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. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.
Original language | English |
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Pages (from-to) | 705-720 |
Number of pages | 16 |
Journal | Journal of Alzheimer's Disease |
Volume | 44 |
Issue number | 2 |
Early online date | 30 Dec 2014 |
DOIs | |
Publication status | Published - 22 Jan 2015 |
Keywords
- Alzheimer's disease
- controlled clinical trial
- intervention studies
- methylthioninium
- safety
- tau protein
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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.Profiles
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Charles Harrington
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Senior Research Fellow
- Institute of Medical Sciences
Person: Academic Related - Research
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John Storey
- School of Natural & Computing Sciences, Chemistry - Chair in Pharmaceutical Industrial Chemistry
Person: Academic
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Claude Wischik
- School of Medicine, Medical Sciences & Nutrition, Applied Medicine - Chair in Mental Health (Clin)
- Institute of Medical Sciences
Person: Clinical Academic