title: The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.
abstract: BACKGROUND
  Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors.
  
  
  METHODS
  In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations.
  
  
  RESULTS
  A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %).
  
  
  CONCLUSIONS
  Extended-release memantine was efficacious, safe, and well tolerated in this population.
authors.affiliation: Department of Neurology and Psychiatry, Saint Louis University School of Medicine, 1438 S. Grand Boulevard, St. Louis, MO 63104, USA. grossbgt@slu.edu
authors.forename: George T
authors.initials: GT
authors.lastname: Grossberg
authors.forename: Facundo
authors.initials: F
authors.lastname: Manes
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Allegri
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Gutiérrez-Robledo
authors.forename: Sergio
authors.initials: S
authors.lastname: Gloger
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
authors.forename: X Daniel
authors.initials: XD
authors.lastname: Jia
authors.forename: Vojislav
authors.initials: V
authors.lastname: Pejović
authors.forename: Michael L
authors.initials: ML
authors.lastname: Miller
authors.forename: James L
authors.initials: JL
authors.lastname: Perhach
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Graham
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000523:psychology; D001118:Argentina; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008800:Mexico; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States
chemical_list: D002800:Cholinesterase Inhibitors; D003692:Delayed-Action Preparations; D018691:Excitatory Amino Acid Antagonists; D008559:Memantine