This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.PRIMARY OBJECTIVE The primary objective of this study is to assess the efficacy of rituximab compared with placebo in achieving and maintaining a major clinical response (MCR) or partial clinical response (PCR) in subjects with moderate to severe systemic lupus erythematosus (SLE). SECONDARY OBJECTIVES The secondary objectives of this study (comparing rituximab with placebo) will be to evaluate the following: o Ability of rituximab to decrease overall SLE disease activity as measured by time-adjusted area under the curve minus baseline (AUCMB) scoring with the British Isles Lupus Assessment Group (BILAG) assessment over 52 weeks o Ability of rituximab to induce MCRs (excluding PCRs) or PCRs (including MCRs) o Safety and tolerability of rituximab o Ability of rituximab-treated subjects to achieve a BILAG C or better at Week 24 o Ability of rituximab to prolong the time to a moderate or severe flare o Ability of rituximab to improve quality of life as measured by SLE Expanded Health Survey (SF-36 index with additional elements specific to lupus) o Corticosteroid-sparing in subjects receiving rituximab o Pharmacokinetics of rituximab in subjects with SLE STUDY DESIGN This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe SLE. The primary efficacy endpoint of the trial will be evaluated at 52 weeks. The study will enroll approximately 250 subjects at approximately 55 centers in the United States. Subjects will be randomized in a 2:1 ratio to receive rituximab + prednisone or placebo + prednisone. Randomized subjects will receive intravenous (IV) study drug + 2 separated by 15 days that is repeated at 6 months. In addition, subjects will receive 100 mg IV solumedrol 30-60 minutes prior to each study drug (rituximab or placebo) infusion. At entry, subjects must have a BILAG A score in one or more domains or a BILAG B score in two or more domains. Concomitant medications required are azathioprine, 6-mercaptopurine, mycophenolate mofetil (MMF), or methotrexate (MTX); plus prednisone and antimalarials (hydroxychloroquine or chloroquine). After screening, eligible subjects will receive daily oral prednisone (0.5 mg/kg, 0.75 mg/kg, or 1.0 mg/kg), based on their BILAG score and prestudy prednisone dose. Subjects will be assigned a prespecified prednisone taper starting on Day 16 for 10 weeks until a prednisone dose of = 10 mg/day is reached. After 10 weeks, subjects will continue to taper their corticosteroid as tolerated to a target dose of = 5 mg/day to Week 52. After Week 52, eligible subjects may enter an open-label retreatment study (under a separate protocol). Subjects who do not enter the retreatment study will be followed for at least 52 weeks after their last dose of study drug at Week 26. Subjects who do not enter the retreatment study will be followed by the investigator until Week 78 or until B-cell recovery, whichever is longer. B-cell recovery is defined as B-cell levels that have returned to baseline (Day 1) or to the lower limit of normal, as defined by the central laboratory.
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