A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Chris H. Polman, M.D., Paul W. O'Connor, M.D., Eva Havrdova, M.D., Michael Hutchinson, M.D., Ludwig Kappos, M.D., David H. Miller, M.D., J. Theodore Phillips, M.D., Ph.D., Fred D. Lublin, M.D., Gavin Giovannoni, M.D., Andrzej Wajgt, M.D., Martin Toal, M.B., M.F.P.M., Frances Lynn, M.Sc., Michael A. Panzara, M.D., M.P.H., Alfred W. Sandrock, M.D., Ph.D., for the AFFIRM Investigators
Background Natalizumab is the first 4 integrin antagonist ina new class of selective adhesion-molecule inhibitors. We reportthe results of a two-year phase 3 trial of natalizumab in patientswith relapsing multiple sclerosis.
Methods Of a total of 942 patients, 627 were randomly assignedto receive natalizumab (at a dose of 300 mg) and 315 to receiveplacebo by intravenous infusion every four weeks for more thantwo years. The primary end points were the rate of clinicalrelapse at one year and the rate of sustained progression ofdisability, as measured by the Expanded Disability Status Scale,at two years.
Results Natalizumab reduced the risk of sustained progressionof disability by 42 percent over two years (hazard ratio, 0.58;95 percent confidence interval, 0.43 to 0.77; P<0.001). Thecumulative probability of progression (on the basis of Kaplan–Meieranalysis) was 17 percent in the natalizumab group and 29 percentin the placebo group. Natalizumab reduced the rate of clinicalrelapse at one year by 68 percent (P<0.001) and led to an83 percent reduction in the accumulation of new or enlarginghyperintense lesions, as detected by T2-weighted magnetic resonanceimaging (MRI), over two years (mean numbers of lesions, 1.9with natalizumab and 11.0 with placebo; P<0.001). There were92 percent fewer lesions (as detected by gadolinium-enhancedMRI) in the natalizumab group than in the placebo group at bothone and two years (P<0.001). The adverse events that weresignificantly more frequent in the natalizumab group than inthe placebo group were fatigue (27 percent vs. 21 percent, P=0.048)and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivityreactions of any kind occurred in 25 patients receiving natalizumab(4 percent), and serious hypersensitivity reactions occurredin 8 patients (1 percent).
Conclusions Natalizumab reduced the risk of the sustained progressionof disability and the rate of clinical relapse in patients withrelapsing multiple sclerosis. Adhesion-molecule inhibitors holdpromise as an effective treatment for relapsing multiple sclerosis.(ClinicalTrials.gov number, NCT00027300
[ClinicalTrials.gov]
.)
Source Information
From the Vrije Universiteit Medical Center, Amsterdam (C.H.P.); St. Michael's Hospital, Toronto (P.W.O.); General Teaching Hospital, Prague, Czech Republic(E.H.); St. Vincent's University Hospital, Dublin, Ireland (M.H.); University Hospital Basel, Basel, Switzerland (L.K.); Institute of Neurology, London (D.H.M., G.G.); Texas Neurology, Dallas (J.T.P.); Mt. Sinai School of Medicine, New York (F.D.L.); Silesian Medical University, Katowice, Poland (A.W.); and Biogen Idec, Cambridge, Mass. (M.T., F.L., M.A.P., A.W.S.).
Address reprint requests to Dr. Polman at the VU Medical Center, P.O. Box 7057, Amsterdam 1007 MB, the Netherlands, or at ch.polman{at}vumc.nl.
Natalizumab for Relapsing Multiple Sclerosis
Tenser R. B., Jeffery D. R., Meyer M. A., Polman C. H., Rudick R. A., Major E. O., Yousry T. A., Clifford D. B., Ropper A. H.
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N Engl J Med 2006;
354:2387-2389, Jun 1, 2006.
Correspondence
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4 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. 
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