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 |
|---|---|
| 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 |
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Keywords
- Alzheimer's disease
- controlled clinical trial
- intervention studies
- methylthioninium
- safety
- tau protein
Cite this
Tau Aggregation Inhibitor Therapy : An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease. / Wischik, Claude M; Staff, Roger T; Wischik, Damon J; Bentham, Peter; Murray, Alison D; Storey, John M D; Kook, Karin A; Harrington, Charles R.
In: Journal of Alzheimer's Disease, Vol. 44, No. 2, 22.01.2015, p. 705-720.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tau Aggregation Inhibitor Therapy
T2 - An Exploratory Phase 2 Study in Mild or Moderate Alzheimer's Disease
AU - Wischik, Claude M
AU - Staff, Roger T
AU - Wischik, Damon J
AU - Bentham, Peter
AU - Murray, Alison D
AU - Storey, John M D
AU - Kook, Karin A
AU - Harrington, Charles R
N1 - ACKNOWLEDGMENTS 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
PY - 2015/1/22
Y1 - 2015/1/22
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - controlled clinical trial
KW - intervention studies
KW - methylthioninium
KW - safety
KW - tau protein
U2 - 10.3233/JAD-142874
DO - 10.3233/JAD-142874
M3 - Article
C2 - 25550228
VL - 44
SP - 705
EP - 720
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 2
ER -