A Study of the Safety of Rituximab in Combination With Other Anti-Rheumatic Drugs in Subjects With Active Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Rituximab; Anti-inflammatory drugs
Intervention description: Rituximab was supplied as a concentrate for IV administration at a concentration of 10 mg/mL in 500 mg (50 mL) single-use vials.; Each rituximab infusion was preceded by methylprednisolone 100 mg IV. Use of stable doses of oral corticosteroids was permitted (≤ 10 mg of prednisone or equivalent per day) as were stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs).
Intervention MeSH terms: Anti-Inflammatory Agents; Rituximab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 578.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Rituxan; RA; DMARD; Active 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<TM> 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<TM> 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