Vitamin B12 and muscle strength: the early-ALS injection trial did not establish a 16-week MMT benefit

Useful facts when choosing a product

• The principal evidence concerns E0302 IM injection with methylcobalamin as the sole active vitamin.
• Trial exposure was50mg twice weekly for16weeks,not personal-use instructions.
• Placebo comparison and permitted stable riluzole are distinguished.

What the research actually shows

# Vitamin B12 and muscle strength: the early-ALS injection trial did not establish a 16-week MMT benefit

## Reader answer and original question

Whether B12 improves strength in adults with weakness must be separated by population, deficiency, molecular form and route. In the principal JETALS trial, methylcobalamin 50 mg intramuscularly twice weekly for 16 weeks produced a placebo-adjusted MMT difference of **+0.8 points(95%CI−0.6 to2.3; P=.27)**. Strength benefit was not established, but neither exact zero nor equivalence was demonstrated. The positive ALSFRS-R functional result is a different endpoint. [S01:Table 2; S02:§10.2.5; S03:§6.5.2.4]

The original question is: “What effects, differences or risks link vitamin B12 with muscle strength in adults with reduced strength?” Proposed single-ingredient oral treatment, grip and a general adult comparator were research assumptions, not verified trial facts. A placebo-controlled single-B12 trial in an actual weakness disorder was prioritized; ordinary oral supplementation is not declared ineffective. **Efficacy D·28, safety Caution and manuscript quality A are separate assessments.** [Supplied task; S01–S08; supplied grading policy]

## Why this one endpoint and time were chosen

The page primary is **MMT total-score change from allocation baseline to16 weeks**. JETALS combines an actual neurogenic weakness disorder, single active B12, placebo comparison and direct strength assessment. MMT covers several muscles and avoids choosing the more favorable hand. Sixteen weeks is the specified blinded-treatment endpoint, not an invented time. The overall trial primary is ALSFRS-R change; MMT and right/left grip are secondary. Original registry fields/history remain separately unverified. [S01 Outcomes/Table 2; S02–S03]

The deficient oral study is nutritionally relevant but cannot provide a controlled causal estimate. B-PROOF is larger but tests B12 plus folic acid on a common vitaminD background and does not select low-strength patients. Kaji’s earlier long-duration ALS study and Shibuya’s IV neuropathy study differ in duration, scope and design; they are not pooled as matching independent replications. [S05–S08]

## Actual evidence: keep trials and scopes separate

| Study/access | Population, intervention and comparator | Direct strength endpoint, time and denominator | Reported result and role | |---|---|---|---| | JETALS, Oki 2022; full text/protocol/SAP | Early ALS; methylcobalamin 50 mg IM twice weekly16 weeks versus placebo; stable riluzole allowed | MMT change at 16 weeks; randomized 65/65, FAS 65/64 | Changes−2.9(SE0.7) versus−3.7(SE0.7); adjusted+0.8 points(CI−0.6 to2.3), P=.27. Primary page estimate. [S01–S03] | | JETALS, same trial | Same exposure and population | Right/left grip inkg,16 weeks; same FAS | Right−0.2(CI−1.6 to1.3), P=.83; left+0.4(CI−0.9 to1.7), P=.54. Not two independent trials or dominant-hand results. [S01–S02] | | B-PROOF, Swart 2016; full text/PDF | Age≥65, Hcy12–50µmol/L, not selected for weakness; B12 500 µg+folic acid400 µg/day2 years versus placebo; both arms vitaminD600 IU | Average of each hand’s maximum; Takei TKK5401; at-least-one-visit analysis1453/1455;2-year observations1304/1309 | Adjusted+0.1 kg(CI−0.2 to0.4), SE0.14, P=.48. Nonsignificant combination contrast, not B12 alone. [S05 Table 2] | | Sharma 2024; full text/PDF figure |28 volunteers age≥60;20 withB12<148 pmol/L;14 accepted cyanocobalamin 100 µg/day3 months | Nondominant hand, mean of 3maximal voluntary grip trials; Takei;14 before/after |23.4→32.2 kg, pairedP<.05. +8.8 kg is separate arithmetic, not a controlled contrast. Eight replete volunteers’31.8 kg is baseline only. [S06 Figure 2] | | Kaji 2019; relevant full-text sections |373ALS participants, onset≤36 months; IM25/50 mg twice weekly versus placebo182 weeks |MMT/grip secondary; matching16-week estimate not obtained |No established significant full-cohort MMT benefit in the narrative; the early-onset post hoc subset informed JETALS. Same program is not automatic independent replication. [S07] | | Shibuya 2014; official abstract only |14chronic neuropathy patients; IV25 mg/day10days then monthly5 months; uncontrolled |1-yearMRC, improvement in≥2of20 muscles;12 evaluable |7/12improved, two withdrawals. Not a controlled effect or evidence of ALS/oral equivalence. [S08] |

## Measurement, participants, numbers and analysis

The protocol body specifies **11 muscles**: neck anteflexion and bilateral shoulder abduction, elbow flexion, wrist dorsiflexion, hip flexion and ankle dorsiflexion. With 0–5permuscle, a nominal0–55sum follows arithmetically. However, Appendix5 omits a neck row and labels wrist/ankle flexion, so agreement with the implemented examination sheet is unconfirmed. MMT is a clinician’s ordinal manual-resistance score, not gripkg, forceN or isokinetic torqueNm. Higher scores are better. [S02 §10.2.5/Appendix5]

Of 203entering observation,130 were randomized. One placebo participant was rediagnosed with cervical canal stenosis after allocation and excluded, leaving FAS/safety denominators65/64. Two/one withdrew consent, leaving overall completers63/63. Those numbers are not substituted for observed16-week MMT counts. The tabulated−2.9 and−3.7 are estimated mean changes; parenthetical0.7 values are **SEs, not SDs**. Both groups worsened; +0.8 represents estimated lesser decline with injection. [S01 Figure 1/Table 2]

The public SAP specifies a repeated-measures mixed-model framework with analogous MMT analyses. Treatment, time, interaction, minimization factors and planned baseline adjustment are distinguished. The primary framework does not impute missing values; supplemental death-related missing-data analyses are separately planned. Without the implemented MMT design matrix, covariance and individual data, SAS/MMRM was not refitted here. P=.27 is the reported value, not an invented multiplicity-adjusted result. Exact contrastSE, individual-changeSD, a matching between-group MCID and equivalence margin remain null. [S01 StatisticalAnalysis; S03 §§6.5.1–6.5.2.5]

## Nutritional status, background therapy and contrasting findings

Baseline B12 was585.9±373.0 pg/mL with injection and571.8±719.9 pg/mL with placebo(mean±SD). Group means do not prove that every participant was replete. Stable riluzole was permitted, with 58 participants in each arm. The Table 1 total 119(92%) conflicts with 58+58 and the Results’116(90%). Arithmetic verifies116 without silently editing the original table or claiming identical background exposure for every participant. Edaravone was restricted; individual exercise/protein/vitaminD exposures are unknown. [S01 Table 1/Results; S02]

In the same trial, the ALSFRS-R difference of 1.97 points(CI0.44–3.50), P=.01 was significant. That is a functional-decline result, not “43%greater muscle strength.” Serum B12, homocysteine, CMAP/conduction, gait, balance, fatigue, muscle mass and anemia were not substituted for strength. [S01 Table 2]

Sharma’s positive oral before-after finding is retained but cannot remove time, learning, selection or baseline age/nutritional confounding. B-PROOF’s nonsignificant combination result is not exact zero or proof against all deficiency treatment. Reviews, follow-up reports and subgroups do not multiply trial families into independent studies. [S05–S08]

## Safety, funding and scope

Over 16 weeks in JETALS, adverse events occurred in 40/65 with injection versus 42/64 with placebo; drug-related reactions in 5/65versus1/64; serious events in 1/65versus2/64. Severe events occurred in one participant per arm, while AE-related discontinuations were reported as zero in both arms. Observed zero is not absence of all risk. The protocol excludes ALS worsening except death from AEs, and safety assessors were unmasked. These16-week data cannot establish longer-term, pregnancy/lactation, pediatric or severe renal/hepatic safety. [S01 Table 3; S02 §12]

Public AMED/MHLW grants coexist with Eisai product/nonfinancial support and author-disclosed support during conduct, leading to I1 for funding independence. No correction/retraction notice was identified on the accessed pages, but no exhaustive clearance is claimed. B-PROOF’s discussion of a cancer signal and Sharma’s14-person no-observed-AE statement remain distinct evidence layers. [S01 ArticleInformation; S05 Discussion; S06 Results]

The reported study exposures are not personal injection/dosing or treatment-change instructions. Pharmacologic IM treatment in early ALS is not converted into ordinary nutritional supplementation, nor are routes or molecular forms declared equivalent.

## Seven assessment explanations

### effect

MMT worsened in both arms; the estimated smaller decline with added injection was not statistically established. Direction, magnitude and clinical importance are separate, and nonsignificance is not equivalence.

### certainty

Direct randomized strength data exist, but this is a small secondary-outcome analysis with narrow applicability. The policy D28 is not a treatment-success probability, official GRADE rating or overall ALS drug verdict.

### applicability

The primary conclusion concerns trial-eligible adults with early ALS, methylcobalamin 50 mg IM twice weekly for 16 weeks, versus placebo with permitted stable background therapy. It is not generalized to ordinary oral supplementation, deficiency replacement or all adults with weakness.

### safety

The separate label is Caution. Actual16-week AE counts and denominators are reported, without excluding rare, long-term or special-population harm. Nonreporting, observed zero events, severe and serious are distinguished.

### verification

The 3165-record index,10 native candidates,286 selected prior originals and current recipient90 FULL receipts were checked. Strength gaps were verified against primary publications/protocol/SAP/figures; original-calculator and separate arithmetic receipts are provided. This is not independent external review.

### limitations

Original registry history, individual MMT data, a between-group MCID, observed endpoint counts and agreement of the implemented examination sheet remain uncertain. Conflicting source riluzole totals and all access failures are disclosed.

### score_note

For B/P/R1/I1/E0/B1/C0, the original calculator’s D is adopted. The supplied D/zero-strength numeric anchor is28, separate from the letter function. Coincidence with memory verdict3164D28 is not inheritance. Manuscript quality A and safety Caution are separate.

## Reasons for the seven final axes

| Axis | Value | Reason | |---|---|---| | claim_type | B | B: This is a human clinical muscle-strength claim, not a physical fact about molecules, serum B12 or nerve conduction. | | endpoint | P | P: Clinician-assessed direct strength is a functional treatment target under the supplied policy, not a hard event H or biomarker S. The code’s abbreviated label does not make MMT patient self-report. | | replication | R1 | R1: JETALS directly supplies this early-ALS/IM-dose/MMT/16-week contrast. Kaji’s different duration and post hoc subset, IV neuropathy, deficient before-after data and B-PROOF combination data are not counted as matching independent replications. | | independence | I1 | I1: Public AMED/MHLW funding coexists with Eisai product/nonfinancial support and author-disclosed Eisai support during conduct. This is neither manufacturer-only I0 nor exclusively public I2. | | effect | E0 | E0: The 16-week MMT difference is+0.8 points,95%CI−0.6 to2.3, P=.27: benefit is not demonstrated. This code does not mean exact zero, equivalence or exclusion of clinically important benefit. Positive ALSFRS-R is not repurposed as positive strength. | | bias | B1 | B1: One verified criterion in policy axis6 applies:130 randomized participants, below200. Central allocation, masked efficacy assessment and low overall attrition were verified. Unconfirmed masking success, secondary status and registry access limits are disclosed without inventing a second proven defect. Funding and CI are not double-counted as bias. | | precision | C0 | C0: The CI includes zero and benefit, with no matching between-group MMT MCID to exclude meaningful benefit. The CI is available, so this is not CX. RX/C1/F are not fabricated. |

## Twelve classification facets and displayed values

**kind** — M — The decisive exposure is an investigational pharmacologic IM product, replacing provisional S after evidence review.

**canonical_entity** — Vitamin B12; retain the supplied original tag and existing representative list.

**source_part** — Single B12 molecular form methylcobalamin; plant part/species is not applicable. Manufacturing raw-material origin is unconfirmed.

**formulation** — Lyophilized E0302 injection, B12 as the sole active vitamin; distinguish B-combination trials.

**route** — Intramuscular; no equivalence to oral, sublingual, intravenous or transdermal exposure.

**dose** — Trial exposure50 mg methylcobalamin per administration, twice weekly; not personal dosing instructions.

**duration** — 12-week observation followed by 16-week randomized treatment; page time is16 weeks from allocation baseline, not the open-label extension.

**population** — Early ALS adults entering observation within 1 year of onset, declining1–2ALSFRS-R points over 12 weeks, ambulatory withFVC>60%. Not selected for B12 deficiency or sarcopenia.

**claim** — Change in direct muscle strength, not gait, balance, falls, CMAP, fatigue, muscle mass, anemia or biomarkers.

**primary_endpoint** — MMT total change at 16 weeks; clinician MRC manual-resistance assessment of nominally11 muscles. A positive contrast means less worsening. Not labeled as the original registered sole primary.

**comparator** — Placebo injection; stable riluzole allowed(58 perarm), edaravone restricted. Background drugs were not identical for every individual.

**duplicate_key** — Internal TASK-1051 boundary: B12/methylcobalamin/IM/earlyALS/MMT/16 weeks/placebo. Not a newly assigned site semantic code.

## All unknown, conflicting and nonapplicable details

**U01 · original_registry · inaccessible** — JETALS original registry fields and amendment history were inaccessible. The publication and supplied publisher protocol/SAP identify primary ALSFRS-R and secondary MMT, but this is not a verified comparison of all original registry fields. [S01/S02/S03/S09]

**U02 · baseline_strength · not_reported** — Baseline MMT mean/SD and a numeric low-strength entry threshold were not established. Eligibility concerns early ALS and progression, not general sarcopenia. [S01/S02]

**U03 · B12_status · not_reported** — Only group baseline B12 means/SDs were verified. Individual deficiency status, MMA, malabsorption, total intake and causes are unavailable; not every participant is declared replete. [S01 Table 1]

**U04 · MMT_sheet · conflicting** — The protocol body specifies11 muscles and wrist/ankle dorsiflexion, but Appendix5 lacks a neck row and labels flexion. The nominal11×5=55 maximum is arithmetic; agreement with the implemented sheet and its valid range is not confirmed. [S02 §10.2.5 / Appendix5]

**U05 · observed_denominator · not_reported** — FAS 65/64 and overall16-week completers63/63 differ from endpoint-specific observed MMT counts. Table 2 does not supply the latter;126 measured MMT participants are not invented. [S01 Figure 1/Table 2]

**U06 · MMT_variance · not_reported** — The table’s0.7 values are SEs of estimated mean changes. Individual-change SDs, contrast SE, repeated-measure covariance and model degrees of freedom are unavailable; exact values were not back-calculated from rounded CIs. [S01 Table 2]

**U07 · MCID · not_reported** — A 16-week between-group MCID, equivalence margin and trial-specific reliability for this MMT sum were not verified. ALSFRS-R thresholds, grip-kg thresholds and Cohen conventions are not substituted. [S01/S02/S03]

**U08 · model_reproduction · inaccessible** — Individual data, analysis code and the implemented design matrix were unavailable. MMRM/adjusted CIs and P values were not refitted; reading a plan is not running SAS. [S01/S03]

**U09 · missingness · not_reported** — Overall withdrawals and the no-imputation framework were verified, but visit-specific MMT missingness, the plausibility of MAR and all implemented supplemental results were not established. [S01/S03]

**U10 · multiplicity · not_reported** — MMT is secondary and was not the power target. No MMT-specific multiplicity-adjusted result was verified; P=.27 is retained as reported, not converted using the primary endpoint’s one-sided threshold. [S01/S03]

**U11 · blinding · not_reported** — Masked efficacy assessment and separate administration staff were verified. Precautions addressed red urine, but successful participant masking was not tested in the accessible report; failure is not asserted as proven. [S01/S02]

**U12 · riluzole_total · conflicting** — Table 1 gives58+58 participants but total 119(92%). The Results text116(90%) agrees with the arm values and arithmetic. The discrepancy is retained, not silently repaired in the source. [S01 Table 1/Results]

**U13 · cointerventions · not_reported** — Stable riluzole was allowed and edaravone was restricted. Actual individual exercise, protein, vitaminD and diet exposures and their effect modification were not established. [S01/S02]

**U14 · grip_detail · not_reported** — JETALS grip uses separate right/left maxima, not dominance analysis. Device brand/model, calibration, posture, rest and a matching MCID were not verified. No knee-extension or isokinetic torque result is substituted. [S02 §10.2.6]

**U15 · generalization · not_applicable** — This pharmacologic IM ALS result does not establish equivalent effects in general aging, sarcopenia, deficient anemia, malabsorption or peripheral neuropathy, or with oral/sublingual/IV B12. [S01/S05/S06/S08]

**U16 · longterm_safety · not_reported** — A 16-week safety table cannot establish longer-term, pregnancy/lactation, pediatric, severe renal/hepatic or all-drug-combination safety. ALS worsening except death was excluded from AE classification, and safety assessors were unmasked. [S01/S02]

**U17 · funding_scope · confirmed** — Public grants coexist with Eisai product/nonfinancial support and disclosed support during the trial, supporting I1. This is not an allegation of manipulation, nor does same-model self-review constitute independent external review. [S01 ArticleInformation]

**U18 · Sharma_control · not_applicable** — The 14-person deficient before-after improvement in Sharma is not a randomized treatment contrast. Baseline grip in 8 replete volunteers is not a concurrent treated-control arm; +8.8 kg is not assigned as a causal B12 effect. [S06 Figure 2]

**U19 · Sharma_variance_registration · not_reported** — Sharma’s exact paired P, change SD/CI, IPD, original registered primary and complete tablet actives were not verified. Printed figure values were read; error bars were not digitized from pixels. [S06/S11]

**U20 · BPROOF_attribution · not_applicable** — B-PROOF adds folic acid and gives vitaminD to both arms. It cannot isolate B12’s contribution and did not select a low-grip treatment population. [S05]

**U21 · BPROOF_form_safety · not_reported** — B-PROOF’s B12 molecular form, matching MCID, original registry fields/history and detailed re-extraction of its cancer signal were not established. Its2.3 kg power assumption is not an MCID. [S05/S10]

**U22 · other_trials · inaccessible** — A fully matching16-week MMT estimate from Kaji and Shibuya’s full-text measurement details were not obtained. Different durations, routes and diseases are not invented as matching replications or controlled effects. [S07/S08]

**U23 · corrections_retractions · not_reported** — No correction/retraction notice was identified on the accessed publication pages, and internal discrepancies are disclosed separately. Several exact searches returned irrelevant results; no exhaustive clearance or guarantee of absence is claimed. [Search log / S01–S08]

**U24 · raw_downloads · inaccessible** — Relevant full text and PDF pages were read through web tools, but filesystem downloads failed. Newly fetched article PDF/HTML bytes or hashes are not purportedly included; structured extractions, direct sources and failures are supplied. [source_snapshots/fetch_receipt.json]

**U25 · marketing · not_searched** — Advertising copy was not collected, so what_ads is null. The original research question is not repurposed as a marketing claim. [Task scope]

## Editorial, publication and reuse status

This is a completed new independent claim. Manuscript quality A denotes completeness of source tracking, numbers, uncertainties, language and structure—not infallibility or independent certification. Review is by the same model, independent=false, with initial corrections=[]. Pre-submission findings, fixes and access failures are recorded separately. clinical_todo=[]; clinical recalculation or re-investigation is not delegated to the recipient.

Existing IDs110,1059,1340,1440,3111–3114,3164,3165 retain their original values, bilingual text and unknowns. B-PROOF from1340 and other completed families were reused; only strength gaps were researched. The supplied latest state is84published,6exactduplicates,10pending,native3165,recipientFULL2/5. This handoff is not publication:ID/site_id/slug/URL/semanticcode/firstpublication remain null. The displayed original is identical in en.body_markdown,en.what_research andpublication.en.md.

## Direct sources

**S01** — Efficacy and Safety of Ultrahigh-Dose Methylcobalamin in Early-Stage Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. DOI 10.1001/jamaneurol.2022.0901. https://jamanetwork.com/journals/jamaneurology/fullarticle/2792228 Access: full_text_html; Methods: Participants, Randomization, Intervention, Outcomes, Statistical Analysis; Figure 1; Table 1; Table 2: MMT and right/left grip, week 16; Table 3; Limitations; Article Information: Conflict of Interest Disclosures; Funding/Support.

**S02** — JETALS protocol E0302-TOK-763, Supplement 1 to Oki 2022. DOI 10.1001/jamaneurol.2022.0901. https://jamanetwork.com/journals/jamaneurology/fullarticle/2792228 Access: full_pdf_via_signed_publisher_link_relevant_sections; Section 8: central allocation and blinding; Section 10.2.5, printed p41 / PDF page index40: MMT muscles; Section 10.2.6: grip procedure; Section 12: adverse events; Section 18.2: analysis; Appendix 5, printed pp79–80 / PDF page indices78–79: MRC grades and examination sheet.

**S03** — JETALS statistical analysis plan, Supplement 2 to Oki 2022. DOI 10.1001/jamaneurol.2022.0901. https://jamanetwork.com/journals/jamaneurology/fullarticle/2792228 Access: full_pdf_via_signed_publisher_link_relevant_sections; Sections 4.4 and 6.5.1, printed pp21–22; Section 6.5.2.4, printed p23 / PDF page index22: MMT; Section 6.5.2.5: right/left grip; Section 6.6 safety.

**S04** — JETALS supplementary results, Supplement 3 to Oki 2022. DOI 10.1001/jamaneurol.2022.0901. https://jamanetwork.com/journals/jamaneurology/fullarticle/2792228 Access: full_pdf_available_selected_sections_read; eTable adverse events; eAppendix eligibility; eAppendix sample size and 16-week rationale.

**S05** — A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study. DOI 10.1007/s00223-015-0059-5. https://link.springer.com/article/10.1007/s00223-015-0059-5 Access: full_text_html_and_pdf; Methods: participants/intervention, handgrip, statistical analysis; Figure 1; Table 1; Table 2; Discussion and Acknowledgments.

**S06** — Vitamin B12 status and skeletal muscle function among elderly: A literature review and pilot study on the effect of oral vitamin B12 supplementation in improving muscle function. DOI 10.1002/agm2.12346. https://onlinelibrary.wiley.com/doi/10.1002/agm2.12346 Access: full_text_html_and_pdf; Methods: subjects, handgrip, supplementation and statistical analysis; Table 1; Figure 2: visible value labels; PDF page index6; Results: compliance and adverse effects; Acknowledgments and conflicts.

**S07** — Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. DOI 10.1136/jnnp-2018-319294. https://pmc.ncbi.nlm.nih.gov/articles/PMC6581107/ Access: full_text_html_selected_strength_and_design_sections; Methods: trial population and secondary outcomes; Results: full cohort and post hoc early-onset subgroup; Discussion: MMT trend; Funding.

**S08** — Safety and Efficacy of Intravenous Ultra-high Dose Methylcobalamin Treatment for Peripheral Neuropathy: A Phase I/II Open Label Clinical Trial. DOI 10.2169/internalmedicine.53.1951. https://www.jstage.jst.go.jp/article/internalmedicine/53/17/53_53.1951/_article Access: official_journal_abstract_only; Abstract: Methods and Results.

**S09** — ClinicalTrials.gov NCT03548311 access attempt. https://clinicaltrials.gov/study/NCT03548311 Access: inaccessible_record_fields_js_shell; Record landing shell only; API attempt failed.

**S10** — ClinicalTrials.gov NCT00696514 access attempt. https://clinicaltrials.gov/study/NCT00696514 Access: inaccessible_record_fields_js_shell; Record shell; publication reports NTR1333/NCT00696514.

**S11** — CTRI search interface access attempt. https://ctri.nic.in/ Access: search_interface_only_record_not_retrieved; CTRI/2009/091/000493 reported in S06; original record unavailable in this run.

Why this is classified as D (28)

For B/P/R1/I1/E0/B1/C0, the original calculator’s D is adopted. The supplied D/zero-strength numeric anchor is28, separate from the letter function. Coincidence with memory verdict3164D28 is not inheritance. Manuscript quality A and safety Caution are separate.

Counterpoint. Original registry history, individual MMT data, a between-group MCID, observed endpoint counts and agreement of the implemented examination sheet remain uncertain. Conflicting source riluzole totals and all access failures are disclosed.

Review performed and remaining limitations

Original registry history, individual MMT data, a between-group MCID, observed endpoint counts and agreement of the implemented examination sheet remain uncertain. Conflicting source riluzole totals and all access failures are disclosed.

Evidence Table

| Study/access | Population, intervention and comparator | Direct strength endpoint, time and denominator | Reported result and role | |---|---|---|---| | JETALS, Oki 2022; full text/protocol/SAP | Early ALS; methylcobalamin 50 mg IM twice weekly16 weeks versus placebo; stable riluzole allowed | MMT change at 16 weeks; randomized 65/65, FAS 65/64 | Changes−2.9(SE0.7) versus−3.7(SE0.7); adjusted+0.8 points(CI−0.6 to2.3), P=.27. Primary page estimate. [S01–S03] | | JETALS, same trial | Same exposure and population | Right/left grip inkg,16 weeks; same FAS | Right−0.2(CI−1.6 to1.3), P=.83; left+0.4(CI−0.9 to1.7), P=.54. Not two independent trials or dominant-hand results. [S01–S02] | | B-PROOF, Swart 2016; full text/PDF | Age≥65, Hcy12–50µmol/L, not selected for weakness; B12 500 µg+folic acid400 µg/day2 years versus placebo; both arms vitaminD600 IU | Average of each hand’s maximum; Takei TKK5401; at-least-one-visit analysis1453/1455;2-year observations1304/1309 | Adjusted+0.1 kg(CI−0.2 to0.4), SE0.14, P=.48. Nonsignificant combination contrast, not B12 alone. [S05 Table 2] | | Sharma 2024; full text/PDF figure |28 volunteers age≥60;20 withB12<148 pmol/L;14 accepted cyanocobalamin 100 µg/day3 months | Nondominant hand, mean of 3maximal voluntary grip trials; Takei;14 before/after |23.4→32.2 kg, pairedP<.05. +8.8 kg is separate arithmetic, not a controlled contrast. Eight replete volunteers’31.8 kg is baseline only. [S06 Figure 2] | | Kaji 2019; relevant full-text sections |373ALS participants, onset≤36 months; IM25/50 mg twice weekly versus placebo182 weeks |MMT/grip secondary; matching16-week estimate not obtained |No established significant full-cohort MMT benefit in the narrative; the early-onset post hoc subset informed JETALS. Same program is not automatic independent replication. [S07] | | Shibuya 2014; official abstract only |14chronic neuropathy patients; IV25 mg/day10days then monthly5 months; uncontrolled |1-yearMRC, improvement in≥2of20 muscles;12 evaluable |7/12improved, two withdrawals. Not a controlled effect or evidence of ALS/oral equivalence. [S08] |

Receipt — 11 References

Evidence access cutoff: 2026-09-18. Each citation states its actual access level (full-text transcription, abstract, index, or other) and remaining limitations. Bibliographic checking does not certify the study results or treatment efficacy.

What this document does and does not do

Chamgap is an information source. It reports what research has and has not confirmed; it does not tell readers what to take or buy. That decision belongs to readers and, when needed, medical or legal professionals. This verdict reflects literature available up to the search date and may change as new research appears. Nothing here is medical advice.