A Phase II Trial of Tideglusib in Alzheimer's Disease

作者：Lovestone, Simon; Boada, Merce; Dubois, Bruno; Huell, Michael; Rinne, Juha O.; Huppertz, Hans-Juergen; Calero, Miguel; Andres, Maria V.; Gomez-Carrillo, Belen; Leon, Teresa; del Ser, Teodoro^*

来源：Journal of Alzheimer's Disease, 2015, 45(1): 75-88.

DOI：10.3233/JAD-141959

• Alzheimer's disease
• GSK-3
• pharmacological treatment
• randomized controlled clinical trial
• tideglusib

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-cog(15) 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-beta, 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-cog(15), 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.

• 出版日期2015