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:

* 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.
B: Inclusion Criteria:

* Diagnosis of RA
* Currently receiving an adequate dose of methotrexate (MTX) for treatment of RA
* Active RA at time of screening and baseline

Exclusion Criteria:

* Previous or current treatment with etanercept (ETN), other tumor necrosis factor-alpha inhibitors, or other biologic agents
* Concurrent treatment with a DMARD, other than MTX, at screening
* Receipt of any DMARD, other than MTX, within 3 months before screening
C: Inclusion Criteria:

* Diagnosis of Rheumatoid Arthritis
* At least 3 months prior treatment with Methotrexate (MTX)
* At least 10 swollen joints and 12 tender joints and C-Reactive Protein of at least 1 mg/dl
* Washout required for other disease modifying anti-rheumatic drugs (DMARDS)

Exclusion Criteria:

* participants who have failed more than 3 DMARDs
* participants previously treated with an approved biologic drug
* History of cancer in the last 5 years
* Severe or recurrent bacterial infection
* Any previous or current medical conditions that are contraindications to the use of TNF blocking agents
* Women of Child Bearing Potential
D: Other protocol-defined inclusion/exclusion criteria may apply

CORE STUDY

Inclusion Criteria

Core Study Inclusion Criteria At Screening

1. Cooperative male or non-pregnant, non-lactating female patients at least 18 years of age who signed an informed consent before the initiation of any study procedure.
2. Diagnosis of rheumatoid arthritis (RA) classified by American College of Rheumatology (ACR) 1987 revised criteria and with symptoms for at least 3 months before randomization.
3. Functional status class I, II or III classified according to the ACR 1991 revised criteria.
4. Patients treated with methotrexate (MTX) at the maximum tolerated (≤25 mg/week) and stable dose of ≥7.5 mg/week for at least 12 weeks before randomization.
5. Patients who had failed any disease-modifying antirheumatic drugs (DMARDs) (including biologic agents and any DMARD used in combination with MTX) were allowed.
6. For patients with previous treatment of biological therapy, the following wash-out periods were required before randomization:

   * 3 days for Kineret™ (anakinra) - with a terminal half-life of 4 to 6 hours (s.c. route).
   * 4 weeks for Enbrel® (etanercept) - with a terminal half-life of 102 ± 30 hours (s.c.

   route).
   * 8 weeks for Remicade® (infliximab) - with a terminal half-life of 8.0-9. 5 days (intravenous (i.v.) infusion).
   * 12 weeks for Humira® (adalimumab) - with a terminal half-life of 10-20 days (average 2 weeks) (subcutaneous (s.c.) route).
   * 12 weeks for Orencia® (abatacept) - with a terminal half-life of 13.1 (8-25) days (i.v. infusion).
   * 26 weeks for any other biologic - or 10 half-lives, whichever was longer.
7. Patients who took systemic corticosteroids had to be on a stable dose of ≤10 mg/d prednisone or equivalent for at least 4 weeks before randomization.
8. Patients who were regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors or paracetamol/ acetaminophen as part of their RA therapy must have been on a stable dose for at least 4 weeks before randomization. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen as needed within 2 weeks before randomization had to stop their medication at least 24 hours before an ACR visit (i.e. Visits 3, 7, 8, 10 and 12 \[End of Study\]). Patients taking folic acid supplementation had to be on stable dose for at least 4 weeks before randomization.
9. Patients with a history of immunization for Influenza (within past 12 months) and Pneumococcal vaccination (within 4 years) were included. If not already immunized, vaccination was completed when medically indicated (only during flu season for influenza) and such patients were included after approximately a 3 week window post-immunization to allow immunity to develop for vaccine.
10. Weight ≥45 kg and body mass index (BMI) \<34.0
11. Women of non-child-bearing potential, defined as all women physiologically not capable of becoming pregnant.

Core Study Inclusion criteria At Baseline (Visit 3)

1. Disease activity criteria of ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints.
2. One of the following also had to be present:

   1. High-sensitive C-Reactive Protein (hsCRP) concentration ≥10 mg/L
   2. Erythrocyte Sedimentation Rate (ESR) ≥28 mm/1st hr
   3. a. + b. based on screening values.

EXCLUSION

1. History of hypersensitivity to study drug or to molecules with similar structures.
2. Any therapy by intra-articular injections (e.g. corticosteroid) required for treatment of acute RA flare within 4 weeks before randomization.
3. Current use of DMARDs other than MTX. DMARDs included but were not limited to: biologic agents, thiolates (D-penicillamine, thiopronine), sulfasalazine, gold compounds, antimalarials, cyclosporine A, azathioprine, leflunomide, and alkylating agents such as cyclophosphamide.
4. If a patient had been discontinued from DMARDs, the patient should have been off the agent for at least 4 weeks, except leflunomide which was 8 weeks.
5. Patients with evidence of active pulmonary disease (e.g. tuberculosis, fungal diseases).
6. Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
7. Who had a live vaccination within 12 weeks before randomization, or were planning to have one during the study and were not willing/able to postpone until study completion.
8. a) With bacterial, fungal or viral infections at the time of enrollment, including patients with evidence of human immunodeficiency virus (HIV) infection, hepatitis B and hepatitis C infection.

   b) History of a positive purified protein derivative (PPD) of tuberculin skin test without a follow-up of a negative chest X-ray.

   c) Patients requiring administration of antibiotics against latent tuberculosis, e.g. isoniazide.
9. Underlying metabolic, hematologic, renal, hepatic, infectious or gastrointestinal conditions which in the opinion of the investigator immunocompromised the patient and/or placed the patient at unacceptable risk for participation in an immunomodulatory therapy. In particular, clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty's syndrome.
10. With significant medical problems, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure, type-I-diabetes(well controlled type-II-diabetes was allowed even when requiring insulin), thyroid disease (unless the patient was taking a stable dose of thyroid hormone for at least 12 weeks before randomization).
11. Other rheumatic diseases that could confound the evaluation of efficacy, including but not limited to primary fibromyalgia, ankylosing spondylitis, Lyme disease, adult juvenile RA, systemic lupus erythematosus, gout and pseudo gout, vasculitis, psoriatic arthritis, reactive arthritis, primary Sjoegren's Syndrome, and Behcet's Syndrome.
12. Any medical or psychiatric condition which, in the Investigator's opinion, would preclude the participant from adhering to the protocol or completing the study per protocol.
13. History of malignancy of any organ system, treated or untreated, within the past 5 years (with the exception of adequately treated basal cell carcinoma or squamous-cell carcinoma of the skin, carcinoma in situ of the cervix, colon polyps with non-invasive malignancy that have been removed).
14. Use of any investigational drug other than RA therapy and/or devices at the time of randomization, or within 30 days or 5 half- lives of randomization, whichever was longer.

STUDY EXTENSIONS

Extension Studies Inclusion Criteria:

1. Patients who completed the core CACZ885A2201 study may enter the first extension study upon signing informed consent. A patient is defined as completing the study if he/she completed the core CACZ885A2201 study up to and including Visit 12.
2. Patients who completed the first extension study, may enter the second.

Extension Studies Exclusion Criteria

1. Patients for whom continued treatment in the extension is not considered appropriate by the treating physician.
2. Patients who were non-compliant or who demonstrated a major protocol violation in the core CACZ885A2201 study.
3. Patients who discontinued from the core CACZ885A2201 study before Visit 12.

Answer: A