The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., Currier, G. W., Melvin, G. A., Greenhill, L., Shen, S., et al. (2011) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2011.10111704 · Cited by 5,157
(2015) · HAL · Cited by 2,238
The clinical use of structural MRI in Alzheimer disease
Frisoni, G. B., Fox, N. C., Jack, C. R., Scheltens, P., & Thompson, P. M. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.215 · Cited by 2,113
Self-citationTwo Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960
Defeating Alzheimer's disease and other dementias: a priority for European science and society
Winblad, B., Amouyel, P., Andrieu, S., Ballard, C., Brayne, C., Brodaty, H., Cedazo-Minguez, A., Dubois, B., Edvardsson, D., Feldman, H., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)00062-4 · Cited by 1,676
Self-citationPhase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease
Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1312889 · Cited by 1,668
Inestrosa, N. C., Alvarez, A. R., Pérez, C. A., Moreno, R. D., Vicente, M., Linker, C., Casanueva, O. I., Soto, C. A., & Garrido, J. (1996) · Neuron · doi:10.1016/s0896-6273(00)80108-7 · Cited by 1,117
Wischik, C. M., Novak, M., Thøgersen, H. C., Edwards, P. C., Runswick, M. J., Jakes, R., Walker, J. E., Milstein, C., Roth, M., & Klug, A. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.12.4506 · Cited by 939
Self-citationThe pathological process underlying Alzheimer’s disease in individuals under thirty
Braak, H., & Del Tredici, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-010-0789-4 · Cited by 812
Maruyama, M., Shimada, H., Suhara, T., Shinotoh, H., Ji, B., Maeda, J., Zhang, M.-R., Trojanowski, J. Q., Lee, V. M.-Y., Ono, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.037 · Cited by 760
Cited by
Sorted by citations
Items 401–429 of 429
Peng, D., Xu, S., Zou, T., Wang, Y., Ouyang, W., Zhang, Y., Dong, C., Li, D., Guo, J., Shen, Q., et al. (2024) · Figshare · doi:10.6084/m9.figshare.24630451
Peng, D., Xu, S., Zou, T., Wang, Y., Ouyang, W., Zhang, Y., Dong, C., Li, D., Guo, J., Shen, Q., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24630304
Wang, H., & Yao, Z. (2025) · Neuropharmacology and Therapy · doi:10.15212/npt-2025-0026
Applying the Estimand Framework: Case Studies in Neuroscience
Burger, H. U., Sfikas, N., Magnusson, B., Josiassen, M. K., Quarg, P., Monnet, A., Anzures‐Cabrera, J., Shariati, N., & Delmar, P. (2025) · Springer series in pharmaceutical statistics · doi:10.1007/978-3-032-02192-2_9
Marqueurs périphériques de l'inflammation et déclin cognitif au cours de la maladie d'Alzheimer
Julian, A. (2018) · theses.fr (ABES) · doi:10.70675/0f58e0a1z28d9z40b7z886fz752caf42c261
Caractérisation d'anticorps à domaine unique dirigés contre la protéine Tau
Danis, C. (2018) · theses.fr (ABES) · doi:10.70675/c783a062zb57bz4024z85d0z509baaed8a1b
Altered neuronal activity in the hippocampal CA3 region in an in vitro model of tauopathy
Goncalves, A. (2020) · theses.fr (ABES) · doi:10.70675/b42db6dez88a0z4a14z93eez8f51d19d46f5
Lelong, E. (2021) · theses.fr (ABES) · doi:10.70675/7cda5a3ez022cz475az9b2bz977814a60663
Poulot-Becq-Giraudon, Y. (2024) · theses.fr (ABES) · doi:10.70675/0d7a8b92z8393z4d76z82a8z87efe0790346
Role of T-cell immunity in the pathophysiology of Alzheimer’s disease and other Tauopathies
Matta, K. (2024) · theses.fr (ABES) · doi:10.70675/cea4fe5ez67c3z4445z92f7z39af62ba059b
Siddique, I. A., Hong, M., & Bitan, G. (2026) · Topics in medicinal chemistry · doi:10.1007/7355_2026_189
Ugwah-Oguejiofor, C. J., Okechukwu, P. N., Mathias, S. N., Ofokansi, M. N., & Janakiraman, A. K. (2026) · Studies in natural products chemistry · doi:10.1016/b978-0-443-49144-3.00007-1
Kashtiban, B. A., Rezazadeh, M., Gharesouran, J., Jafari, B., & Ghafouri‐Fard, S. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.111974
Wu, Y., Di, Y., Wang, H. W., Wang, L., Zhang, J., Zhang, Y., & Lyu, D. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103216
The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer’s disease
Singh, A. K., Supraja, M. R., Amal, P. S., Krishnamoorthi, S., Iyaswamy, A., & Durairajan, S. S. K. (2026) · International review of neurobiology · doi:10.1016/bs.irn.2026.06.002
Small Molecules as Anti-Alzheimer’s Scaffolds
Hazra, R., Roy, S., Gayen, S., Parui, A., Arshad, A., Roy, N., & Sarkar, A. N. (2026) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9798898815646126010013
Zhao, T., Wang, T.-Y., Wang, H.-S., Lim, Y., Zhang, Z.-J., Duan, X.-R., Liang, L., & Li, Y. (2026) · ACS Chemical Biology · doi:10.1021/acschembio.6c00096
Shawaqfeh, B., Hughes, C. M., McGuinness, B., & Barry, H. E. (2026) · International Journal of Pharmacy Practice · doi:10.1093/ijpp/riag107
Chemical probes for Alzheimer’s disease targets
Aiken, S., Zarganes‐Tzitzikas, T., & Brennan, P. E. (2026) · Essays in Biochemistry · doi:10.1042/ebc20260014
Tau-targeting pharmacological strategies in neurodegenerative disease
Zheng, H., & Zheng, J. (2026) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2026.07.008
Towards a future without dementia
Spires‐Jones, T. L. (2026) · Oxford University Press eBooks · doi:10.1093/9780198995296.003.0008
Yin, L., Ren, R., Leo, C., & Lu, Y. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108439
Huerta‐Cervantes, M., Peña‐Montes, D. J., López‐Vázquez, M. A., Saavedra‐Molina, A., Pérez-Vega, M. I., & Olvera‐Cortés, M. E. (2026) · Biology · doi:10.3390/biology15201801
Genome-wide association studies of osteoarthritis: from genetic discovery to precision medicine
Wu, Y., Hong, Y., Lyu, X., Wang, P., Zheng, H., & Su, J. (2026) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2026.10.005
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
