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Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial
Open accessAbstract
Background Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease.Methods We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11).Findings Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants.Interpretation The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon.Funding TauRx Therapeutics.
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“Two earlier studies (NCT01689233 and NCT01689246) conducted on participants with mild AD and mild to moderate AD, respectively, indicated that the drug demonstrated good safety and potential benefits as a monotherapy.466,467”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [467]
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“Clinical trials of methylene blue-derived tau inhibitors in AD have generally yielded disappointing results [47–49].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [47]
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“Unfortunately, in two different phase 3 trials testing LMTM in all-cause dementia and mild-to-moderate AD, there was no reduction in rate of decline of cognition or ADL compared to placebo (Gauthier et al., 2016).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gauthier et al., 2016
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“Whether LMTM at the doses administered prevented accumulation of aggregated tau or decreased existing deposits was not tested.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gauthier et al., 2016
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“Unfortunately, these new medications faced unusual rates of clinical failures [12–14]; AD clinical trials accomplished a success rate of only 0.4% from 2002 to 2012 [15].”
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Twenty years of therapeutic development in tauopathy mouse models: a scoping review
Langness, V. F., Simmons, D. A., McHugh, T. L. M., Butler, R. R., Zhou, J., Liu, H., Yang, T., Ellerby, L., & Longo, F. M. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70578 · Cited by 9
Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives
Hroudová, J., & Fišar, Z. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111491 · Cited by 9
Targeting tau in Alzheimer’s Disease: rationale, approach and challenges
Aslanyan, A., Foiani, M. S., Giovannucci, T. A., McDade, E., Duff, K., Mummery, C. J., Schöll, M., Wildsmith, K. R., & Paterson, R. W. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00925-5 · Cited by 10
“Phase 3 trials in humans showed no safety concerns [205, 206] and although the initial results were reported to show no overall differences in the clinical or neuro-imaging outcomes, it was later suggested that the lack of clinical difference was due to combination activity of hydromethylthionine…”
Tau and β-Amyloid Relevant Pathology as a Central Therapeutic Target in Alzheimer’s Disease
Strużyńska, L., Adamiak, K., & Sidoryk‐Wȩgrzynowicz, M. (2026) · Biomolecules · doi:10.3390/biom16040595 · Cited by 9
“However, clinical trials have not confirmed this effectiveness [87].”
Zheng, X., Tang, Y., Yang, Q., Wang, S., Chen, R., Tao, C., Zhang, P., Fan, B., Zhan, J., Tang, C., et al. (2022) · Journal of the American Geriatrics Society · doi:10.1111/jgs.18025 · Cited by 10
Kammula, S. V., Tripathi, S., Wang, N., Dawson, V. L., Dawson, T. M., & Mao, X. (2023) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2023.20 · Cited by 9
Wang, F., Feng, J., Yang, Y., Liu, J., Liu, M., Wang, Z., Pei, H., Wei, Y., & Li, H. (2018) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s175484 · Cited by 8
“11 Other proposed hypotheses for AD pathogenesis, such as oxidative stress and metal-ion accumulation, have been demonstrated to play a key role in blood–brain barrier (BBB) disruption, with BBB disruption possibly upstream of A β deposition and/or tau hyperphosphorylation in the pathogenic cascade…”
de Oliveira, B. S. A., Milanezi, D. S., Gonzaga, P. D. V., Detoni, F. R., & Soriano, R. N. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e12172 · Cited by 10
Focusing on oligomeric tau as a therapeutic target in Alzheimer’s disease and other tauopathies
Rayman, J. B. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2206561 · Cited by 11
“including LMTM (TRx0237) [65], which failed in Phase 3 clinical trials for AD (NCT01689246 and NCT01689233).”
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Zhang, L., Wang, Z., Yuan, X., Sui, R., & Falahati, M. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.05.018 · Cited by 9
Alzheimer’s Disease and Dementia
Lewis, P. A., & Spillane, J. E. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-811069-0.00002-1 · Cited by 9
Diverse influences on tau aggregation and implications for disease progressionPreprint
Alstyne, M. V., Pratt, J., & Parker, R. (2025) · Genes & Development · doi:10.1101/gad.352551.124 · Cited by 11
“A derivative hydromethylthionine mesylate has progressed to phase III trials where it failed to show clinical benefit (Gauthier et al. 2016), though additional trials have continued (Wischik et al. 2022).”
Treating Alzheimer’s Disease: Focusing on Neurodegenerative Consequences
Sun, M., & Alkon, D. L. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240479 · Cited by 8
Deep brain stimulation of the nucleus basalis of Meynert in severe Alzheimer’s disease
Xu, J., Liu, B., Shang, G., Liu, S., Feng, Z., Yang, H., Liu, D., Chang, Q., Chen, Y., Yu, X., et al. (2024) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823241296780 · Cited by 8
Foressi, N. N., Rodríguez, L. C., & Celej, M. S. (2024) · Biophysical Reviews · doi:10.1007/s12551-024-01259-6 · Cited by 8
“However, it failed to show efficacy in phase III clinical trials (Gauthier et al. 2016).”
Overview of Proteomic Analysis of Amyloid Plaques and Neurofibrillary Tangles in Alzheimer’s Disease
Grewal, A., Raikundalia, S., Zaia, J., & Sethi, M. K. (2025) · Biomolecules · doi:10.3390/biom15091310 · Cited by 9
“Tau aggregation inhibitors, such as LMTX (leuco-methylthioninium bis(hydromethanesulfonate)), have shown promise by disrupting tau fibril formation, with Phase III trial data suggesting clinical benefits for patients not on concomitant AD medications [29,30].”
Santos, R. X., Melis, V., Goatman, E. A., Leith, M., Baddeley, T. C., Storey, J. M. D., Riedel, G., Wischik, C. M., & Harrington, C. R. (2022) · Biomedicines · doi:10.3390/biomedicines10040867 · Cited by 8
“effective as a monotherapy, suggesting that comedication with classical symptomatic therapies would affect the efficacy of HMTM [36,37].”
BackgroundSelf-citationEffect of Vitamin E on Transcriptomic Alterations in Alzheimer’s Disease
Ekeuku, S. O., Murshid, N. M., Shukri, S. N., Sahardi, N. F. N. M., & Makpol, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512372 · Cited by 9
Исаев, Н. К., Генрихс, Е. Е., & Stelmashook, E. V. (2024) · Reviews in the Neurosciences · doi:10.1515/revneuro-2024-0007 · Cited by 8
Tau-based therapies for Alzheimer’s disease: Promising novel neuroprotective approaches
Sayas, C. L. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814037-6.00005-7 · Cited by 9
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Musa, M. S., Islam, M. T., Billah, W., Hossain, M. S., Rahat, M. S. S., Bayıl, İ., Munni, Y. A., & Ganguli, S. (2024) · PLoS ONE · doi:10.1371/journal.pone.0311401 · Cited by 7
RetractedAfrakoti, L. G. M. P., Moghadam, S. D., & Hadinezhad, P. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823251329188 · Cited by 12
Glial Cells in Alzheimer’s Disease: Pathogenic Mechanisms and Therapeutic Frontiers
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Investigational therapeutics for the treatment of progressive supranuclear palsy
Coughlin, D. G., & Litvan, I. (2022) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2022.2087179 · Cited by 8
“However, studies in AD and behavioral variant frontotemporal dementia failed to show benefits, calling into doubt whether these derivatives will be useful in PSP [74,75] (NCT01689233, NCT01689246, NCT01626378).”
BackgroundXu, J., Liu, B., Feng, Z., Yu, X., Shang, G., Liu, Y., Sun, Y., Yang, H., Chen, Y., Zhang, Y., et al. (2024) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823241297852 · Cited by 6
The tauopathies: Neuroimaging characteristics and emerging experimental therapies
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Metadata
- Authors
- Gauthier, S., Feldman, H. H., Schneider, L. S., Wilcock, G. K., Frisoni, G. B., Hardlund, J. H., Moebius, H. J., Bentham, P., Kook, K. A., Wischik, D. J., Schelter, B. O., Davis, C. S., Staff, R. T., Bracoud, L., Shamsi, K., Storey, J. M. D., Harrington, C. R., & Wischik, C. M.
- Affiliations
- Douglas Mental Health University Institute (CA)
- University of California San Diego (US)
- University of Southern California (US)
- University of Oxford (GB)
- University of Geneva (CH)
- TauRx (United Kingdom) (GB)
- University of Aberdeen (GB)
- Corresponding author
- Wischik, Claude M
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 388
- Issue
- 10062
- Pages
- 2873-2884
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5164296
- OpenAlex
- W2553774099
- Cited by
- 427
- References
- 31
- Citations by year
- 2026: 25 · 2025: 46 · 2024: 47 · 2023: 41 · 2022: 47 · 2021: 46 · 2020: 48 · 2019: 47 · 2018: 48 · 2017: 27 · 2016: 4
- FWCI
- 33.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- PubMed Central (acceptedVersion)
- Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- TauRx Pharmaceuticals
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, tau aggregation, methylene blue, disease progression, ADAS-Cog, cognitive decline, activities of daily living, methemoglobinemia, drug safety, mild to moderate Alzheimer's disease, amyloid PET, FDG-PET
- MeSH terms
- Activities of Daily Living, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, tau Proteins, Treatment Failure, Mice
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