Official Title: “CSP#551 - Rheumatoid Arthritis: Comparison of Active Therapies in Patients With 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 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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Efficacy Study

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.

Intervention(s) in this Clinical Trial

• Drug: etanercept
• Drug: sulfasalazine
• Drug: hydroxychloroquine
• Drug: methotrexate

• A.

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 methotrexate 20 to 25 mg/week (unless intolerant and on a minimum 15 mg/week) at a constant dose for at least one month, and on any methotrexate for no less than four months.
• 5. All patients will have active disease as defined by a DAS28 of e 4.4.
• 6. If patients are receiving corticosteroids, they must have been on stable dose (d 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 enrollment.
• 8. If patients have taken leflunomide, cyclosporine, gold, Anakinra, azathiprine, or penicillamine in combination with methotrexate, they must have stopped this therapy at least 2 months prior to randomization.
• 9. Laboratory tests must meet the following criteria within 2 weeks of randomization:
• 1. Serum creatinine d 1.8 mg/dL
• 2. Hemoglobin e 9 g/dL
• 3. WBC e 3000 mc/L
• 4. Neutrophils e 1000 mc/L
• 5. Platelets e 100,000 mc/L
• 6. Serum transaminase levels (ALT or AST) not exceeding 1.2 times upper limits of normal
• 7. Albumin above lower limit of normal
• 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. Negative PPD, or PPD of <5 mm with no chest x-ray findings consistent with tuberculosis, within 3 months of randomization.

B. Exclusion Criteria:

• 1. Previous intolerance to methotrexate (unless able to tolerate at least 15 mg/day)
• 2. Sensitivity to study medications
• 3. Previous treatment with methotrexate, sulfasalazine or hydroxychloroquine in combination with each other.
• 4. No bed or wheelchair-bound patients
• 5. Active tuberculosis or evidence of latent tuberculosis (positive PPD skin test or a chest x-ray with evidence of tuberculosis) without previous adequate therapy.
• 6. Previous treatment with a TNF inhibitor (etanercept, infliximab or adalimumab)
• 7. Evidence of important acute or chronic infections (no IV antibiotics within 1 month, and no PO antibiotics within 2 weeks)
• 8. Pregnant or nursing women
• 9. Women of childbearing potential or their partners who are not practicing an acceptable form of birth control as defined by investigator
• 10. Active substance abuse or psychiatric illness likely to interfere with protocol completion
• 11. History of multiple sclerosis, transverse myelitis, or optic neuritis
• 12. History of macular degeneration
• 13. New York Heart Association Class III or IV congestive heart failure
• 14. Active malignancy (other than in situ cervical cancer or non-melanoma skin cancer), or history of lymphoma
• 15. History of HIV
• 16. History of any opportunistic infection . to include but not limited to Pneumocystis carinii, aspergillosis, histoplasmosis, or atypical mycobacterium
• 17. History of porphyria
• 18. Diagnosis of SLE or seronegative spondyloarthropathy or any other form of concomitant arthritis (osteoarthritis is permitted)
• 19. Diagnosis of psoriasis unless rheumatoid factor positive
• 20. Any significant unstable medical condition considered a contraindication by investigator
• 21. Any participation in another investigational drug study during the 90 days preceding randomization.
• 22. Receipt of a live vaccine within 90 days of study entry.
• 23. History of oral or IV cyclophosphamide use
• 24. Life expectancy less than 2 years
• 25. Receipt of steroid injection, intravenous, intramuscular, or subcutaneously, within 30 days of randomization.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Department of Veterans Affairs

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00405275

Study ID Number: 551

ClinicalTrials.gov Identifier: NCT00405275

Health Authority: United States: Food and Drug Administration