title: Efficacy and safety profile of memantine in patients with cognitive impairment in multiple sclerosis: A randomized, placebo-controlled study.
abstract: Memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients.
  
  
  OBJECTIVE
  The purpose of the "EMERITE" (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS).
  
  
  METHODS
  The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18-60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial.
  
  
  RESULTS
  Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p=0.88). Adjusted mean score difference (memantine minus placebo), was -0.40 (95% confidence interval: -5.5; +4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine.
  
  
  CONCLUSIONS
  No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected.
authors.affiliation: Department of Biostatistics and Clinical Research, Centre Hospitalier Universitaire de Caen, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Peyro Saint Paul
authors.affiliation: Department of Biostatistics and Clinical Research, Centre Hospitalier Universitaire de Caen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Creveuil
authors.affiliation: Department of Neurology, Centre Hospitalier de Poissy, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Heinzlef
authors.affiliation: Department of Neurology, Centre Hospitalier Régional et Universitaire de Strasbourg, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: De Seze
authors.affiliation: Department of Neurology, Centre Hospitalier Régional et Universitaire de Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vermersch
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Nîmes, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Castelnovo
authors.affiliation: Department of Neurology, Centre Hospitalier de Fort-de-France, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cabre
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Nancy, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Debouverie
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Bordeaux, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brochet
authors.affiliation: Department of Neurology, Centre Hospitalier de Cherbourg, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Dupuy
authors.affiliation: Department of Neurology, Centre Hospitalier de Cherbourg, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lebiez
authors.affiliation: Department of Neurology, Centre Hospitalier de Lorient, France.
authors.forename: Éric
authors.initials: É
authors.lastname: Sartori
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Clavelou
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Toulouse, France.
authors.forename: David
authors.initials: D
authors.lastname: Brassat
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Nice, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lebrun-Frenay
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Daplaud
authors.affiliation: Department of Neurology, Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Marseille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Pelletier
authors.affiliation: Department of Neurology, Assistance Publique des Hôpitaux de Paris, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Coman
authors.affiliation: Department of Neurology, Groupement des Hôpitaux de l'Institut Catholique de Lille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hautecoeur
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Reims, France.
authors.forename: Ayman
authors.initials: A
authors.lastname: Tourbah
authors.affiliation: Department of Neurology, Centre Hospitalier Universitaire de Caen, France; INSERM U 919, GIP Cyceron, Caen, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Defer
mesh_terms: D000328:Adult; D003072:Cognition Disorders / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy*; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008559:Memantine / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008559:Memantine
keywords: Clinical trial; Cognitive disorders; Cognitive impairment; Memantine; Multiple sclerosis; PASAT; Patient safety; Placebo-controlled; Randomized; Test of Attentional Performance