This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy of retreatment with rituximab in subjects with active rheumatoid arthritis (RA) who are receiving Methotrexate (MTX). The study consists of four parts: screening, treatment period (open-label rituximab for first course and, for eligible subjects, double-blind, randomized retreatment), safety follow-up, and B cell follow-up.

Condition	Intervention	Phase
Rheumatoid Arthritis	Drug: Rituximab	Phase III

Further study details as provided by Genentech:

Primary Outcomes: To evaluate the efficacy of retreatment with rituximab in subjects with active rheumatoid arthritis who are receiving methotrexate and who have had an inadequate response to tumor necrosis factor inhibitors.
Secondary Outcomes: To evaluate the safety of rituximab and retreatment with rituximab in subjects with active rheumatoid arthritis who are receiving methotrexate and who have had an inadequate response to TNF inhibitors.
Expected Total Enrollment:  555

Ages Eligible for Study:  18 Years   -   80 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Signed informed consent form
• Ability and willingness to comply with the requirements of the study protocol
• Age 18-80 years
• Diagnosis of RA for at least 6 months, according to the revised 1987 ACR criteria for the classification of RA
• Receiving treatment for RA on an outpatient basis
• Documented moderate to severe active RA activity at screening as follows: TJC >= 8; SJC >= 8 (66 joint count);abnormal CRP of >= 0.6 mg/dL or ESR of >= 28 mm/hr
• Documented inadequate response to previous or current treatment with one or more of the following: etanercept, infliximab, and/or adalimumab because of toxicity or inadequate efficacy
• Use of MTX 10-25 mg/wk for >= 12 weeks prior to Day 1 at a stable dose for >= 4 weeks
• Willingness to receive oral folic acid
• If taking a background corticosteroid (<= 10 mg/day prednisone or equivalent), use of the corticosteroid must be at a stable dose during the 4 weeks prior to Day 1
• Use of one NSAID is permitted if the dose is stable for >= 2 weeks prior to Day 1
• For men and women of reproductive potential, willingness to use a reliable means of contraception (e.g., hormonal contraceptive, intrauterine device, physical barrier) for >= 30 days prior to Day 1 and for the study duration or the duration that the subject''''s peripheral CD19 B cells are depleted, whichever is longer

Exclusion Criteria:

• Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty''''s syndrome)
• History of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, or Lyme disease) or other systemic rheumatic disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, or overlap syndrome)
• Functional Class IV, as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis
• Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement), within 12 weeks prior to Day 1 or planned within 48 weeks after Day 1
• Known hypersensitivity to any component of a humanized or murine monoclonal antibody
• Receipt of a live vaccination within 4 weeks prior to Day 1
• Significant cardiac or pulmonary disease, including obstructive pulmonary disease
• Evidence of significant uncontrolled concomitant disease, such as, but not limited to nervous system, renal, hepatic, endocrine, or gastrointestinal disorders
• Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease but excluding fungal infections of the nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Day 1 or oral antibiotics within 2 weeks of Day 1
• History of serious recurrent or chronic infection (a chest X-ray will be performed at screening if one has not been performed within 12 weeks of screening that showed no clinically significant abnormality)
• History of or currently active primary or secondary immunodeficiency, including HIV infection
• History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that has been excised and cured)
• History of significant cytopenias or other bone marrow disorders
• History of alcohol, drug, or chemical abuse within 24 weeks prior to Day 1
• Pregnancy or lactation
• Neuropathies and neurovasculopathies that might interfere with pain evaluation
• Poor peripheral venous access
• Intolerance or contraindications to oral or IV corticosteroids
• Hemoglobin < 8.0 g/dL
• Absolute neutrophil count < 1.5 x 10^3/uL
• IgM < 0.40 mg/mL
• IgG < 5.0 mg/mL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x the upper limit of normal
• Positive hepatitis B surface antigen or hepatitis C antibody serology
• For women of childbearing potential (including those who have had a tubal ligation), a positive serum pregnancy test at screening
• Current use of any DMARD other than MTX
• Concurrent treatment with any biologic agent
• Treatment with any investigational agent within 4 weeks prior to Day 1 or five half-lives of the investigational drug (whichever is longer)
• Any previous treatment with rituximab or other cell-depleting therapies, including CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, BLys/ BAFF, and other anti-CD20 agents
• Previous treatment with an anti-<alpha> 4 integrin agent, including natalizumab
• Previous treatment within 6 months of screening with IV & globulin or the Prosorba(R) Column

Please refer to this study by ClinicalTrials.gov identifier  NCT00266227

Luara Resnansky       laurares@gene.com

Study chairs or principal investigators

Sunil Agarwal, M.D.,  Study Director,  Genentech   

Study ID Numbers:  U3384g
Last Updated:  December 15, 2005
Record first received:  December 14, 2005
ClinicalTrials.gov Identifier:  NCT00266227
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2006-01-10