Concentration-Dependent Activity of Hydromethylthionine on Clinical Decline and Brain Atrophy in a Randomized Controlled Trial in Behavioral Variant Frontotemporal Dementia

J Alzheimers Dis. 2020;75(2):501-519. doi: 10.3233/JAD-191173.


Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins.

Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD.

Methods: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug.

Results: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day.

Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

Keywords: Behavioral variant frontotemporal dementia; TDP-43; clinical trials; hydromethylthionine; leucomethylthioninium; tau protein.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Atrophy / diagnostic imaging
  • Atrophy / drug therapy*
  • Atrophy / pathology
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain / pathology
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Frontotemporal Dementia / diagnostic imaging
  • Frontotemporal Dementia / drug therapy*
  • Frontotemporal Dementia / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Methylene Blue / analogs & derivatives*
  • Methylene Blue / pharmacology
  • Methylene Blue / therapeutic use
  • Middle Aged
  • Treatment Outcome


  • hydromethylthionine
  • Methylene Blue