Ocrelizumab versus placebo in primary progressive multiple sclerosis

ORATORIO Clinical Investigators

Research output: Contribution to journalArticle

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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 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 brainvolume 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.

Original languageEnglish (US)
Pages (from-to)209-220
Number of pages12
JournalNew England Journal of Medicine
Volume376
Issue number3
DOIs
StatePublished - Jan 19 2017

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ocrelizumab
Chronic Progressive Multiple Sclerosis
Placebos
B-Lymphocytes
Magnetic Resonance Imaging
Confidence Intervals

ASJC Scopus subject areas

  • Medicine(all)

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Ocrelizumab versus placebo in primary progressive multiple sclerosis. / ORATORIO Clinical Investigators.

In: New England Journal of Medicine, Vol. 376, No. 3, 19.01.2017, p. 209-220.

Research output: Contribution to journalArticle

ORATORIO Clinical Investigators. / Ocrelizumab versus placebo in primary progressive multiple sclerosis. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 3. pp. 209-220.
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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 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 brainvolume 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.",
author = "{ORATORIO Clinical Investigators} and X. Montalban and Hauser, {S. L.} and L. Kappos and Arnold, {D. L.} and A. Bar-Or and G. Comi and {De Seze}, J. and G. Giovannoni and Hartung, {H. P.} and B. Hemmer and F. Lublin and Rammohan, {Kottil W} and K. Selmaj and A. Traboulsee and A. Sauter and D. Masterman and P. Fontoura and S. Belachew and H. Garren and N. Mairon and P. Chin and Wolinsky, {J. S.}",
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T1 - Ocrelizumab versus placebo in primary progressive multiple sclerosis

AU - ORATORIO Clinical Investigators

AU - Montalban, X.

AU - Hauser, S. L.

AU - Kappos, L.

AU - Arnold, D. L.

AU - Bar-Or, A.

AU - Comi, G.

AU - De Seze, J.

AU - Giovannoni, G.

AU - Hartung, H. P.

AU - Hemmer, B.

AU - Lublin, F.

AU - Rammohan, Kottil W

AU - Selmaj, K.

AU - Traboulsee, A.

AU - Sauter, A.

AU - Masterman, D.

AU - Fontoura, P.

AU - Belachew, S.

AU - Garren, H.

AU - Mairon, N.

AU - Chin, P.

AU - Wolinsky, J. S.

PY - 2017/1/19

Y1 - 2017/1/19

N2 - 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 brainvolume 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.

AB - 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 brainvolume 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.

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