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Study · Randomized controlled trial · n = 598 · 2026

2 results

Clinical, imaging and blood biomarker outcomes in a Phase 3 clinical trial of tau aggregation inhibitor hydromethylthionine mesylate in mild cognitive impairment and mild to moderate dementia due to Alzheimer's disease.

Wischik CM, Stefanacci R, Bentham P, Gauthier S, Zetterberg H, Wilcock GK, Froelich L, Burns A, MacSweeney E, Ballard C, Yu JT, Choon TS and 21 more

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Asvatourian V, Muehlemann N, Priel J, Kook K, Sullivan T, Downie D, Miller S, Pringle C, Storey JMD, Baddeley T, Harrington CR, Penny LK, Arastoo M, Staff R, Sandu AL, Shiells H, Lo S, Nazlee N, Evans E, Hull C, Schelter BO

The journal of prevention of Alzheimer's disease21 Jan 2026Cited by 6 (Europe PMC)

PMID41570392 (opens in a new tab)PMCIDPMC12861207 (opens in a new tab)DOI10.1016/j.tjpad.2026.100480 (opens in a new tab)PepBankPUB-41570392
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Summary

BackgroundHydromethylthionine mesylate (HMTM) targets tau pathology and has tau-independent symptomatic activity.ObjectivesTo evaluate the safety and efficacy of HMTM in participants with mild cognitive impairment (MCI) and mild to moderate dementia due to Alzheimer's disease (AD).Setting82 centres in Canada, European Union, United Kingdom and United States of America.ParticipantsA total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.InterventionHMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.MeasurementsHMTM and MTC were compared on cognitive and functional endpoints for the first 52 weeks followed by all receiving HMTM 16 mg/day to 104 weeks in a modified delayed-start trial design. Biomarker outcomes included change in plasma levels of neurofilament light chain (NfL), pTau217 and MRI measures of grey matter atrophy.ResultsIt was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm. In participants with MCI, statistically significant differences in cognitive decline (ADAS-cog13) emerged at 78 weeks (p = 0·0291) and 104 weeks (p = 0·0308) between early- and delayed-start HMTM 16 mg/day in analyses specified prior to the 24-month database lock. Statistically significant cognitive improvement over baseline score was sustained for 78 weeks in the early start MCI group, with no significant cognitive or functional decline to 104 weeks. There was a significant reduction in progression of neurodegeneration measured by NfL change (p = 0·0291) at 52 weeks in the whole population, consistent with significant reductions in progression of grey matter atrophy at 52 and 104 weeks, and a reduction in progression of tau pathology (pTau217, p = 0·0165) in MCI. Headache (1·5%) and diarrhoea (1·2%) were the most frequent adverse effects.ConclusionsAlthough HMTM 16 mg/day arrested progression of neurodegeneration and reduced grey matter atrophy at 52 weeks, symptomatic activity in the control arm precluded separation of treatment arms at 52 weeks on primary clinical endpoints. In participants with MCI, significant clinical separation was seen only at 78 and 104 weeks. This effect has been confirmed in a further study. HMTM was well tolerated and has the potential to offer an accessible oral treatment option with a benign safety profile which could be delivered with minimal patient/physician burden.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

2 results from studies that gave the peptide. 2 results from people.

  1. 01HumanRandomized controlled trialEfficacy outcome

    In participants with MCI or mild to moderate Alzheimer's dementia, no significant difference between HMTM and methylthioninium chloride 4 mg twice weekly was demonstrated on ADAS-cog11 at 52 weeks, which the authors attribute to symptomatic activity in the control arm.

    In plain wordsIn Alzheimer's disease, no difference in cognitive scores was shown at 52 weeks, which the authors link to activity in the control arm.

    Peptide
    Methylene blue
    Outcome
    No significant changeADAS-cog11
    Study

    n = 598

    Comparator
    HMTM 16 mg/day and 8 mg/day
    Analysis
    Primary
    Outcome group
    Cognition and memory · Nervous system and cognition
    Studied dose
    4 mg twice weekly · 52 weeksAs given in this study (human).

    Source sentences

    Summary
    It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm.
    2 context sentences
    Summary · context
    A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.
    Summary · context
    HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.
  2. 02HumanRandomized controlled trialEfficacy outcome

    In participants with MCI or mild to moderate Alzheimer's dementia, no significant difference between HMTM and methylthioninium chloride 4 mg twice weekly was demonstrated on ADCS-ADL23 at 52 weeks, which the authors attribute to symptomatic activity in the control arm.

    In plain wordsIn Alzheimer's disease, no difference in daily functioning was shown at 52 weeks, which the authors link to activity in the control arm.

    Peptide
    Methylene blue
    Outcome
    No significant changeADCS-ADL23
    Study

    n = 598

    Comparator
    HMTM 16 mg/day and 8 mg/day
    Analysis
    Primary
    Outcome group
    Cognition and memory · Nervous system and cognition
    Studied dose
    4 mg twice weekly · 52 weeksAs given in this study (human).

    Source sentences

    Summary
    It was not possible to demonstrate significant differences on the co-primary clinical endpoints (ADAS-cog11 and ADCS-ADL23) at 52 weeks due to symptomatic activity in the control arm.
    2 context sentences
    Summary · context
    A total of 598 amyloid β-PET positive participants were included; 44% (263) met clinical criteria for MCI due to Alzheimer's disease and 56% (335) were diagnosed with mild to moderate dementia due to AD.
    Summary · context
    HMTM 16 mg/day and 8 mg/day were compared with methylthioninium chloride (MTC) 4 mg twice weekly, intended as an inactive urinary colourant to preserve blinding with respect to possible urinary discolouration caused by HMTM.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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