Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-center, Randomized, Double-Blind, Active-Controlled Study Evaluating Efficacy and Safety of Etanercept 50 mg Twice Weekly (BIW) in Rheumatoid Arthritis Subjects Who Are Sub-optimal Responders to Etanercept 50 mg Once Weekly (QW)
Brief Summary: The purpose of this study objective will be to evaluate the efficacy and safety of etanercept 50 mg BIW in RA subjects who showed a sub-optimal response to standard dose etanercept (50 mg QW) and concomitant methotrexate therapy.


Options:
A: Inclusion Criteria:

* Diagnosis of Rheumatoid Arthritis
* RA with a disease duration \> 6 months
* Current and prior but continuous etanercept (50 mg weekly) treatment for at least 5 months prior to screening
* Subjects must be receiving methotrexate (MTX) at a stable dose \> 15 mg/week at least 4 weeks prior to screening
* Sub-optimal response to etanercept defined by the presence of the following criteria (based on 28 joint count) at screening: 5 or more swollen joints and 5 or more tender joints
* Subjects who are currently receiving oral corticosteroids must be on a dose equivalent to prednisone less than or equal to 10 mg/day at screening
* Subjects who are currently receiving non-steroidal anti-inflammatory drugs (NSAIDs), must be on a stable dose for at least 2 weeks prior to screening
* Subjects who are currently receiving DMARD therapy (including sulfasalazine, hydroxy-chloroquine and leflunomide), must be on a stable dose for at least 4 weeks prior to screening

Exclusion Criteria:

* Nursing mothers, female subjects planning on becoming pregnant, or male subjects planning a pregnancy with their spouse/partner while in the study
* ACR functional class IV
* Receipt of any investigational drug or biologic within 4 weeks of study drug initiation
* Concurrent or history of psychiatric disease that would interfere with ability to comply with study protocol or give informed consent
* History of alcohol or drug abuse within 12 months of screening visit
* Severe comorbidities including: History of cancer (other than resected cutaneous basal and squamous cell carcinoma, and in situ cervical cancer) within 5 years of screening visit. Documentation of disease-free state since treatment required; Diagnosis of Class III or IV congestive heart failure (CHF) or myocardial infarction (MI) within 12 months of screening; Unstable or stable angina pectoris; Uncontrolled hypertension (defined as systolic blood pressure measurement of greater than 180 mm Hg or a diastolic blood pressure of greater than 110 mm Hg); Oxygen-dependent pulmonary disease; Known HIV-positive status or other immunodeficiency syndromes; Chronic hepatitis B (HbsAg) or C (HCV); Systemic lupus erythematosus (SLE); CNS demyelinating events suggestive of multiple sclerosis; Presence of active infection or any underlying diseases that could predispose subjects to infection (e.g., history of recurrent infections, non-healing leg ulcers, advanced or poorly controlled diabetes); Active or prior history of tuberculosis (or known exposure).
* Concurrent treatment with cyclophosphamide
B: Inclusion Criteria:

* Patients received placebo in main double-blind study (P04280, NCT00202852)
* Patients received Infliximab-containing regimen showing clinical response at week 30 in main double-blind study (P04280)

\[Main double-blind study (P04280, NCT00202852) inclusion criteria\]

* Diagnosis of rheumatoid arthritis (RA) according to the revised 1987 criteria of the American Rheumatism Association (Arnett et al, 1988). The disease should have been diagnosed \>6 months prior to screening.
* Active disease at the time of screening and pre-infusion as defined by:

  * \>=6 swollen joints
  * \>=6 tender joints and
* 2 of the following:

  * morning stiffness \>=45 min
  * erythrocyte sedimentation rate (ESR) \>=28 mm/h
  * C-reactive protein (CRP) \>=20 mg/L
* Men and women, \>=18 to \<=75 years of age
* Men and women of childbearing potential must be using adequate birth control measures (abstinence, oral contraceptives, intrauterine device (IUD), barrier method with spermicide, or surgical sterilization) and should continue such precautions for 6 months after receiving the last infusion.
* Must have been using oral or parenteral MTX for \>3 months with no break(s) in treatment of \>2 weeks total during this period. Patients must have been on a stable dose of \>=12.5 mg/wk (maximum 20 mg/wk) for at \>4 weeks prior to screening.
* Must be on a stable dose of folic acid prophylaxis for \>4 weeks prior to screening.
* Patients using oral corticosteroids, must have been on a stable dose of \<=10 mg/day for \>4 weeks prior to screening. If currently not using corticosteroids the patient must have not received corticosteroids for \>4 weeks prior to screening.
* If using nonsteroidal anti-inflammatory drugs (NSAIDs), patients should have been on a stable dose for \>4 weeks prior to screening.
* The screening laboratory tests must meet the following criteria:

  * Hemoglobin \>=5.3 mmol/L (\>=8.5 g/dL), providing a low hemoglobin level is not due to nutritional deficiencies or due to diseases other than chronic RA
  * white blood cell (WBC) \>=3.5 x 10\^9/L (\>=3.5 x 10\^3/mm\^3)
  * Neutrophils \>=1.5 x 10\^9/L (\>=1.5 x 103/mm\^3)
  * Platelets \>=100 x 10\^9/L (\>=100 x 103/mm\^3)
  * Serum transaminase \<=2 times the upper limit of normal
  * Alkaline phosphatase levels \<=2 times the upper limit of normal
  * Serum creatinine \<=150 µmol/L (\<=1.7 mg/dL)
* Must be able to adhere to the study visit schedule and other protocol requirements.
* Must be capable of giving informed consent and the consent must have been obtained prior to any study procedures including wash-out period.

Exclusion Criteria:

* Exclusion criteria below of main double-blind study (P04280, NCT00202852)

\[Main double-blind study (P04280, NCT00202852) exclusion criteria\]

* Pregnant women, nursing mothers, or a planned pregnancy within 1.5 years of enrollment.
* Patients who are incapacitated, largely or wholly bedridden or confined to a wheelchair, and who have little or no ability for self-care.
* Patients who have any current systemic inflammatory condition with signs and symptoms that might confound the evaluations of benefit from infliximab, eg Lyme disease, or a rheumatic disease other than RA.
* Use of disease modifying anti-rheumatic drugs (DMARDs) other than MTX within 4 weeks prior to screening. (If a patient had prior exposure to leflunomide within the past 6 months, cholestyramine 8 g should be given 3 times daily for 11 days to rapidly lower the plasma level of leflunomide.)
* Use of intra-articular, i.m. or i.v. corticosteroids (including i.m. ACTH) within 4 weeks prior to screening.
* Have been previously treated with infliximab or genetic recombinant therapy with RA (e.g. etanercept, adalimumab)
* Treatment with any other therapeutic agent targeted at reducing TNF (eg, pentoxifylline or thalidomide) within the previous 3 months.
* Treatment with any investigational drug within the previous 3 months.
* Prior use of cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents.
* History of any clinically significant adverse reaction to murine or chimeric proteins, including but not limited to allergic reactions.
* History of infected joint prosthesis within previous 5 years.
* Serious infections, such as hepatitis, pneumonia, pyelonephritis in the previous 3 months.
* Chronic infectious disease such as chronic renal infection, chronic chest infection with bronchiectasis or sinusitis.
* Active tuberculosis (TB). Also excluded are patients who have evidence of latent TB (positive purified protein derivative \[PPD\] skin test or a history of latent TB) without adequate therapy for TB initiated prior to first infusion of study drug. Also excluded are patients with evidence of an old or latent TB infection without documented adequate therapy, if they will not be treated with antitubercular therapy during the trial. Patients with a current close contact with an individual with active TB will also be excluded. Additionally, patients who have completed treatment for active TB within the previous 2 years are now explicitly excluded from the trial. Patients with a household member who has a history of active pulmonary TB should have had a thorough evaluation for TB prior to study enrollment as recommended by a local infectious disease specialist or published local guidelines of TB control agencies. Also excluded are patients with opportunistic infections, including but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, aspergillosis, or atypical mycobacterial infection, etc, within the previous 6 months.
* Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
* History of lymphoproliferative disease including lymphoma or signs suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (such as nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic areas), or splenomegaly.
* Any current known malignancy or history of malignancy within the previous 5 years, except for squamous or basal cell carcinoma of the skin that have been treated with no evidence of recurrence.
* Patients with moderate or severe heart failure (New York Heart Association \[NYHA\] class III/IV).
* Patients with pre-existing or recent onset of central nervous system demyelinating disorders.
* Known recent substance abuse (drug or alcohol).
* Patients in whom multiple venipunctures are not feasible due to poor tolerability or lack of easy access.
* Have a known infection with HIV or known active hepatitis B/C infection (including associated chronic active hepatitis).
C: Inclusion Criteria:

* Diagnosis of RA according to the revised 1987 criteria of the American Rheumatism Association (Arnett et al, 1988). The disease should have been diagnosed at least 6 months prior to screening.
* Active disease at the time of screening and pre-infusion as defined by:

  * \>=6 swollen joints
  * \>=6 tender joints and 2 of the following:

    * morning stiffness \>=45 min
    * ESR \>=28 mm/h
    * CRP \>=20 mg/L
* Men and women, \>=18 to \<=75 years of age
* Men and women of childbearing potential must be using adequate birth control measures (abstinence, oral contraceptives, IUD, barrier method with spermicide or, surgical sterilization) and should continue such precautions for 6 months after receiving the last infusion.
* Patients must have been using oral or parenteral MTX for at least 3 months with no break(s) in treatment of more than 2 weeks total during this period. Patients must have been on a stable dose of \>=12.5 mg/wk (maximum 20mg/wk) for at least 4 weeks prior to screening.
* Patients must be on a stable dose of folic acid prophylaxis for at least 4 weeks prior to screening.
* Patients using oral corticosteroids, must have been on a stable dose of \<=10 mg/day for at least 4 weeks prior to screening. If currently not using corticosteroids the patient must have not received corticosteroids for at least 4 weeks prior to screening.
* If using NSAIDs, patients should have been on a stable dose for at least 4 weeks prior to screening. If currently not using NSAIDs the patient must have been off for at least 4 weeks prior to screening.
* The screening laboratory tests must meet the following criteria:

  * Hemoglobin \>=5.3 mmol/L (\>=8.5 g/dL), providing a low hemoglobin level is not due to nutritional deficiencies or due to diseases other than chronic RA
  * WBC \>=3.5 x 10\^9/L
  * Neutrophils \>=1.5 x 10\^9/L
  * Platelets \>=100 x 10\^9/L
  * Serum transaminase \<=2 times the upper limit of normal
  * Alkaline phosphatase levels \<=2 times the upper limit of normal
  * Serum creatinine \<=150 µmol/L (\<=1.7 mg/dL)
* Patient must be able to adhere to the study visit schedule and other protocol requirements.
* Patient must be capable of giving informed consent and the consent must have been obtained prior to any study procedures including wash-out period.

Exclusion Criteria:

* Pregnant women, nursing mothers or a planned pregnancy within 1.5 years of enrollment.
* Patients who are incapacitated, largely or wholly bedridden or confined to a wheelchair, and who have little or no ability for self-care.
* Patients who have any current systemic inflammatory condition with signs and symptoms that might confound the evaluations of benefit from the Infliximab therapy, eg Lyme disease, or a rheumatic disease other than RA.
* Use of DMARDs other than MTX within 4 weeks prior to screening. (If a patient had prior exposure to leflunomide within the past 6 months, cholestyramine 8 g should be given 3 times daily for 11 days to rapidly lower the plasma level of leflunomide.)
* Use of intra-articular, i.m. or i.v. corticosteroids (including i.m. ACTH) within 4 weeks prior to screening.
* Have been previously treated with infliximab or genetic recombinant therapy with RA (e.g. etanercept, adalimumab).
* Treatment with any other therapeutic agent targeted at reducing TNF (eg, pentoxifylline or thalidomide) within the previous 3 months.
* Treatment with any investigational drug within the previous 3 months.
* Prior use of cyclophosphamide, nitrogen mustard, chlorambucil, or other alkylating agents.
* Have a history of any clinically significant adverse reaction to murine or chimeric proteins, including but not limited to allergic reactions.
* History of infected joint prosthesis within previous 5 years.
* Serious infections, such as hepatitis, pneumonia, pyelonephritis in the previous 3 months.
* Chronic infectious disease such as chronic renal infection, chronic chest infection with bronchiectasis or sinusitis.
* Have active TB. Also excluded are patients who have evidence of latent TB (positive PPD skin test or a history of latent TB) without adequate therapy for TB initiated prior to first infusion of study drug. Also excluded are patients with evidence of an old or latent TB infection without documented adequate therapy, if they will not be treated with antitubercular therapy during the trial. Patients with a current close contact with an individual with active TB will also be excluded. Additionally, patients who have completed treatment for active TB within the previous 2 years are now explicitly excluded from the trial. Patients with a household member who has a history of active pulmonary TB should have had a thorough evaluation for TB prior to study enrollment as recommended by a local infectious disease specialist or published local guidelines of TB control agencies. Also excluded are patients with opportunistic infections, including but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, aspergillosis, or atypical mycobacterial infection, etc, within the previous 6 months.
* Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic or cerebral disease.
* History of lymphoproliferative disease including lymphoma or signs suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (such as nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic areas), or splenomegaly.
* Any current known malignancy or history of malignancy within the previous 5 years, except for squamous or basal cell carcinoma of the skin that have been treated with no evidence of recurrence.
* Patients with moderate or severe heart failure (NYHA class III/IV)
* Patients with pre-existing or recent onset of central nervous system demyelinating disorders
* Known recent substance abuse (drug or alcohol).
* Patients in whom multiple venipunctures are not feasible due to poor tolerability or lack of easy access.
* Have a known infection with HIV or known active hepatitis B/C infection (including associated chronic active hepatitis).
D: Inclusion Criteria:

* Have a diagnosis of rheumatoid arthritis (according to the 1987 ACR classification criteria OR a score of ≥6 as defined by the ACR/European League Against Rheumatism Classification and Diagnostic Criteria for rheumatoid arthritis ) for at least 6 months prior to screening
* Must have been treated with MTX 12.5-25 mg/week, for at least 6 weeks prior to screening. Doses of 10 to \< 12.5mg/week are allowed if there is documented intolerance
* Have moderately to severely active rheumatoid arthritis disease with at least 6 tender and 6 swollen joints
* CRP ≥1.2 times the upper limit of normal (central laboratory) or erythrocyte sedimentation rate of more than 28mm/hour
* Intolerant or inadequate response to treatment (ie, TNF blocker failure)≥1 licensed TNF-blocker therapies within 2 years of screening

Exclusion Criteria:

* Have a diagnosis of any other inflammatory arthritis or secondary, noninflammatory type of arthritis, such as psoriatic arthritis, lupus, gout, or ankylosing spondylitis
* Wheelchair bound or bedridden.
* Disease modifying antirheumatic drugs (DMARDs) other than MTX.
* Treatment with tocilizumab or any other anti-IL-6 investigational therapies at any time.
* Treatment with other biologics within 4-24 weeks (depending on the biologic)
* History of ongoing, chronic or recurrent infections or recent serious or life-threatening infection
* Known concurrent acute or chronic viral hepatitis B or C infection or human immunodeficiency virus (HIV) infection.
* Vaccinations (other than injectable influenza or pneumococcal) within 8 weeks prior to screening or plan to receive vaccines during the study
* Concurrent or history of malignancy with the exception of nonmelanoma skin cancer successfully treated more than 2 years prior to screening or cervical cancer successfully treated more than 5 years prior to screening.
* History of chronic alcohol abuse or drug addiction within the last 1 year or current drug addiction or use of illicit drugs.

Answer: A