title: A phase II trial of tideglusib in Alzheimer's disease.
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.
authors.affiliation: University of Oxford, Department of Psychiatry, Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Boada
authors.affiliation: Institut de la Mémoire, INSERM U1127, ICM, Université Pierre et Marie Curie-Paris 6, Hôpital de la Salpêtrière, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Centre for Geriatric Medicine Freiburg and Emmendingen Centre for Psychiatry, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hüll
authors.affiliation: Turku PET Centre and Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Juha O
authors.initials: JO
authors.lastname: Rinne
authors.affiliation: Swiss Epilepsy Centre, Zürich, Switzerland.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Huppertz
authors.affiliation: Chronic Disease Program, CIBERNED, and CIEN Foundation, Carlos III Institute of Health, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Calero
authors.affiliation: Clinical Department, Noscira SA, Madrid, Spain.
authors.forename: María V
authors.initials: MV
authors.lastname: Andrés
authors.affiliation: Clinical Department, Noscira SA, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Gómez-Carrillo
authors.affiliation: Medical Department, Noscira SA, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: León
authors.affiliation: Medical Department, Noscira SA, Madrid, Spain.
authors.forename: Teodoro
authors.initials: T
authors.lastname: del Ser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D013830:Thiadiazoles / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D018696:Neuroprotective Agents; D013830:Thiadiazoles; C520571:tideglusib
keywords: Alzheimer's disease; GSK-3; pharmacological treatment; randomized controlled clinical trial; tideglusib