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

Gordon K Wilcock, Serge Gauthier, Giovanni B Frisoni, Jianping Jia, Jiri H Hardlund, Hans J Moebius, Peter Bentham, Karin A Kook, Bjoern Olaf 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. StoreyCharles R Harrington, Claude M Wischik

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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.
Original languageEnglish
Pages (from-to)435-457
Number of pages24
JournalJournal of Alzheimer's Disease
Issue number1
Early online date17 Nov 2017
Publication statusPublished - 28 Nov 2017



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

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