Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Placebo-controlled Study of Two Treatment Strategies Based on Tocilizumab (TCZ) With or Without Methotrexate (MTX) and Possible Addition of Other Disease-modifying Anti-rheumatic Drugs (DMARDs) in Patients...
Brief Summary: This 2 arm study will compare 2 treatment strategies based on tocilizumab in combination with methotrexate or placebo in patients with moderate to severe rheumatoid arthritis. Patients receiving methotrexate treatment will be randomized to receive either a) tocilizumab 8 mg intravenous (iv) every 4 weeks + methotrexate orally (po) weekly or b) tocilizumab 8 mg iv every 4 weeks + placebo po weekly. After the first 24 weeks of blinded treatment, treatment adjustments (increase or decrease of treatment intensity) may be introduced at intervals, based on response. The anticipated time on study treatment is up to 3 years, and the target sample size is approximately 470 patients.


Options:
A: Inclusion Criteria:

* The patient has a diagnosis of RA based upon the American College of Rheumatology (ACR) 1987 Revised Criteria.
* The patient must have had an inadequate response to methotrexate and have active disease, as defined by both: ≥6 joints tender or painful on motion; and ≥6 joints swollen; and fulfills 1 of the following 2 criteria at Screening: 1.ESR (Westergren method) \>28 mm in the local laboratory. 2. CRP \>7 mg/L in the central laboratory.
* No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis.
* The patient must have been on a stable dose of 7.5 mg to 25 mg weekly of methotrexate and washed out of all other DMARDs.

Exclusion Criteria:

* Blood dyscrasias including confirmed: 1. Hemoglobin \<9 g/dL or Hematocrit \<30%; 2. White blood cell count \<3,000 cu.mm. Absolute neutrophil count \<1,200 cu.mm; 4. Platelet count \<100,000/L
* History of any other autoimmune rheumatic disease other than Sjogren's syndrome
* No malignancy or history of malignancy.
* History of infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the 6 months prior to the first dose of study drug
* Patients who have failed any TNFi for either lack of efficacy or a TNFi mechanism related adverse event.
* Patients who have previously received adalimumab therapy for any reason.
* Patients who are contraindicated for treatment with adalimumab in accordance with the approved local label.
* Patients meeting the New York Heart Association Class III and Class IV Congestive Heart failure
B: Inclusion Criteria

1. Male and female subjects aged ≥18 years at the time of signing the Informed Consent Form.
2. Patients with a diagnosis of rheumatoid arthritis as per the ACR/EULAR 2010 classification criteria (Appendix 7) confirmed at least 24 weeks prior to the screening visit.
3. Patients who have failed conventional DMARD therapy as per NICE/BSR Guidelines (49) i.e. failure of at least 2 DMARDS including MTX.
4. Patients with persistent RA disease activity despite having been treated with a current initial TNFi agent for at least 12 weeks. Active RA defined as\*:

   1. Primary non-response: failing to improve DAS28 by \> 1.2 (Appendix 6) or failing to achieve DAS28 ≤ 3.2 within the first 12 to 24 weeks of starting the initial TNFi.

      • This may include patients that have shown a reduction in DAS28 of \> 1.2 but still demonstrate unacceptably high disease activity in the physician's judgement with evidence of an overall DAS28 of ≥ 3.2 OR
   2. Secondary non-response: defined as inefficacy to first TNFi (having demonstrated prior satisfactory response) as per clinician judgement; with intolerance not the reason for cessation of first TNFi.
5. MTX dose stable for 4 weeks prior to the screening visit and to be continued for the duration of the study.
6. Patients on NSAIDs and / or corticosteroids (oral prednisolone not exceeding 10mg daily) who have been on an unchanged regimen for at least 4 weeks prior to the screening visit and are expected to remain on a stable dose until the baseline assessments have been completed.
7. Provided written informed consent prior to any trial-specific procedures.

Exclusion Criteria

1. Major surgery (including joint surgery) within 8 weeks prior to the screening visit or planned major surgery within 52 weeks following randomization.
2. Patients with inflammatory joint disease of different origin, mixed connective tissue disease, Reiter's syndrome, psoriatic arthritis, systemic lupus erythematosus, or any arthritis with onset prior to 16 years of age.
3. Patients receiving doses of prednisolone \> 10mg/day within the 4 weeks prior to the screening visit.
4. Patients receiving intra-articular or intra-muscular steroid injections within 4 weeks prior to the screening visit.
5. Patients who have previously received more than 1 TNFi drug OR any other biological therapy for the treatment of RA.
6. Patients unable or unwilling to stop treatment with a prohibited DMARD (i.e synthetic DMARD aside from MTX e.g. oral or injectable gold, chloroquine, hydroxychloroquine, cyclosporine, azathioprine, leflunomide, sulphasalazine) prior to the start of protocol treatment.
7. Treatment with any investigational drug in the last 12 weeks prior the start of protocol treatment.
8. Patients with other co-morbidity including acute, severe infections, uncontrolled diabetes, uncontrolled hypertension, unstable ischaemic heart disease, moderate/severe heart failure (Class III/IV of the New York Heart Association (NYHA) functional classification system (79)), active bowel disease, active peptic ulcer disease, recent stroke (within 12 weeks before the screening visit), or any other condition which, in the opinion of the investigator, would put the patient at risk to participate in the study or would make implementation of the protocol difficult.
9. Patients with any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 12 weeks of start of treatment protocol or oral antibiotics within 4 weeks of start of protocol treatment.
10. Patients at significant risk of infection, which in the opinion of the investigator would put the patient at risk to participate in the study (e.g. leg ulceration, indwelling urinary catheter, septic joint within 52 weeks (or ever if prosthetic joint still in situ)).
11. Patients with known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections including herpes zoster (for tuberculosis and Hepatitis B and C see below), but excluding fungal infections of nail beds as per clinical judgment.
12. Patients with untreated active current or latent tuberculosis (TB). Patients should have been screened for latent TB (as per BSR guidelines) within 24 weeks prior to the screening visit and, if positive, treated following local practice guidelines prior to the start of protocol treatment.
13. Patients with active current hepatitis B and/or C infection. Patients should have been screened for hepatitis B and C within 24 weeks prior to the screening visit and if positive, excluded from the study.
14. Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
15. Pregnancy, lactation or women of child-bearing potential (WCBP) unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.
16. Men whose partners are of child-bearing potential but who are unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and after the last dose of protocol treatment as indicated in the relevant SmPC/IB.
17. Patients with known significantly impaired bone marrow function as for example significant anaemia, leukopaenia, neutropaenia or thrombocytopaenia as shown by the following laboratory values at the time of the screening visit:

    * Haemoglobin \< 8.5 g/dl
    * Platelet count \< 100 x 109 / L
    * White blood cell count \< 2.0 x 109 / L
    * Neutrophil count \< 1 x 109 / L
18. Patients with known severe hypoproteinaemia at the time of the screening visit, e.g. in nephrotic syndrome or impaired renal function, as shown by:

    * Serum Creatinine \> 150 umol / L
C: Inclusion Criteria:

* adult patients, ≥ 18 years of age;
* moderate to severe active rheumatoid arthritis (Disease Activity Score (DAS28) \> 4.4);
* inadequate response to methotrexate;
* on a stable dose of ≥ 15mg/week methotrexate for at least 6 weeks.

Exclusion Criteria:

* prior treatment with a biologic;
* Rheumatoid arthritis (RA) functional class IV;
* known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections;
* evidence of active malignant disease.
D: Inclusion Criteria:

* Subject was age 18 or older and in good health (Investigator discretion) with a recent stable medical history.
* Diagnosis of rheumatoid arthritis (RA) as defined by the 1987-revised American College of Rheumatology (ACR) criteria, with a disease duration less than 3 years, at least 8 swollen joints out of the 66 joints assessed, at least 10 tender joints out of the 68 joints assessed, at least 1 joint erosion or rheumatoid factor (RF) positivity, erythrocyte sedimentation rate (ESR) \>= 28 mm/1h or C-reactive protein (CRP) \>= 1.5 mg/dl

Exclusion Criteria:

* Chronic arthritis diagnosed before the age of 16
* Preceding treatment with MTX, cyclophosphamide, cyclosporin, azathioprine or more than 2 other disease-modifying anti-rheumatic drugs (DMARDs)
* Subject previously received anti-tumor necrosis factor (TNF) therapy
* Permanently wheelchair-bound or bedridden patients
* Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study
* Female subject who is pregnant or breast-feeding or considering becoming pregnant

Answer: C