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

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


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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / 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*
  • Methylene Blue / therapeutic use
  • Middle Aged
  • Treatment Outcome*


  • Antipsychotic Agents
  • hydromethylthionine
  • Methylene Blue