Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Placebo-controlled, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Alpha Therapies
Brief Summary: This study will assess the safety and efficacy of rituximab combined with MTX in participants with active rheumatoid arthritis (RA) who have had an inadequate response to anti-Tumor Necrosis (TNF) alpha therapy. The anticipated time in the study is up to 2 years and the target sample size is 500 participants. Eligible participants may receive re-treatment with rituximab under a separate protocol WA17531.


Options:
A: Inclusion Criteria:

1. Must give written informed consent. If required by local law, candidates must also authorize the release and use of protected health information (PHI).
2. Male or female participants, between 18 and 65 years of age, who have a diagnosis of active RA for at least 6 months, diagnosed according to the revised 1987 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis (RA).
3. Must have at least 5 tender and 5 swollen joints at Screening and Day 1.
4. Must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week) or adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.
5. Must have been treated with methotrexate (MTX) greater than or equal to 15 mg per week and less than or equal to 25 mg per week (dose may be as low as 10 mg if unable to tolerate higher dose) for at least 12 weeks immediately prior to Day 1, at a stable dose for at least 4 weeks.
6. Must be willing to receive oral folate.
7. Oral glucocorticoids must not exceed 10 mg per day of prednisone (or equivalent dose) and must have been administered at a stable dose for at least 4 weeks prior to Day 1.
8. Any concomitant non-steroidal antiinflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1.
9. For participants of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation.

   Exclusion Criteria:

   Exclusions Related to RA
10. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty's syndrome). Secondary Sjögren's syndrome or secondary limited cutaneous vasculitis with RA is permitted.
11. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
12. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus \[SLE\], inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome).
13. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.

    Exclusions Related to General Health
14. 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.
15. Lack of peripheral venous access.
16. Pregnancy or breast feeding.
17. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
18. History of chronic heart failure (CHF), SLE-like syndrome, neuropathy or myelitis, optic neuritis, or pancytopenia while on etanercept or adalimumab.
19. Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the investigator's opinion, would preclude subject participation.
20. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection.
21. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti infectives within 4 weeks of Day 1 or completion of oral anti infectives within 2 weeks of Day 1.
22. History of positive purified protein derivative (PPD) not adequately treated.
23. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of Day 1.
24. History of serious infection or opportunistic infection in the last 2 years (to screen for a chest infection, a chest radiograph will be performed at Screening if one was not performed within 12 weeks prior to Screening).
25. History of seizures.
26. 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).
27. Any neurological (congenital or acquired), vascular, or systemic disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinsons disease, cerebral palsy, diabetic neuropathy).
28. Currently active alcohol or drug abuse or history of alcohol or drug abuse (as determined by the Investigator) within 1 year prior to Day 1.

    Exclusions Related to Medications
29. History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.
30. Previous treatment with an anti alpha 4 integrin agent or costimulation modulator.
31. Concurrent treatment with any biologic agent other than etanercept or adalimumab, or disease-modifying anti-rheumatic drug (DMARD) other than MTX. Treatment with any biologic or DMARD except etanercept or adalimumab, and MTX must be discontinued 14 days prior to baseline, except for the following: azathioprine for 28 days; leflunomide for 8 weeks (or 14 days after 11 days of standard cholestyramine or activated charcoal washout).
32. Previous treatment with any cell depleting therapies, including investigational agents (e.g., Campath \[alemtuzumab\], anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti CD11a, anti-CD22, B lymphocyte stimulator/B-cell activating factor \[BLys/BAFF\], and anti-CD20).
33. Treatment with another investigational drug within 4 weeks prior to Day 1 or 5 half lives of the investigational drug (whichever is the longer).
34. Receipt of a live/attenuated vaccine within 4 weeks prior to Day 1.
35. Intra-articular or parenteral glucocorticoids within 4 weeks prior to Day 1.
36. Intolerance or contraindications to IV glucocorticoids.

    Exclusions Related to Laboratory Findings
37. For women of childbearing potential, a positive serum pregnancy test at screening and/or a positive urine pregnancy test on Day 1.
38. Positive hepatitis B surface antigen (HBsAg).
39. Positive hepatitis B core antibody (HBcAb) associated with positive hepatitis B viral DNA (HBV DNA).
40. Positive hepatitis C antibody.
41. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 times upper limit of normal.
42. Hemoglobin \<8.0 g/dL.
43. Levels of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) below 5.0 and 0.4 mg/mL, respectively.
44. Absolute neutrophil count (ANC) \<1500/mL.

    Miscellaneous Exclusions
45. Current enrollment in any other investigational or other drug study.
46. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening visit.
B: Inclusion Criteria:

* Adult participants 18-80 years of age with active RA for at least 6 months;
* Received treatment for RA on an outpatient basis and experienced an inadequate response or intolerance to treatment with at least 1 anti-TNF alpha therapy (etanercept, infliximab or adalimumab);
* Must have received MTX for a minimum of 12 weeks, with the last 4 weeks, prior to screening at a stable dose;
* Participants with swollen joint count (SJC) and tender joint count (TJC) of at least 8 joints at screening and at randomization;
* Radiographic evidence of at least 1 joint with a definite erosion due to RA;
* Participants of reproductive potential must be using reliable contraceptive methods.

Exclusion Criteria:

* Bone or joint surgery within 8 weeks prior to screening or joint surgery planned within 24 weeks of randomization;
* Class IV functional status of RA;
* Previous treatment within 6 months with intravenous gamma globulin, or the Prosorba column;
* Intraarticular or parenteral corticosteroids within 4 weeks prior to screening visit;
* With a live vaccine within 4 weeks prior to randomization;
* Previous treatment with rituximab or other cell-depleting therapies;
* Concurrent treatment with any disease-modifying anti-rheumatic drug (except for MTX) or any anti-TNF alfa factor or other biologic therapy;
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies;
* Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders;
* Known contraindications to receiving rituximab;
* Known active bacterial, viral, fungal, mycobacterial or other infection;
* History of recurrent significant infection or history of recurrent bacterial infections;
* Primary or secondary immunodeficiency (history of, or currently active);
* History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that have been excised and cured);
* Women who are pregnant or breast-feeding;
* History of alcohol, drug or chemical abuse within 6 months prior to screening;
* Neuropathies and neurovasculopathies which might interfere with pain evaluation;
* Participants with poor peripheral venous access;
* Intolerance or contraindications to oral or intravenous corticosteroids.
C: 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
D: Inclusion criteria:

* Adult patients 18-80 years of age
* RA for ≥ 2 months;
* Receiving outpatient treatment
* Patients naive to, and considered to be candidates for, methotrexate treatment

Exclusion criteria:

* Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA
* Inflammatory joint disease other than RA, or other systemic autoimmune disorder
* Diagnosis of juvenile rheumatoid arthritis, or RA before the age of 16
* Surgery within 12 weeks of study
* Previous treatment with any approved or investigational biologic agent for RA, an anti-alpha4-integrin antibody or co-stimulation modulator, or cell-depleting therapy
* Concurrent treatment with any biologic agent or DMARD other than methotrexate

Answer: B