a study of the safety of rituximab in combination with other anti-rheumatic drugs in subjects with active rheumatoid arthritis

Conditions: Rheumatoid Arthritis

Summary: this is a phase iii, open-label study of a total of approximately 560 subjects with active rheumatoid arthritis (ra) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (dmards). enrollment in the study was conducted in two stages. in stage i of the study, approximately 400 subjects receiving non-biological dmards (with the exception of methotrexate \[mtx\] monotherapy or mtx and leflunomide combination therapy) were enrolled. in stage ii of the study, approximately 160 subjects receiving a federal drug administration-approved biological dmard at the time of screening were enrolled.


Eligibility criteria:
inclusion criteria (stage i): * male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active rheumatoid arthritis (ra) for ≥ 6 months * receiving treatment for ra on an outpatient basis * have had an inadequate response to at least one non-biological disease-modifying anti-rheumatic drug (dmard) and have been receiving this dmard(s) for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline * demonstrated tolerability to currently prescribed dmards * if taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to the first day of treatment with rituximab (day 1) * use of one nonsteroidal anti-inflammatory drug (nsaid) is permitted if the dose is stable for ≥ 2 weeks prior to day 1 exclusion criteria (stage i): * rheumatic autoimmune disease other than ra or significant systemic involvement secondary to ra (including but not limited to vasculitis, pulmonary fibrosis, or felty's syndrome) * functional class iv as defined by the american college of rheumatology (acr) classification of functional status in rheumatoid arthritis * history of or current inflammatory joint disease other than ra or other systemic autoimmune disorder * diagnosis of juvenile idiopathic arthritis, or juvenile ra, and/or ra before age 16 years * any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of enrollment * lack of peripheral venous access * 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 that, in the investigator's opinion, would preclude subject participation * primary or secondary immunodeficiency (history of or currently active), including known history of human immunodeficiency virus (hiv) infection * known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with intravenous (iv) antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline * history of medically significant opportunistic infection * history of serious recurrent or chronic infection * history of deep space/tissue infection within 52 weeks prior to baseline * history of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have 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 baseline * pregnancy or lactation * neuropathies and neurovasculopathies that might interfere with pain evaluation * methotrexate (mtx) monotherapy at the time of screening * concurrent treatment with mtx and leflunomide in combination * concurrent treatment with any biologic agent * prior to day 1, subjects will be discontinued from all dmards/combinations that are prohibited in the protocol * history of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins * previous treatment with an anti-α4 integrin agent * previous treatment with any cell-depleting therapies, including investigational agents * receipt of any vaccine within 28 days prior to baseline * intolerance or contraindications to iv corticosteroids * receipt of iv immunoglobulin (ivig) or prosorba\ column within 6 months prior to baseline * any previous treatment with rituximab * positive hepatitis b surface antigen, hepatitis b core antibody, or hepatitis c antibody inclusion criteria (stage ii): * male or female subjects, between 18 and 80 years of age, who have a documented diagnosis of active ra for ≥ 6 months, diagnosed according to the revised 1987 acr criteria for the classification of ra * receiving treatment for ra on an outpatient basis * have had an inadequate response to at least one biologic dmard and have been receiving this agent at screening and for ≥ 12 weeks prior to baseline, with stable dose greater than or equal to 4 weeks prior to baseline * have demonstrated tolerability to currently prescribed dmards/biologics * if taking a background corticosteroid, use of the corticosteroid must be at a stable dose during the 4 weeks prior to baseline * use of one nsaid is permitted if the dose is stable for ≥ 2 weeks prior to baseline exclusion criteria (stage ii): * rheumatic autoimmune disease other than ra, or significant systemic involvement secondary to ra (including but not limited to vasculitis, pulmonary fibrosis, or felty's syndrome) * functional class iv as defined by the acr classification of functional status in rheumatoid arthritis * history of, or current, inflammatory joint disease other than ra or other systemic autoimmune disorder * diagnosis of juvenile idiopathic arthritis, or juvenile ra, and/or ra before age 16 years * any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of randomization * lack of peripheral venous access * 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 that, in the investigator's opinion, would preclude subject participation * primary or secondary immunodeficiency (history of or currently active), including known history of hiv infection * known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with iv antibiotics within 4 weeks of baseline or completion of oral antibiotics within 2 weeks prior to baseline * history of medically significant opportunistic infection * history of serious recurrent or chronic infection * history of deep space/tissue infection within 52 weeks prior to baseline * history of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have 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 baseline * pregnancy or lactation * neuropathies and neurovasculopathies that might interfere with pain evaluation * infliximab monotherapy at the time of screening (infliximab should be in combination with mtx) * concurrent treatment with mtx and leflunomide in combination * concurrent treatment with more than one biologic agent * prior to day 1, subjects will be discontinued from all dmards/combinations that are prohibited in the protocol * history of a severe allergic or anaphylactic reaction to a biologic agent, or known hypersensitivity to any component of rituximab or to murine proteins * previous treatment with an anti-α4 integrin agent * previous treatment with any cell-depleting therapies * treatment with any investigational agent within 28 days of baseline or 5 half-lives of the investigational drug (whichever is the longer) * receipt of any vaccine within 28 days prior to baseline * intolerance or contraindications to iv corticosteroids * receipt of ivig or prosorba\ column within 6 months prior to baseline * any previous treatment with rituximab * positive hepatitis b surface antigen, hepatitis b core antibody, or hepatitis c antibody * positive purified protein derivative (ppd) skin test not adequately treated according to center for disease control (cdc) guidelines

Keywords: rituxan ra dmard active rheumatoid arthritis