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J Alzheimers Dis. 2018;61(1):435-457. doi: 10.3233/JAD-170560.

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.

Author information

1
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
2
McGill Centre for Studies in Aging, Alzheimer's Disease Research Unit, and Douglas Mental Health University Institute, Montreal, QC, Canada.
3
University Hospitals and University of Geneva, Geneva, Switzerland.
4
Beijing Institute for Brain Disorders Alzheimer's Disease Centre, Beijing, China.
5
TauRx Therapeutics, Aberdeen, UK.
6
Moebius-Consult, Baar, Switzerland.
7
Birmingham and Solihull Mental Health Foundation Trust, Birmingham, UK.
8
Salamandra LLC, Bethesda, MD, USA.
9
Institute for Complex Systems and Mathematical Biology, University of Aberdeen, Aberdeen, UK.
10
Computer Laboratory, University of Cambridge, Cambridge, UK.
11
CSD Biostatistics, Tucson, AZ, USA.
12
Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
13
BioClinica, Lyon, France.
14
RadMD, New York, NY, USA.
15
MNI Imaging, New Haven, CT, USA.
16
School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
17
Department of Chemistry, University of Aberdeen, Aberdeen, UK.

Abstract

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.

KEYWORDS:

ADAS-cog; Alzheimer’s disease; amyloid protein; clinical trial; cohort study; methylthioninium; tau protein; treatment

PMID:
29154277
PMCID:
PMC5734125
DOI:
10.3233/JAD-170560
[Indexed for MEDLINE]
Free PMC Article

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