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.