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.

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.

• Authors: Gordon K Wilcock, Serge Gauthier, Giovanni B Frisoni, Jianping Jia, Jiri H Hardlund, Hans J Moebius, Peter Bentham, Karin A Kook, Bjoern O Schelter, Damon J Wischik, Charles S Davis, Roger T Staff, Vesna Vuksanovic, Trevor Ahearn, Luc Bracoud, Kohkan Shamsi, Ken Marek, John Seibyl, Gernot Riedel, John M D Storey, Charles R Harrington, Claude M Wischik
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 61 Issue 1 Pg. 435-457 ( 2018) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 29154277 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Antipsychotic Agents
• hydromethylthionine
• Methylene Blue

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnostic imaging, drug therapy)
• Antipsychotic Agents (therapeutic use)
• Cohort Studies
• Double-Blind Method
• Female
• Humans
• International Cooperation
• Male
• Mental Status and Dementia Tests
• Methylene Blue (analogs & derivatives, therapeutic use)
• Middle Aged
• Treatment Outcome