Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease

Claude M Wischik, Roger T Staff, Damon J Wischik, Peter Bentham, Alison D Murray, John M D Storey, Karin A Kook, Charles R Harrington

Research output: Contribution to journalArticlepeer-review

198 Citations (Scopus)
15 Downloads (Pure)


Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer's disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg/day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.

Original languageEnglish
Pages (from-to)705-720
Number of pages16
JournalJournal of Alzheimer's Disease
Issue number2
Early online date30 Dec 2014
Publication statusPublished - 22 Jan 2015

Bibliographical note

We thank patients and their caregivers for their participation in the study and are indebted to all the investigators involved in the study, particularly Drs. Douglas Fowlie and Donald Mowat for their helpful contributions to the clinical execution of the study in Scotland. We thank Sharon Eastwood, Parexel, for assistance in preparing initial drafts of the manuscript.
We acknowledge constructive comments provided by Professors G. Wilcock and S. Gauthier on drafts of the article. CMW, CRH, and JMDS are officers of,
and hold beneficial interests in, TauRx Therapeutics. RTS, PB, KK, and DJW are paid consultants to TauRx Therapeutics. The study was financed entirely by TauRx Therapeutics


  • Alzheimer's disease
  • controlled clinical trial
  • intervention studies
  • methylthioninium
  • safety
  • tau protein


Dive into the research topics of 'Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease'. Together they form a unique fingerprint.

Cite this