Xavier Montalban1, Stephen L Hauser1, Ludwig Kappos1, Douglas L Arnold1, Amit Bar-Or1, Giancarlo Comi1, Jérôme de Seze1, Gavin Giovannoni1, Hans-Peter Hartung1, Bernhard Hemmer1, Fred Lublin1, Kottil W Rammohan1, Krzysztof Selmaj1, Anthony Traboulsee1, Annette Sauter1, Donna Masterman1, Paulo Fontoura1, Shibeshih Belachew1, Hideki Garren1, Nicole Mairon1, Peter Chin1, Jerry S Wolinsky1. 1. From Hospital Vall d'Hebron University, Barcelona (X.M.); University of California, San Francisco, San Francisco (S.L.H.), and Genentech, South San Francisco (D.M., H.G., P.C.) - both in California; University Hospital Basel, University of Basel (L.K.), and F. Hoffmann-La Roche (A.S., P.F., S.B., N.M.), Basel, Switzerland; McGill University (D.L.A., A.B.-O.) and NeuroRx Research (D.L.A.), Montreal, and University of British Columbia, Vancouver (A.T.) - both in Canada; University Vita-Salute San Raffaele, Milan (G.C.); University Hospital of Strasbourg, Clinical Investigation Center (INSERM Unité 1434), Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France (J.S.); Barts and the London School of Medicine and Dentistry, London (G.G.); Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf (H.-P.H.), and Technical University of Munich and Munich Cluster for Systems Neurology, Munich (B.H.) - both in Germany; Icahn School of Medicine at Mount Sinai, New York (F.L.); University of Miami, Miami (K.W.R.); Medical University of Łódź, Łódź, Poland (K.S.); and McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.).
Abstract
BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receiveintravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).
RCT Entities:
BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).
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