Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.

Abstract

BACKGROUND:

Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD).

OBJECTIVES:

The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY).

DESIGN:

The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase.

SETTING:

76 clinical research sites in North America and Europe.

PARTICIPANTS:

545 patients with probable AD or MCI-AD in the final version of the protocol.

INTERVENTION:

Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose.

MEASUREMENTS:

Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography.

RESULTS:

446 participants are expected to complete the 12-month placebo-controlled phase in March 2022.

CONCLUSIONS:

If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

• Authors: C M Wischik, P Bentham, S Gauthier, S Miller, K Kook, B O Schelter
• Journal: The journal of prevention of Alzheimer's disease (J Prev Alzheimers Dis) Vol. 9 Issue 4 Pg. 780-790 ( 2022) ISSN: 2426-0266 [Electronic] Switzerland
• PMID: 36281683 (Publication Type: Randomized Controlled Trial, Clinical Trial, Phase III, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• hydromethylthionine
• Fluorodeoxyglucose F18
• Mesylates

Topics

• Humans
• Alzheimer Disease (drug therapy)
• Activities of Daily Living
• Fluorodeoxyglucose F18
• Atrophy (drug therapy)
• Mesylates (therapeutic use)