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ABSTRACT

Background Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an ₄ integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies.

Methods We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years.

Results Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan–Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T₂-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients.

Conclusions Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966 [ClinicalTrials.gov] .)

Source Information

From the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland (R.A.R.); the MS Center of Atlanta, Atlanta (W.H.S.); the Johns Hopkins Multiple Sclerosis Center, Baltimore (P.A.C.); Hôpital Neurologique, Lyon, France (C.C.); University of Pennsylvania School of Medicine, Philadelphia (S.L.G.); University Hospital Basel, Basel, Switzerland (E.-W.R.); Mt. Sinai School of Medicine, New York (F.D.L.); Baird Multiple Sclerosis Center, State University of New York at Buffalo, Buffalo (B.W.-G.); Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill. (D.R.W.); and Biogen Idec, Cambridge, Mass. (F.L., M.A.P., A.W.S.).

Address reprint requests to Dr. Rudick at the Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, or at rudickr{at}ccf.org.

Full Text of this Article

Related Letters:

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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