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.

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.