title: A controlled trial of natalizumab for relapsing multiple sclerosis.
abstract: BACKGROUND
  In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.
  
  
  METHODS
  In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
  
  
  RESULTS
  There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
  
  
  CONCLUSIONS
  In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
authors.affiliation: Department of Neuroinflammation, Institute of Neurology, London, United Kingdom. d.miller@ion.ucl.ac.uk
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.forename: Omar A
authors.initials: OA
authors.lastname: Khan
authors.forename: William A
authors.initials: WA
authors.lastname: Sheremata
authors.forename: Lance D
authors.initials: LD
authors.lastname: Blumhardt
authors.forename: George P A
authors.initials: GP
authors.lastname: Rice
authors.forename: Michele A
authors.initials: MA
authors.lastname: Libonati
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Willmer-Hulme
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Dalton
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Miszkiel
authors.forename: Paul W
authors.initials: PW
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001921:Brain / Q000473:pathology*; D004311:Double-Blind Method; D005260:Female; D005682:Gadolinium; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D000069442:Natalizumab; D018709:Statistics, Nonparametric
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D005682:Gadolinium