Simon Lovestone1, Mercè Boada2, Bruno Dubois3, Michael Hüll4, Juha O Rinne5, Hans-Jürgen Huppertz6, Miguel Calero7, María V Andrés8, Belén Gómez-Carrillo8, Teresa León9, Teodoro del Ser9. 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.
RCT Entities:
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) ADpatients 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 ADpatients 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 ADpatients.
Authors: Cheril Tapia-Rojas; Fabian Cabezas-Opazo; Carol A Deaton; Erick H Vergara; Gail V W Johnson; Rodrigo A Quintanilla Journal: Prog Neurobiol Date: 2018-12-31 Impact factor: 11.685
Authors: Mansi R Khanna; Jane Kovalevich; Virginia M-Y Lee; John Q Trojanowski; Kurt R Brunden Journal: Alzheimers Dement Date: 2016-10 Impact factor: 21.566