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JETALS

Year of Publication: 2022

Journal: JAMA Neurology

Link: https://doi.org/10.1001/jamaneurol.2022.0901

PDF: https://jamanetwork.com/journals/jamaneu...article/2792001

Clinical Question

Does twice-weekly IM ultrahigh-dose methylcobalamin 50 mg slow ALSFRS-R decline in early-stage ALS with moderate progression rate?

Bottom Line

In 129 Japanese ALS patients enrolled within 1 year of onset who dropped 1-2 points on ALSFRS-R during 12-week observation, IM methylcobalamin 50 mg twice weekly slowed 16-week decline to -2.66 vs -4.63 with placebo (LSM difference 1.97 points; 95% CI 0.44-3.50; p=0.01) — a 43% reduction in functional deterioration. Safety profile matched placebo. Supports a role for ultrahigh-dose methylcobalamin in early, moderate-progressor ALS.

        Major Points
        Investigator-initiated multicenter double-blind placebo-controlled phase 3 RCT at 25 Japanese neurology centers, Oct 2017 - Sept 2019 (Oki/Izumi 2022)
Enriched design: 12-week observation filtered to moderate progressors (1- or 2-point ALSFRS-R drop)
N=130 randomized; N=129 in full analysis set after exclusion of one misdiagnosis; 126 (97%) completed
Intervention: IM methylcobalamin 50 mg or placebo twice weekly for 16 weeks
Primary endpoint: LSM difference in ALSFRS-R from baseline to week 16
Result: methylcobalamin -2.66 vs placebo -4.63, difference 1.97 (95% CI 0.44-3.50; p=0.01)
43% reduction in functional deterioration — matches 45% effect in prior post-hoc analysis
Week 4 difference already significant (0.99; p=0.003); slope analysis confirms durable effect
Plasma homocysteine dropped significantly with methylcobalamin (target engagement confirmed)
FVC, manual muscle test, Norris scale, ALSAQ-40 showed numerical but non-significant trends
Safety excellent: no deaths, no respiratory events, AE rates similar (62% vs 66%); 91% on concomitant riluzole
Supports regulatory approval in Japan for early-stage moderate-progressor ALS; open-label extension continues to 2024

      

Design

Study Type: Multicenter double-blind placebo-controlled phase 3 RCT (NCT03548311)

Randomization: 1

Blinding: Double-blind (separate blinded efficacy and unblinded safety evaluators per site)

Follow-up Duration: 12-week observation + 16-week randomized + open-label extension to March 2024

Sample Size: 130

Analyzed: 129

Analysis: Linear mixed-effect model for repeated measures, unstructured covariance; 1-tailed p<0.025 significance

Inclusion Criteria

Adults ≥20 years ambulatory
Sporadic or familial ALS: definite, probable, or probable laboratory-supported per updated Awaji criteria
Within 1 year of ALS symptom onset
1- or 2-point ALSFRS-R decrease over 12-week observation period
FVC >60%; no prior non-invasive respiratory support or tracheostomy

Exclusion Criteria

ALSFRS-R unchanged or ≥3-point decline over observation (too stable or too rapid)
FVC ≤60%
Any history of non-invasive respiratory support or tracheostomy
Edaravone use within 4 weeks of observation period or during double-blind
Pregnancy or other active serious medical condition

Baseline Characteristics

Characteristic	Control	Active
N	64	65
Age	60.8 ± 12.1	61.2 ± 11.4
Male	40 (63%)	34 (52%)
Onset to enrollment (mo)	8.5 ± 2.3	8.2 ± 2.4
ALSFRS-R baseline	42.3 ± 2.7	42.4 ± 2.6
FVC %	90.6 ± 16.9	93.4 ± 16.9
Riluzole concomitant	58 (91%)	58 (89%)
Bulbar onset	19 (30%)	19 (29%)

Arms

Field	Control	Methylcobalamin
N	64	65
Intervention	Placebo IM (2 mL) twice weekly in thigh/buttock/deltoid (4 mL total across 2 sites)	Methylcobalamin 50 mg IM twice weekly (2 mL per site, 2 sites)
Duration	16 weeks	16 weeks + open-label extension

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in ALSFRS-R total score from baseline to week 16	Primary	-4.63 (SE 0.60)	-2.66 (SE 0.61)		p=0.01
ALSFRS-R change to week 4	Secondary	-1.19 (SE 0.35)	-0.20 (SE 0.36)	Difference 0.99 (95% CI 0.34-1.65)	p=0.003
ALSFRS-R change to week 8	Secondary	-2.33 (SE 0.43)	-1.34 (SE 0.44)	Difference 0.99 (95% CI 0.04-1.95)	p=0.04
Slope of ALSFRS-R (points/week)	Secondary	Steeper decline	Shallower decline	Diff -0.12 (95% CI -0.22 to -0.02)	p=0.02
Plasma homocysteine change at week 16	Secondary	0.00 (SE 0.28) µmol/L	-1.71 (SE 0.29) µmol/L	Diff -1.71 (95% CI -2.23 to -1.20)	p<0.001
FVC % change	Secondary	-9.4 ± 1.8	-7.4 ± 1.8	Diff 2.0 (-1.9 to 5.8)	p=0.31
Manual muscle test total score	Secondary	-3.7 ± 0.7	-2.9 ± 0.7	Diff 0.8 (-0.6 to 2.3)	p=0.27
Norris scale total score	Secondary	-9.9 ± 1.5	-7.0 ± 1.6	Diff 2.9 (-0.5 to 6.3)	p=0.10
Respiratory events / death (composite)	Secondary	0	0		None occurred in 16 weeks
Total AEs	Adverse	42 (66%)	40 (62%)		Similar
Adverse drug reactions	Adverse	1 (2%)	5 (8%)		Mostly injection-site related
Serious AEs	Adverse	2 (3%)	1 (2%)		None drug-related
AE leading to discontinuation	Adverse	0	0		None
Nasopharyngitis	Adverse	7 (11%)	4 (6%)		Common
Contusion at injection site	Adverse	7 (11%)	5 (8%)		Injection-related
Constipation	Adverse	4 (6%)	3 (5%)		Low
Deaths	Adverse	0	0		None

Subgroup Analysis

In patients using concomitant riluzole (90% of cohort), LSM difference was 2.11 points (95% CI 0.46-3.76; p=0.01) — essentially identical to the full cohort, confirming additive benefit. Subgroups by onset site (bulbar, upper extremity, lower extremity) and ALS severity grade (1 vs 2) showed directionally consistent effects, though individual subgroup analyses were not formally powered. The 43% reduction in decline closely matches the 45% effect from post-hoc analysis of the prior phase 2/3 trial, supporting reproducibility in the early-stage moderate-progressor population.

Criticisms

Only Japanese patients — generalizability to non-Asian populations uncertain
Short 16-week treatment; survival benefit from the earlier trial (>600 days) was not replicated because this design had no event endpoints
Enriched enrollment restricts findings to moderate progressors (1-2 point drop over 12 weeks); unclear whether fast or slow progressors benefit
Homocysteine reduction confirms target engagement but did not correlate with ALSFRS-R change, leaving mechanism unclear
Open-label extension continues to 2024 — long-term durability data still maturing at publication
Primary analysis was 1-tailed at 2.5% — slightly less conservative than a 2-tailed 5% test; effect is still statistically significant either way

Funding

Japan Agency for Medical Research and Development (AMED); Eisai Co, Ltd (investigational drug supply)

Based on: JETALS (JAMA Neurology, 2022)

Content summarized and formatted by NeuroTrials.ai.

JETALS

(2022)

Objective

Ultrahigh-dose methylcobalamin 50 mg IM twice weekly vs placebo — to validate efficacy and safety in early-stage ALS with moderate progression over 16 weeks.

Study Summary

• IM methylcobalamin 50 mg twice weekly slowed ALSFRS-R decline by 1.97 points over 16 weeks vs placebo.
• That difference represents a 43% reduction in clinical deterioration in early-stage moderate progressors.
• Benefit was apparent as early as week 4 (difference 0.99 points; p=0.003) and sustained through week 16.
• Plasma homocysteine fell 1.71 µmol/L more with methylcobalamin, confirming target engagement.
• No deaths, no respiratory events and similar AE rates (62% vs 66%) across 16 weeks.
• Reproduces the 45% effect size from post-hoc analysis of the prior phase 2/3 trial — consistent signal.

Intervention

IM injection of methylcobalamin 50 mg or matching placebo twice weekly for 16 weeks, after a 12-week observation period used to identify moderate progressors. Concomitant riluzole permitted.

Inclusion Criteria

Adults ≥20 years with sporadic or familial ALS (updated Awaji criteria: definite, probable, or probable laboratory-supported), within 1 year of symptom onset, ambulatory, FVC >60%, no prior non-invasive respiratory support or tracheostomy, and 1- or 2-point ALSFRS-R decrease during 12-week observation.

Study Design

Arms: Methylcobalamin 50 mg IM twice weekly vs Placebo IM twice weekly

Patients per Arm: Methylcobalamin 65; Placebo 64

Outcome

• Primary: ALSFRS-R change from baseline to week 16 — methylcobalamin -2.66 (SE 0.61) vs placebo -4.63 (SE 0.60); LSM diff 1.97 (95% CI 0.44-3.50); p=0.01
• Week-4 difference: 0.99 (95% CI 0.34-1.65; p=0.003); week-8 difference 0.99 (95% CI 0.04-1.95; p=0.04)
• Slope of ALSFRS-R: smaller with methylcobalamin by 0.12 points/week (95% CI -0.22 to -0.02; p=0.02)
• Plasma homocysteine: -1.71 µmol/L LSM difference (95% CI -2.23 to -1.20; p<0.001) — target engagement
• No deaths or respiratory events; total AEs 62% methylcobalamin vs 66% placebo; no AE-related discontinuations

Clinical Question

In adults with early-stage ALS (within 1 year of onset) and moderate progression (1-2 point ALSFRS-R decline over 12 weeks), does twice-weekly IM methylcobalamin 50 mg slow functional decline compared with placebo over 16 weeks?

Bottom Line

Major Points

Investigator-initiated multicenter double-blind placebo-controlled phase 3 RCT at 25 Japanese neurology centers, Oct 2017 - Sept 2019 (Oki/Izumi 2022)
Enriched design: 12-week observation filtered to moderate progressors (1- or 2-point ALSFRS-R drop)
N=130 randomized; N=129 in full analysis set after exclusion of one misdiagnosis; 126 (97%) completed
Intervention: IM methylcobalamin 50 mg or placebo twice weekly for 16 weeks
Primary endpoint: LSM difference in ALSFRS-R from baseline to week 16
Result: methylcobalamin -2.66 vs placebo -4.63, difference 1.97 (95% CI 0.44-3.50; p=0.01)
43% reduction in functional deterioration — matches 45% effect in prior post-hoc analysis
Week 4 difference already significant (0.99; p=0.003); slope analysis confirms durable effect
Plasma homocysteine dropped significantly with methylcobalamin (target engagement confirmed)
FVC, manual muscle test, Norris scale, ALSAQ-40 showed numerical but non-significant trends
Safety excellent: no deaths, no respiratory events, AE rates similar (62% vs 66%); 91% on concomitant riluzole
Supports regulatory approval in Japan for early-stage moderate-progressor ALS; open-label extension continues to 2024

Study Design

Study Type: Multicenter double-blind placebo-controlled phase 3 RCT (NCT03548311)
Randomization: Yes
Blinding: Double-blind (separate blinded efficacy and unblinded safety evaluators per site)
Sample Size: 130
Follow-up: 12-week observation + 16-week randomized + open-label extension to March 2024

Primary Outcome

Definition: Change in ALSFRS-R total score from baseline to week 16

Control	Intervention	HR/OR	P-value
-4.63 (SE 0.60)	-2.66 (SE 0.61)	- (0.44 to 3.50)	p=0.01

Limitations & Criticisms

Only Japanese patients — generalizability to non-Asian populations uncertain
Short 16-week treatment; survival benefit from the earlier trial (>600 days) was not replicated because this design had no event endpoints
Enriched enrollment restricts findings to moderate progressors (1-2 point drop over 12 weeks); unclear whether fast or slow progressors benefit
Homocysteine reduction confirms target engagement but did not correlate with ALSFRS-R change, leaving mechanism unclear
Open-label extension continues to 2024 — long-term durability data still maturing at publication
Primary analysis was 1-tailed at 2.5% — slightly less conservative than a 2-tailed 5% test; effect is still statistically significant either way

Citation

View Original Publication →

JETALS

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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