Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial

Authors


  • Potential conflict of interest: Dr Hawker has received honoraria from Biogen IDEC, Teva, Bayer, Genentech and GSK; Dr O'Connor has received honoraria from Bio MS, BiogenIDEC, Teva, Serono, Roche, Genentech, Bayer; Dr Freedman has received honoraria from Sanofi-Aventis, BiogenIdec, EMD Serono, Teva, Bayer Healthcare, Eli Lilly, Eisai, Novartis, Genentech; Dr Calabrasi has received honoraria for consulting from: Teva, Biogen-IDEC, Genentech, Serono, Novartis, Amplimmune, Vertex, and Centacor, PC has received research support from Bayer, Serono, Biogen-IDEC, Teva, and Genentech; Dr Waubant's research has been supported by Biogen-Idec, Pfizer, Sanofi-Aventis, the National MS Society, the Immune Tolerance Network and the Nancy Davis Foundation. Dr Waubant has been a consultant for Artielle and Zymogenetics. She has received honorarium for one educational presentation from Biogen Idec; Dr Hauser, Dr Panitch, Dr Vollmer have nothing to disclose.

  • Other investigators who participated in the OLYMPUS Trial Group are listed in the Appendix on page xxx.

Abstract

Objective

Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks.

Methods

Using 2:1 randomization, 439 PPMS patients received two 1,000mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans.

Results

Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses.

Interpretation

Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions. Ann Neurol 2009;66:460–471

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