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Background: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 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.
Background: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an α 4 integrin antagonist, was to be safe and effective alone and when added to interferon beta-1a in preliminary studies. Methods: We randomly assigned 1171 patients who had either 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 c onfidence 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.