Clinical trial NCT03548311: Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
Official title: Japanese Early-stage Clinical Trial of Ultra-high Dose Methylcobalamin for Amyotrophic Lateral Sclerosis: a Pivotal Phase 3 Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
motor neuron disease
Lou Gehrig's disease
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: University of Tokushima
First posted: 2018-06-07
Enrollment: 130
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double-blinded randomized controlled
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Treatment Phase: ALSFRS-R
timeFrame: during 16 weeks of test period
Secondary outcomes:
measure: Treatment Phase: time to event
timeFrame: during 16 weeks of test period
measure: Treatment Phase: %Functional Vital Capacity (FVC)
timeFrame: during 16 weeks of test period
measure: Treatment Phase: homocystein
timeFrame: during 16 weeks of test period
measure: Treatment Phase: Manual Muscle Testing (MMT)
timeFrame: during 16 weeks of test period
measure: Treatment Phase: Norris scale
timeFrame: during 16 weeks of test period
measure: Treatment Phase: Grip Power
timeFrame: during 16 weeks of test period
measure: Treatment Phase: 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40)
timeFrame: during 16 weeks of test period
Other outcomes:
measure: Treatment Phase: safety
timeFrame: during 16 weeks of test period
measure: OLE Phase: time to event
timeFrame: up to 6 years 11 months
measure: OLE Phase: ALSFRS-R
timeFrame: up to 6 years 11 months
measure: OLE Phase: safety
timeFrame: up to 6 years 11 months
measure: Tsunagi Phase: time to event
timeFrame: up to 6 months
measure: Tsunagi Phase: ALSFRS-R
timeFrame: up to 6 months
measure: Tsunagi Phase: safety
timeFrame: up to 6 months
Locations:
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Miyoshi
country: Japan
facility: Miyoshi Neurological Clinic
state: Hiroshima
city: Sapporo
country: Japan
facility: Sapporo Medical University Hospital
state: Hokkaido
city: Kobe
country: Japan
facility: Kobe Central Munincipal Medical center
state: Hyogo
city: Kanazawa
country: Japan
facility: Ioh National Hospital
state: Ishikawa
city: Sagamihara
country: Japan
facility: Kitasato University East Hospital
state: Kanagawa
city: Otsu
country: Japan
facility: Shiga Medical University Hospital
state: Shiga
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: Murakami Karindo Hospital
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tokyo
country: Japan
facility: Toho University Hospital
city: Tokyo
country: Japan
facility: Teikyo University Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Neurological Hospital
city: Wakayama
country: Japan
facility: Wakayama Medical University Hospital
Study officials:
affiliation: Tokushima University Hospital
name: Ryuji Kaji, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.