Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.
BACKGROUND
Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 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 T(2)-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.).
Rudick
Richard A
RA
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. rudickr@ccf.org
Stuart
William H
WH
Calabresi
Peter A
PA
Confavreux
Christian
C
Galetta
Steven L
SL
Radue
Ernst-Wilhelm
EW
Lublin
Fred D
FD
Weinstock-Guttman
Bianca
B
Wynn
Daniel R
DR
Lynn
Frances
F
Panzara
Michael A
MA
Sandrock
Alfred W
AW
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001921:Brain / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D039441:Integrin alpha4; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000009:adverse effects / Q000627:therapeutic use*; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D000069442:Natalizumab; D016016:Proportional Hazards Models; D055502:Secondary Prevention
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015815:Cell Adhesion Molecules; D000069442:Natalizumab; D039441:Integrin alpha4; D016899:Interferon-beta; D000068556:Interferon beta-1a