Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.
- Wilcock GK Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
- Gauthier S McGill Centre for Studies in Aging, Alzheimer's Disease Research Unit, and Douglas Mental Health University Institute, Montreal, QC, Canada.
- Frisoni GB University Hospitals and University of Geneva, Geneva, Switzerland.
- Jia J Beijing Institute for Brain Disorders Alzheimer's Disease Centre, Beijing, China.
- Hardlund JH TauRx Therapeutics, Aberdeen, UK.
- Moebius HJ Moebius-Consult, Baar, Switzerland.
- Bentham P Birmingham and Solihull Mental Health Foundation Trust, Birmingham, UK.
- Kook KA Salamandra LLC, Bethesda, MD, USA.
- Schelter BO Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK.
- Wischik DJ Computer Laboratory, University of Cambridge, Cambridge, UK.
- Davis CS CSD Biostatistics, Tucson, AZ, USA.
- Staff RT Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
- Vuksanovic V Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
- Ahearn T Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
- Bracoud L BioClinica, Lyon, France.
- Shamsi K RadMD, New York, NY, USA.
- Marek K MNI Imaging, New Haven, CT, USA.
- Seibyl J MNI Imaging, New Haven, CT, USA.
- Riedel G School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
- Storey JMD TauRx Therapeutics, Aberdeen, UK.
- Harrington CR TauRx Therapeutics, Aberdeen, UK.
- Wischik CM TauRx Therapeutics, Aberdeen, UK.
- 2017-11-21
Published in:
- Journal of Alzheimer's disease : JAD. - 2018
ADAS-cog
Alzheimer’s disease
amyloid protein
clinical trial
cohort study
methylthioninium
tau protein
treatment
Aged
Aged, 80 and over
Alzheimer Disease
Antipsychotic Agents
Cohort Studies
Double-Blind Method
Female
Humans
International Cooperation
Male
Mental Status and Dementia Tests
Methylene Blue
Middle Aged
Treatment Outcome
English
BACKGROUND
LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.
OBJECTIVES
To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.
METHODS
Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.
RESULTS
The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.
CONCLUSIONS
The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.
OBJECTIVES
To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD.
METHODS
Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error.
RESULTS
The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy.
CONCLUSIONS
The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.3233/JAD-170560
- PMID 29154277
- Persistent URL
- https://sonar.ch/global/documents/34045
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