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.

Six hundred RA patients with active disease despite treatment with MTX as indicated by a Disease Activity Score with 28 joints (DAS28) of e 4.4 units will be randomized. A DAS improvement of d 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 achievement of a DAS28 of d 3.2 (validated as representing low disease activity) at 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 30 month trial will recruit 600 subjects over 18 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 600 patients have completed the 48 week portion of the trial.

The main objective of this proposal is to compare two successful treatment strategies that have significantly different economic implications head-to-head in patients with rheumatoid arthritis who have active disease despite methotrexate therapy.

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.

Six hundred RA patients with active disease despite treatment with MTX as indicated by a Disease Activity Score with 28 joints (DAS28) of greater than or equal to 4.4 units will be randomized. A DAS improvement of greater than or equal to 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 achievement of a DAS28 of less than or equal to 3.2 (validated as representing low disease activity) at 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 30 month trial will recruit 600 subjects over 18 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 600 patients have completed the 48 week portion of the trial.

• Drug: E-551
• Drug: methotrexate
• Drug: S-551
• Drug: H-551

• Active Comparator: Etanercept and Methotrexate
• Active Comparator: Hydroxychloroquine, sulfasalazine and methotrexate

Inclusion Criteria:

1. All patients must fulfill ACR classification criteria for rheumatoid arthritis.
2. All patients must have been 16 years of age or older at time of diagnosis of rheumatoid arthritis.
3. All patients must be 18 years of age or older at the time of entry into the study.
4. 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.
5. All patients will have active disease as defined by a DAS28 of greater than or equal to 4.4.
6. 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.
7. If patients are using non-steroidal anti-inflammatory drugs (NSAIDs), they must be on stable doses for at least one week prior to screening.
8. 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.

9. Laboratory tests must meet the following criteria within 2 weeks of randomization:

   1. Serum creatinine 1.8 mg/dL
   2. Hemoglobin 9 g/dL
   3. WBC 3000 mc/L
   4. Neutrophils 1000 mc/L
   5. Platelets 100,000 mc/L
   6. Serum transaminase level (AST or ALT, whichever is followed at the site) not exceeding 1.2 times upper limit of normal.
   7. 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).
10. All patients must be capable of giving informed consent and able to adhere to study visit schedule.
11. Subject or designee must have the ability to self-inject investigational product or have a caregiver who can inject subcutaneous injections

12. 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.

    1. Negative PPD; or
    2. Positive PPD <5 mm, with a negative chest x-ray; or
    3. Positive PPD >5mm, treated for at least 28 days with INH.

Exclusion Criteria:

1. Previous intolerance to methotrexate (unless able to tolerate at least 10 mg/week)
2. Sensitivity to study medications
3. 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.
4. No bed or wheelchair-bound patients

5. 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:

   1. Last dose of etanercept must have been at least 4 weeks before screening.
   2. 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.

6. Evidence of important acute or chronic infections (no IV antibiotics within 1 month, and no PO antibiotics within 2 weeks)
7. Pregnant or nursing women
8. Women of childbearing potential or their partners who are not practicing an acceptable form of birth control as defined by investigator
9. Active substance abuse or psychiatric illness likely to interfere with protocol completion
10. History of multiple sclerosis, transverse myelitis, or optic neuritis
11. History of macular degeneration
12. New York Heart Association Class III or IV congestive h