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

A phase II trial of tideglusib in Alzheimer's disease.

Author information

1
University of Oxford, Department of Psychiatry, Oxford, UK.
2
Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
3
Institut de la Mémoire, INSERM U1127, ICM, Université Pierre et Marie Curie-Paris 6, Hôpital de la Salpêtrière, Paris, France.
4
Centre for Geriatric Medicine Freiburg and Emmendingen Centre for Psychiatry, Freiburg, Germany.
5
Turku PET Centre and Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland.
6
Swiss Epilepsy Centre, Zürich, Switzerland.
7
Chronic Disease Program, CIBERNED, and CIEN Foundation, Carlos III Institute of Health, Madrid, Spain.
8
Clinical Department, Noscira SA, Madrid, Spain.
9
Medical Department, Noscira SA, Madrid, Spain.

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

PMID:
25537011
DOI:
10.3233/JAD-141959
[Indexed for MEDLINE]

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