A phase II trial of tideglusib in Alzheimer's disease

J Alzheimers Dis. 2015;45(1):75-88. doi: 10.3233/JAD-141959.

Abstract

Background: The ARGO study was a phase II, double-blind, placebo controlled, four parallel arm trial of tideglusib in Alzheimer's disease (AD).

Objective: To prove the clinical efficacy of an inhibitor of glycogen synthase kinase-3 (GSK-3), in AD.

Methods: Mild to moderate (Mini-Mental State Examination (MMSE) score, 14-26) AD patients on cholinesterase inhibitor and/or memantine treatment were administered tideglusib or placebo for 26 weeks. The ADAS-cog15 was the primary efficacy measure; function, cognition, behavior, and quality of life were assessed as secondary measures; cerebral atrophy in MRI and the levels of tau, amyloid-β, and BACE1 in cerebrospinal fluid (CSF) were exploratory endpoints.

Results: 306 AD patients were randomized to active (1000 mg QD: n = 86, 1000 mg QOD: n = 90, and 500 mg QD: n = 50) or placebo (n = 85) in 55 sites in four European countries. There were no statistically significant differences between either active and placebo arms in the efficacy variables. However, BACE1 in CSF significantly decreased with treatment in a small subgroup of patients. Participants with mild AD in the 500 mg QD group showed significant responses on ADAS-cog15, MMSE, and word fluency. Diarrhea (14-18% in active, 11% placebo) and dose-dependent, mild to moderate, and fully reversible transaminase increase (9-16% in active, 3.5% placebo) were the most frequent adverse events.

Conclusions: Short term (26 weeks) tideglusib was acceptably safe but produced no clinical benefit in this trial. However, given the non-linear dose response, especially in mildly affected patients, further dose finding studies in early disease stages and for longer duration are warranted to examine GSK-3 inhibition in AD patients.

Keywords: Alzheimer's disease; GSK-3; pharmacological treatment; randomized controlled clinical trial; tideglusib.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / metabolism
  • Apolipoproteins E / genetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Neuroprotective Agents / therapeutic use*
  • Psychiatric Status Rating Scales
  • Thiadiazoles / therapeutic use*

Substances

  • Amyloid beta-Peptides
  • Apolipoproteins E
  • NP 031112
  • Neuroprotective Agents
  • Thiadiazoles