Please select the eligibility criteria that correspond to the clinical trial below.
Title: CSP #551 - Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy
Brief Summary: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints leading to joint destruction, with significant long-term morbidity and mortality. Early treatment of RA patients with disease-modifying antirheumatic drugs (DMARDs) significantly decreases these complications. Methotrexate (MTX) is an excellent, economical first-line DMARD used to treat a majority of RA patients. While most patients respond well to MTX, many continue to have active disease. Therefore, understanding how to best treat RA patients with active disease despite MTX therapy is critically important. Although a number of therapies with significantly different economic implications have been shown to be effective when added to MTX, no trial has directly compared active therapies. This study will compare therapeutic strategies using two regimens with proven efficacy when added to MTX therapy; a) hydroxychloroquine and sulfasalazine (cost \~ $1000 per year); b) the tumor necrosis factor inhibitor, etanercept (cost \~ $12,000 per year).

We propose a bi-national multi-center randomized, double-blind equivalency trial comparing (A) the strategy of initially adding hydroxychloroquine and sulfasalazine to MTX in patients with active disease despite MTX, with a switch at 24 weeks to etanercept in nonresponders to (B) a strategy of adding etanercept to MTX, with a switch to hydroxychloroquine and sulfasalazine in nonresponders at 24 weeks. If we find that the strategy of first adding hydroxychloroquine and sulfasalazine to MTX identifies a subset of responsive patients and that there is no harm to nonresponders because of early rescue with etanercept, then this less expensive option should become the standard treatment for MTX resistant patients.

Four hundred and fifty RA patients with active disease despite treatment with MTX as indicated by a Disease Activity Score with 28 joints (DAS28) of \>4.4 units will be randomized. A DAS improvement of \<1.2 (validated as clinically significant) at 24 weeks will be used to identify early nonresponder who will switch therapy. Subjects with a DAS28 improvement of \> 1.2 at 24 weeks will remain on their initial therapy. The primary endpoint is the change of DAS 28 scores from baseline to 48 weeks. The secondary endpoint is comparison of radiographic progression of disease at 48 weeks, as measured by the change in Sharp score. Economic and functional outcomes will be assessed and a serum and DNA bank will be established to evaluate potential biomarkers predictive of treatment response/toxicity and disease progression. This trial will recruit 450 subjects over 40 months. At the end of the 48 week blinded active therapy portion of the trial, the blind will be broken and data will be collected in an open fashion until all 450 patients have completed the 48 week portion of the trial.


Options:
A: Inclusion Criteria:

* All patients must fulfill ACR classification criteria for rheumatoid arthritis.
* All patients must have been 16 years of age or older at time of diagnosis of rheumatoid arthritis.
* All patients must be 18 years of age or older at the time of entry into the study.
* All patients will have been receiving oral or subcutaneous methotrexate 15 to 25 mg/week (unless intolerant and on a minimum 10 mg/week) at a constant dose for at least 4 weeks, and on any methotrexate for no less than 12 weeks.
* All patients will have active disease as defined by a DAS28 of greater than or equal to 4.4.
* If patients are receiving corticosteroids, they must have been on stable dose (less than or equal to 10 mg prednisone or equivalent) for at least two weeks prior to screening.
* If patients are using non-steroidal anti-inflammatory drugs (NSAIDs), they must be on stable doses for at least one week prior to screening.
* If patients have taken leflunomide, cyclosporine, gold, Anakinra, azathioprine, or penicillamine in combination with methotrexate, they must have stopped this therapy at least 8 weeks prior to randomization.
* Laboratory tests must meet the following criteria within 2 weeks of randomization:

  * Serum creatinine 1.8 mg/dL
  * Hemoglobin 9 g/dL
  * WBC 3000 mc/L
  * Neutrophils 1000 mc/L
  * Platelets 100,000 mc/L
  * Serum transaminase level (AST or ALT, whichever is followed at the site) not exceeding 1.2 times upper limit of normal.
  * Albumin no less than 1.0 g/dL (10 g/L) below lower limit of normal. Anything below lower limit of normal must have been stable (or improving) for no less than 90 days. Stable is defined as changes of no more than 0.2 g/dL (2 g/L).
* All patients must be capable of giving informed consent and able to adhere to study visit schedule.
* Subject or designee must have the ability to self-inject investigational product or have a caregiver who can inject subcutaneous injections
* Subjects must meet one of the following criteria with regard to tuberculosis. PPD must be within 180 days of randomization if the patient has no recent exposure/travel history, or within 90 days if the patient has a recent exposure/travel history.

  * Negative PPD; or
  * Positive PPD \<5 mm, with a negative chest x-ray; or
  * Positive PPD \>5mm, treated for at least 28 days with INH.
* Subjects with an Erythrocyte sedimentation rate (ESR) of less than or equal to 10 and a tender and swollen joint count of at least 10 and does not qualify for the study using the DAS28, will be allowed to use the DAS28-CRP rather than the traditional DAS28 to determine eligibility.

Exclusion Criteria:

* Previous intolerance to methotrexate (unless able to tolerate at least 10 mg/week)
* Sensitivity to study medications
* Previous treatment with methotrexate, sulfasalazine or hydroxychloroquine in combination with each other for longer than 4 weeks duration. No combination use is allowed within 4 weeks of screening.
* No bed or wheelchair-bound patients
* Previous treatment with a TNF- inhibitor (etanercept, infliximab or adalimumab) for more than 5 weeks of therapy. Previous treatment with TNF- inhibitor must have been stopped for reasons other than toxicity or efficacy. No TNF- inhibitor therapy is allowed within the following time frames:

  * Last dose of etanercept must have been at least 4 weeks before screening.
  * Last dose of adalimumab or infliximab must have been at least 8 weeks prior to screening.

Example of an eligible patient: A patient found he could not afford the co-pays for a TNF inhibitor after two doses and stopped taking the medication two months before being evaluated for this trial.

* Evidence of important acute or chronic infections (no IV antibiotics within 1 month, and no PO antibiotics within 2 weeks)
* Pregnant or nursing women
* Women of childbearing potential or their partners who are not practicing an acceptable form of birth control as defined by investigator
* Active substance abuse or psychiatric illness likely to interfere with protocol completion
* History of multiple sclerosis, transverse myelitis, or optic neuritis
* History of macular degeneration unless patient has letter from their ophthalmologist that will allow for participation in trial
* New York Heart Association Class III or IV congestive heart failure
* Active malignancy (other than in situ cervical cancer or non-melanoma skin cancer), or history of lymphoma
* History of HIV
* History of any opportunistic infection - to include but not limited to Pneumocystis carinii, aspergillosis, histoplasmosis, or atypical mycobacterium
* History of porphyria
* Diagnosis of SLE or seronegative spondyloarthropathy or any other form of concomitant arthritis (osteoarthritis is permitted)
* Diagnosis of psoriasis unless rheumatoid factor positive
* Any significant unstable medical condition considered a contraindication by investigator
* Any participation in another investigational drug study during the 90 days preceding randomization.
* Receipt of a live vaccine within 90 days of study entry.
* History of oral or IV cyclophosphamide use
* Life expectancy less than 2 years
* Receipt of steroid injection, intravenous, intramuscular, or intraarticular, within 30 days of randomization.
B: Inclusion Criteria:

* Male or female ≥18 and ≤80 years of age at time of screening
* Diagnosed with rheumatoid arthritis as determined by meeting 1987 American College of Rheumatology (ACR) classification criteria and has had rheumatoid arthritis for at least 6 months
* Moderate rheumatoid arthritis during screening, as defined by a disease activity score (28 joint) calculated using the C-reactive protein formula (DAS28-CRP) \> 3.2 and ≤ 5.1
* Active rheumatoid arthritis defined as ≥ 3 swollen joints (out of 28 joints examined) and ≥ 3 tender/painful joints (out of 28 joints examined) at screening and baseline. (A full 66/68 count joint count will be performed at baseline, but only joints in the 28-count joint count will be considered for eligibility. The 28-joint count consists of the finger joints excluding the distal interphalangeal joints, the wrists, elbows, shoulders, and knees)
* Must be currently taking a DMARD such as methotrexate, sulfasalazine, leflunomide, minocycline, and/or hydroxychloroquine

Exclusion Criteria:

* Prosthetic joint infection within 5 years of screening or native joint infection within 1 year of screening
* Class IV rheumatoid arthritis according to ACR revised response criteria
* Any active infection (including chronic or localized infections) for which anti-infectives were indicated within 28 days prior to first investigational product dose
* Previously used more than one experimental biologic DMARD. Patient with prior use of no more than one experimental biologic is permitted if the subject received no more than 8 weeks of treatment. The use of the experimental biologic must not have occurred within 2 months of the first dose of investigational product
* Previously used more than one commercially available biologic DMARD. Subject with prior use of no more than one commercially available biologic is permitted if the patient received no more than 8 weeks of treatment and did not discontinue because of lack of effect. The use of the biologic must not have occurred within 2 months of the first dose of investigational product. Acceptable prior use of biologics include the following examples:
* No more than 4 injections of adalimumab
* No more than 8 (50 mg) injections of etanercept
* No more than 2 infusions of infliximab
* No more than 2 infusions of abatacept
* Additional inclusion (exclusion) criteria may apply
C: Inclusion Criteria:

* adult patients at least 18 years of age with moderate to severe active RA for at least 6 months;
* inadequate response to a stable dose of MTX;
* patients of reproductive potential must be using reliable methods of contraception.

Exclusion Criteria:

* major surgery (including joint surgery) within 8 weeks before entering study, or planned surgery within 6 months after entering study;
* prior treatment failure with an anti-tumor necrosis factor agent;
* women who are pregnant or breast-feeding.
D: 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

Answer: A