Primary outcomes are self-report questionnaires on anxiety and depression symptoms, with caregiver burden and quality of life considered secondary outcomes. Assessment will commence at baseline, immediately following the intervention period, and after a period of 12 weeks to assess the effectiveness and efficacy of participating in an intervention. Patient cognitive and behavioural data will also be considered. Means of treatment and control groups at Time 0 and 1 will be analysed using mixed model multivariate analysis of variance followed by analysis of variance, and treatment effect-sizes will be calculated. This RCT protocol is pre-results and has been registered with an international database resulting in an International Standard Randomised Controlled Trials Number (ISRCTN53226941). ETHICS AND DISSEMINATION:Ethics approval was obtained from the Beaumont Hospital Medical Research Ethics Committee. Results of the main trial will be submitted for publication in a peer-reviewed journal.

Project description:IntroductionAmyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS.Methods and analysisAn open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers.Ethics and disseminationThis study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences.Trial registration numberUMIN000036295; Pre-results, JMA-IIA00419; Pre-results.

Dataset Information

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

Publications

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

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