title: A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
abstract: BACKGROUND
  Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis.
  
  
  METHODS
  Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years.
  
  
  RESULTS
  Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent).
  
  
  CONCLUSIONS
  Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).
authors.affiliation: Vrije Universiteit Medical Center, Amsterdam, The Netherlands. ch.polman@vumc.nl
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Paul W
authors.initials: PW
authors.lastname: O'Connor
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lublin
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wajgt
authors.forename: Martin
authors.initials: M
authors.lastname: Toal
authors.forename: Frances
authors.initials: F
authors.lastname: Lynn
authors.forename: Michael A
authors.initials: MA
authors.lastname: Panzara
authors.forename: Alfred W
authors.initials: AW
authors.lastname: Sandrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001921:Brain / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D018450:Disease Progression; D004342:Drug Hypersensitivity / Q000209:etiology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D039441:Integrin alpha4; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D000069442:Natalizumab; D016016:Proportional Hazards Models; D055502:Secondary Prevention
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015815:Cell Adhesion Molecules; D000069442:Natalizumab; D039441:Integrin alpha4