Clinical Trial of Ultra-high Dose Methylcobalamin for ALS (JETALS)

Japanese Early-stage Clinical Trial of Ultra-high Dose Methylcobalamin for Amyotrophic Lateral Sclerosis: a Pivotal Phase 3 Randomized Controlled Study

To examine the clinical efficacy and safety of ultra-high dose (50mg, im, twice a week) methylcobalamin in retarding the progression of symptoms in amyotrophic lateral sclerosis (ALS) patients, we enroll ALS patients diagnosed by Updated Awaji Criteria within 12 months after the clinical onset. First they are followed for 12 weeks with Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores, and only those who exhibit drops of 1-2 points are allowed to enter into the test period. A total of 128 patients are randomized and the half having placebo. They are blindly evaluated for drops of ALSFRS-R in 16 weeks, as the primary outcome. After this, all subjects receive methylcobalamin.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: saline solution; Drug: methylcobalamin

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan, 260-8677
    • Chiba University Hospital
  • Fukuoka, Japan, 819-8585
    • Murakami Karindo Hospital
  • Okayama, Japan, 770-8558
    • Okayama University Hospital
  • Tokushima, Japan, 770-8503
    • Tokushima University Hospital
  • Tokyo, Japan, 173-8606
    • Teikyo University Hospital
  • Tokyo, Japan, 113-8431
    • Juntendo University Hospital
  • Tokyo, Japan, 143-8541
    • Toho University Hospital
  • Tokyo, Japan, 183-0042
    • Tokyo Metropolitan Neurological Hospital
  • Wakayama, Japan, 641-8509
    • Wakayama Medical University Hospital
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
      • Nagoya University Hospital
  • Hiroshima
    • Miyoshi, Hiroshima, Japan, 728-0013
      • Miyoshi Neurological Clinic
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8543
      • Sapporo Medical University Hospital
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0047
      • Kobe Central Munincipal Medical center
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-0192
      • Ioh National Hospital
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0380
      • Kitasato University East Hospital
  • Shiga
    • Otsu, Shiga, Japan, 520-2192
      • Shiga Medical University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Treatment and OLE Phase:

• ALS patients within 12 months after clinical onset at the entry
• Diagnosed based on updated Awaji criteria: definite, probably or laboratory supported probable
• Decline of ALSFRSR being 1 or 2 during observation period of 12 weeks
• Japanese Clinical Severity Scale 1 or 2
• Those who can visit the participating medical centers

Tsunagi Phase:

- The subjects for the Tsunagi phase are patients with ALS who are continuing the administration of this drug at the time of approval, and have obtained consent for the transition to the Tsunagi phase.

Exclusion Criteria:

Treatment and OLE Phase:

• Those who have tracheostomy
• Those who had NIPPV
• %FVC<60%
• Those who have Chronic Obstructive Pulmonary Disease (COPD)
• Those who have symptoms and signs of B12 deficiency
• Those who had edaravone less than 4 weeks prior to entry
• Those who changed the schedule and dosing of riluzole
• Those who have dementia
• Those who have the possibility of pregnancy
• Those who have serious respiratory or cardiac diseases
• Those who have malignancies
• Those who participated other clinical trials within 12 weeks
• Those who have allergies to B12 and related compounds

Tsunagi Phase:

Not applicable.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Treatment Phase: Placebo; intramuscular injection of saline solution	Drug: saline solution; Patients receive saline solution intramuscular injection twice a week.
Active Comparator: Treatment Phase: methylcobalamin; intramuscular injection of methylcobalamin	Drug: methylcobalamin; Patients receive methylcobalamin 50mg intramuscular injection twice a week.
Experimental: OLE Phase: methylcobalamin; intramuscular injection of methylcobalamin	Drug: methylcobalamin; Patients receive methylcobalamin 50mg intramuscular injection twice a week.
Experimental: Tsunagi Phase: methylcobalamin; intramuscular injection of methylcobalamin	Drug: methylcobalamin; Patients receive methylcobalamin 50mg intramuscular injection twice a week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Phase: ALSFRS-R	Drop of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (maximum or normal 48 and minimum 0; higher values represent better condition)	during 16 weeks of test period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Phase: time to event	time from the randomization to the onset of any of the event (24-hour use of noninvasive respiratory support, use of invasive respiratory support, or death)	during 16 weeks of test period
Treatment Phase: %Functional Vital Capacity (FVC)	changes of per cent Functional Vital Capacity	during 16 weeks of test period
Treatment Phase: homocystein	changes of serum levels of homocystein	during 16 weeks of test period
Treatment Phase: Manual Muscle Testing (MMT)	changes of sum of Medical Research Council scales of manual muscle testing, ranging 5 (normal), 4, 4+, 3, 2, 1, 0 (minimal) ( for analysis each is converted to 6, 5, 4, 3, 2, 1, 0) of the 11 muscles in the limbs (5x2) and neck(1)	during 16 weeks of test period
Treatment Phase: Norris scale	changes of Norris scale (39 normal - 0 worst)	during 16 weeks of test period
Treatment Phase: Grip Power	changes of sum of grip power in kilograms on both sides	during 16 weeks of test period
Treatment Phase: 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)	changes of sum of ALSAQ-40 (40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire) score (40 normal - 200 worst)	during 16 weeks of test period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Phase: safety	any adverse events during the treatment period	during 16 weeks of test period
OLE Phase: time to event	time from the randomization to the onset of any of the event (24-hour use of noninvasive respiratory support, use of invasive respiratory support, or death)	up to 6 years 11 months
OLE Phase: ALSFRS-R	Drop of ALSFRS-R Scale-Revised (maximum or normal 48 and minimum 0; higher values represent better condition)	up to 6 years 11 months
OLE Phase: safety	any adverse events during the OLE period including laboratory tests and vital signs assessment.	up to 6 years 11 months
Tsunagi Phase: time to event	time period from drug assignment to any of the event (24-hour use of noninvasive respiratory support, use of invasive respiratory support, or death)	up to 6 months
Tsunagi Phase: ALSFRS-R	Drop of ALSFRS-R Scale-Revised (maximum or normal 48 and minimum 0; higher values represent better condition)	up to 6 months
Tsunagi Phase: safety	any adverse events during the Tsunagi phase including laboratory tests and vital signs assessment.	up to 6 months

Collaborators and Investigators

• Sponsor: Eisai Co., Ltd.
• Collaborators: University of Tokushima
• Investigators: Study Director: Ryuji Kaji, MD, Tokushima University Hospital

Publications and helpful links

General Publications

• Ikeda K, Iwasaki Y, Kaji R. Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2015 Jul 15;354(1-2):70-4. doi: 10.1016/j.jns.2015.04.052. Epub 2015 May 8.
• Kaji R, Kodama M, Imamura A, Hashida T, Kohara N, Ishizu M, Inui K, Kimura J. Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve. 1998 Dec;21(12):1775-8. doi: 10.1002/(sici)1097-4598(199812)21:123.0.co;2-v.
• 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. Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. 2022 Jun 1;79(6):575-583. doi: 10.1001/jamaneurol.2022.0901.
• 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. The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial. JMIR Res Protoc. 2018 Dec 21;7(12):e12046. doi: 10.2196/12046.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): February 14, 2020
• Study Completion (Actual): February 18, 2025

Study Registration Dates

• First Submitted: May 14, 2018
• First Submitted That Met QC Criteria: May 24, 2018
• First Posted (Actual): June 7, 2018

Study Record Updates

• Last Update Posted (Actual): March 26, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: ALS; motor neuron disease; Lou Gehrig's disease
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Micronutrients; Vitamin B Complex; Vitamins; Vitamin B 12
• Other Study ID Numbers: 763

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: anonymous data are available
• IPD Sharing Time Frame: from October 1, 2017 till March 31, 2020
• IPD Sharing Access Criteria: those who have approval from Institutional Review Board (IRB)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No