title: 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.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  TauRx Therapeutics.
authors.affiliation: McGill Centre for Studies in Aging, Alzheimer's Disease Research Unit, and Douglas Mental Health University Institute, Montreal, QC, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Department of Neurosciences, School of Medicine, University of California, San Diego, CA, USA.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, and Department of Neurology, Keck School of Medicine, Leonard Davis School of Gerontology of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.affiliation: University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.affiliation: TauRx Therapeutics, Aberdeen, UK.
authors.forename: Jiri H
authors.initials: JH
authors.lastname: Hardlund
authors.affiliation: Moebius-Consult, Baar, Switzerland.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Moebius
authors.affiliation: TauRx Therapeutics, Aberdeen, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Bentham
authors.affiliation: Salamandra LLC, Bethesda, MD, USA.
authors.forename: Karin A
authors.initials: KA
authors.lastname: Kook
authors.affiliation: TauRx Therapeutics, Aberdeen, UK.
authors.forename: Damon J
authors.initials: DJ
authors.lastname: Wischik
authors.affiliation: Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK.
authors.forename: Bjoern O
authors.initials: BO
authors.lastname: Schelter
authors.affiliation: CSD Biostatistics, Tucson, AZ, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Davis
authors.affiliation: Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
authors.forename: Roger T
authors.initials: RT
authors.lastname: Staff
authors.affiliation: BioClinica, Lyon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Bracoud
authors.affiliation: RadMD, New York, NY, USA.
authors.forename: Kohkan
authors.initials: K
authors.lastname: Shamsi
authors.affiliation: Department of Chemistry, University of Aberdeen, Aberdeen, UK.
authors.forename: John M D
authors.initials: JM
authors.lastname: Storey
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Harrington
authors.affiliation: TauRx Therapeutics, Aberdeen, UK; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK. Electronic address: cmw@taurx.com.
authors.forename: Claude M
authors.initials: CM
authors.lastname: Wischik
mesh_terms: D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D017211:Treatment Failure; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016875:tau Proteins