Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Multifactorial, Double-blind, Parallel-group, Dose-ranging Study of the Efficacy and Safety of Rituximab (MabThera®/Rituxan®) in Combination With Methotrexate in Patients With Active Rheumatoid Arthritis
Brief Summary: This study will assess the efficacy and safety of different treatment regimens of rituximab (MabThera®/Rituxan®), corticosteroids, and placebo, combined with methotrexate (MTX), in patients with active rheumatoid arthritis (RA).


Options:
A: 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
B: 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
C: Inclusion Criteria:

* adult patients \>=18 years of age;
* RA for \>=6 months;
* receiving outpatient treatment;
* inadequate response to methotrexate, having received and tolerated it for \>=12 weeks, with a stable dose for \>=4 weeks.

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 arthritis, or RA before the age of 16;
* previous treatment with \>1 biologic agent, any cell-depleting therapies, or concurrent treatment with any biologic agent or DMARD other than methotrexate.
D: Eligibility criteria include, but are not limited to the following:

* Are between the ages of 18 and 80 years.
* Have been diagnosed with rheumatoid arthritis for at least 6 months.
* Have failed treatment (lack of efficacy) with at least 1 but no more than 5 disease-modifying anti-rheumatic drugs or biologics (other than methotrexate).

Answer: D