title: Tau aggregation inhibitor therapy: an exploratory phase 2 study in mild or moderate Alzheimer's disease.
abstract: 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.
  
  
  CONCLUSIONS
  The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Claude M
authors.initials: CM
authors.lastname: Wischik
authors.affiliation: Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Staff
authors.affiliation: Computer Science Department, University College London, UK.
authors.forename: Damon J
authors.initials: DJ
authors.lastname: Wischik
authors.affiliation: College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bentham
authors.affiliation: Aberdeen Biomedical Imaging Centre, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Alison D
authors.initials: AD
authors.lastname: Murray
authors.affiliation: Department of Chemistry, University of Aberdeen, Aberdeen, UK.
authors.forename: John M D
authors.initials: JM
authors.lastname: Storey
authors.affiliation: Salamandra LLC, Bethesda, Maryland, USA.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Kook
authors.affiliation: School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Harrington
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004906:Erythrocyte Count; D005260:Female; D006801:Humans; D008297:Male; D008751:Methylene Blue / Q000009:adverse effects / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D018696:Neuroprotective Agents; D016875:tau Proteins; D008751:Methylene Blue
keywords: Alzheimer's disease; controlled clinical trial; intervention studies; methylthioninium; safety; tau protein