Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy

Rheumatoid Arthritis Clinical Trial

— RACAT  

Official title:

CSP #551 - Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405275
• Other study ID #: 551
• Secondary ID: Y1-AR-0048-01
• Status: Completed
• Phase: N/A
• First received: November 29, 2006
• Last updated: November 7, 2013
• Start date: July 2007
• Est. completion date: May 2012

Study information

• Verified date: November 2013
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

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.

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 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 353
• Est. completion date: May 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Etanercept
etanercept, subcutaneous injection
• methotrexate
baseline methotrexate is maintained throughout the study and is not provided by the sponsor
• Sulfasalazine
sulfasalazine, oral
• Hydroxychloroquine
hydroxychloroquine, oral
• Placebo, triple
Participants in Etanercept arm (Arm 1) were given placebo hydroxychloroquine and sulfasalazine pills.
• Placebo, etanercept
Participants in triple arm (Arm 2) were given placebo etanercept injections.

Locations

Country	Name	City	State
Canada	Brampton (CRRC)	Brampton	Ontario
Canada	University of Calgary (CRRC)	Calgary	Alberta
Canada	Credit Valley Rheumatology	Missassauga	Ontario
Canada	Hopital Notre Dame (CRRC)	Montreal	Quebec
Canada	Newmarket (CRRC)	Newmarket	Ontario
Canada	Crc-Chus (Crrc)	Sherbrooke	Quebec
Canada	Mount Sinai Hospital (CRRC)	Toronto	Ontario
Canada	Clinical Research and Arthritis Center	Windsor	Ontario
Canada	University of Manitoba (CRRC)	Winnipeg	Manitoba
United States	Bone, Spine Sports Clinic (RAIN)	Bismarck	North Dakota
United States	Ralph H Johnson VA Medical Center, Charleston	Charleston	South Carolina
United States	VA North Texas Health Care System, Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	St. Mary's/ Duluth Clinic Health System (RAIN)	Duluth	Minnesota
United States	VA Medical Center, Fargo	Fargo	North Dakota
United States	Lincoln Medical Center	Lincoln	Nebraska
United States	VA Medical Center, Loma Linda	Loma Linda	California
United States	VA Medical Center, Long Beach	Long Beach	California
United States	Park Nicollet (RAIN)	Minneapolis	Minnesota
United States	VA Medical Center, Minneapolis	Minneapolis	Minnesota
United States	Univesity of Nebraska Medical Center	Omaha	Nebraska
United States	VA Medical Center, Omaha	Omaha	Nebraska
United States	VA Medical Center, Philadelphia	Philadelphia	Pennsylvania
United States	VA Pittsburgh Health Care System	Pittsburgh	Pennsylvania
United States	VA Medical Center, Portland	Portland	Oregon
United States	Rapid City Medical Center (RAIN)	Rapid City	South Dakota
United States	Mayo Clinic	Rochester	Minnesota
United States	VA Salt Lake City Health Care System, Salt Lake City	Salt Lake City	Utah
United States	VA Medical Center, San Francisco	San Francisco	California
United States	Pacific Arthritis Center (RAIN)	Santa Maria	California
United States	VA Greater Los Angeles HCS, Sepulveda	Sepulveda	California
United States	Avera Research Institute (RAIN)	Sioux Falls	South Dakota
United States	VA Medical Center, St Louis	St Louis	Missouri
United States	Geisinger Medical Group - State College	State College	Pennsylvania
United States	VA Medical Center, DC	Washington	District of Columbia
United States	VA Medical & Regional Office Center, White River	White River Junction	Vermont
United States	Geisinger Medical Group- Wilkes Barre	Wyoming Valley	Pennsylvania

Sponsors (4)

Lead Sponsor	Collaborator
VA Office of Research and Development	Canadian Institutes of Health Research (CIHR), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Rheumatoid Arthritis Investigational Network (RAIN)

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

O'Dell JR, Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, Lew RA, Cannella AC, Kunkel G, Phibbs CS, Anis AH, Leatherman S, Keystone E; CSP 551 RACAT Investigators. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean 48-week Change in DAS28	Average difference between 48-week and Baseline DAS28.; The Disease Activity Score for 28 Joints (DAS28) is a well-validated composite outcome measure ranging from 2-10 (higher scores indicating more disease) that incorporates a tender and swollen joint count of 28 joints, a laboratory measure of systemic inflammation (ESR) and a patient-reported general assessment of health on a visual analog scale (ranging from 0-10cm) all into one measure.; Low disease activity is defined as DAS28 = 3.2 units.	48 weeks after baseline assessment	No