Rheumatoid ArthritisRACATNCT00405275
Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy
A study testing Etanercept, methotrexate and Sulfasalazine in people with Rheumatoid Arthritis, run by US Department of Veterans Affairs at 37 sites in 2 countries.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Etanercept, methotrexate and Sulfasalazine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 353 participants
- Where
- 37 sitesin 2 countries
- Study dates
- Jul 2007to May 2012
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 23Show fewer
- 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.
Who cannot join
- 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.
Show all 27Show fewer
- 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.
Trial locations and contacts
37 sites in 2 countries.
37 sites in 2 countries
United States28 sites
Bone, Spine Sports Clinic (RAIN)
Bismarck, North Dakota, 58501
Ralph H Johnson VA Medical Center, Charleston
Charleston, South Carolina, 29401-5799
VA North Texas Health Care System, Dallas
Dallas, Texas, 75216
Geisinger Medical Center
Danville, Pennsylvania, 17822
St. Mary's/ Duluth Clinic Health System (RAIN)
Duluth, Minnesota, 55804
VA Medical Center, Fargo
Fargo, North Dakota, 58102
Lincoln Medical Center
Lincoln, Nebraska, 68506
VA Medical Center, Loma Linda
Loma Linda, California, 92357
VA Medical Center, Long Beach
Long Beach, California, 90822
Park Nicollet (RAIN)
Minneapolis, Minnesota, 55417
VA Medical Center, Minneapolis
Minneapolis, Minnesota, 55417
VA Medical Center, Omaha
Omaha, Nebraska, 68105-1873
Univesity of Nebraska Medical Center
Omaha, Nebraska, 68198
VA Medical Center, Philadelphia
Philadelphia, Pennsylvania, 19104
VA Pittsburgh Health Care System
Pittsburgh, Pennsylvania, 15240
VA Medical Center, Portland
Portland, Oregon, 97201
Rapid City Medical Center (RAIN)
Rapid City, South Dakota, 57701
Mayo Clinic
Rochester, Minnesota, 55905
VA Salt Lake City Health Care System, Salt Lake City
Salt Lake City, Utah, 84148
VA Medical Center, San Francisco
San Francisco, California, 94121
Pacific Arthritis Center (RAIN)
Santa Maria, California, 93454-6945
VA Greater Los Angeles HCS, Sepulveda
Sepulveda, California, 91343
Avera Research Institute (RAIN)
Sioux Falls, South Dakota, 57117-5046
VA Medical Center, St Louis
St Louis, Missouri, 63106
Geisinger Medical Group - State College
State College, Pennsylvania, 16801
VA Medical Center, DC
Washington D.C., District of Columbia, 20422
VA Medical & Regional Office Center, White River
White River Junction, Vermont, 05009-0001
Geisinger Medical Group- Wilkes Barre
Wyoming Valley, Pennsylvania, 18711
Canada9 sites
Brampton (CRRC)
Brampton, Ontario, L6T 3J1
University of Calgary (CRRC)
Calgary, Alberta, T2N 4N1
Credit Valley Rheumatology
Missassauga, Ontario, L5M 2V8
Hopital Notre Dame (CRRC)
Montreal, Quebec, H2L 4M1
Newmarket (CRRC)
Newmarket, Ontario, L3Y 3R7
Crc-Chus (Crrc)
Sherbrooke, Quebec, J1H 5N4
Mount Sinai Hospital (CRRC)
Toronto, Ontario, M5T 3L9
Clinical Research and Arthritis Center
Windsor, Ontario, N8X 5A6
University of Manitoba (CRRC)
Winnipeg, Manitoba, R3A 1M4
About this study
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.
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.
Read the detailed 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.
- Conditions
- Rheumatoid Arthritis
- Being tested
- Etanercept, methotrexate, Sulfasalazine, Hydroxychloroquine, Placebo, triple
- Keywords
- antineoplastic, antiparasitics, antirheumatics, chronic diseases, clinical trial, connective tissue, double-blind, drug treatment, gastric medications, joint, multi-site trial, musculoskeletal, randomized, rheumatoid arthritis
- Medical subject headings
- Arthritis, Rheumatoid, Chronic Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EtanerceptDrug
Also called Enbrel
etanercept, subcutaneous injection
methotrexateDrug
baseline methotrexate is maintained throughout the study and is not provided by the sponsor
SulfasalazineDrug
sulfasalazine, oral
Also called Plaquenil
hydroxychloroquine, oral
Placebo, tripleDrug
Participants in Etanercept arm (Arm 1) were given placebo hydroxychloroquine and sulfasalazine pills.
Placebo, etanerceptDrug
Participants in triple arm (Arm 2) were given placebo etanercept injections.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Active comparator | Etanercept and Methotrexate. Participants also received placebo hydroxychloroquine and sulfasalazine Receives: Drug: Etanercept; Drug: methotrexate; Drug: Placebo, triple |
| Arm 2 | Active comparator | Hydroxychloroquine, sulfasalazine and methotrexate. Participants also received placebo etanercept. Receives: Drug: methotrexate; Drug: Sulfasalazine; Drug: Hydroxychloroquine; Drug: Placebo, etanercept |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 48 weeks after baseline assessment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2006 (estimated)
- Study startJul 2007
- Primary completionDec 2011
- Study completionMay 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 353 participants (actual)
Sponsor and investigators
- Lead sponsor
- US Department of Veterans Affairs
- Sponsor type
- US federal agency
- Collaborators
- Canadian Institutes of Health Research (CIHR), Rheumatoid Arthritis Investigational Network (RAIN), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Responsible party
- Sponsor
- Investigators
- James R. O'Dell, Study chair, VA Medical Center, Omaha
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00405275
- Sponsor's protocol ID
- 551
- Other IDs
- Y1-AR-0048-01
- Acronym
- RACAT
- Status last verified
- Nov 2013
- First submitted
- 29 Nov 2006
- Last updated
- 3 Dec 2013
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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. 2013 Jul 25;369(4):307-18. doi: 10.1056/NEJMoa1303006. Epub 2013 Jun 11.
PubMed 23755969Peper SM, Lew R, Mikuls T, Brophy M, Rybin D, Wu H, O'Dell J. Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept. Arthritis Care Res (Hoboken). 2017 Oct;69(10):1467-1472. doi: 10.1002/acr.23255. Epub 2017 Sep 6.
PubMed 28388820Quach LT, Chang BH, Brophy MT, Soe Thwin S, Hannagan K, O'Dell JR. Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events. Rheumatology (Oxford). 2017 Mar 1;56(3):378-383. doi: 10.1093/rheumatology/kew412.
PubMed 27994091Bansback N, Keystone E, O'Dell J, Phibbs CS, Hannagan K, Brophy M, Anis A. Making smart investment decisions in clinical research. Trials. 2015 Dec 29;16:590. doi: 10.1186/s13063-015-1123-1.
PubMed 26712327
Study at a glance
From the registry record, last updated by the sponsor on 3 Dec 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CSP #551 - Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy
- ClinicalTrials.gov ID
- NCT00405275
- Acronym / sponsor ID
- RACAT / 551
- Conditions
- Rheumatoid Arthritis
- Keywords
- antineoplastic, antiparasitics, antirheumatics, chronic diseases, clinical trial, connective tissue, double-blind, drug treatment
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 353 participants (actual)
- Lead sponsor
- US Department of Veterans AffairsUS federal agency
- Collaborators
- Canadian Institutes of Health Research (CIHR), Rheumatoid Arthritis Investigational Network (RAIN), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- Study start
- Jul 2007
- Primary completion
- Dec 2011 (actual)
- Study completion
- May 2012 (actual)
- First posted
- 30 Nov 2006 (estimated)
- Results
- Posted 3 Dec 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Active comparator | Drug: Etanercept, Drug: methotrexate, Drug: Placebo, tripleEtanercept and Methotrexate. Participants also received placebo hydroxychloroquine and sulfasalazine |
| Arm 2 | Active comparator | Drug: methotrexate, Drug: Sulfasalazine, Drug: Hydroxychloroquine, Drug: Placebo, etanerceptHydroxychloroquine, sulfasalazine and methotrexate. Participants also received placebo etanercept. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- 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.
Key exclusion criteria (27 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EtanerceptAlso: Enbreletanercept, subcutaneous injection | Drug | Arm 1 |
| methotrexatebaseline methotrexate is maintained throughout the study and is not provided by the sponsor | Drug | Arm 1, Arm 2 |
| Sulfasalazinesulfasalazine, oral | Drug | Arm 2 |
| HydroxychloroquineAlso: Plaquenilhydroxychloroquine, oral | Drug | Arm 2 |
| Placebo, tripleParticipants in Etanercept arm (Arm 1) were given placebo hydroxychloroquine and sulfasalazine pills. | Drug | Arm 1 |
| Placebo, etanerceptParticipants in triple arm (Arm 2) were given placebo etanercept injections. | Drug | Arm 2 |
Primary outcome
Mean 48-week Change in DAS28
Time frame: 48 weeks after baseline assessment
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Dec 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23755969O'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. 2013 Jul 25;369(4):307-18. doi: 10.1056/NEJMoa1303006. Epub 2013 Jun 11.
- Derived from this study: PubMed 28388820Peper SM, Lew R, Mikuls T, Brophy M, Rybin D, Wu H, O'Dell J. Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept. Arthritis Care Res (Hoboken). 2017 Oct;69(10):1467-1472. doi: 10.1002/acr.23255. Epub 2017 Sep 6.
- Derived from this study: PubMed 27994091Quach LT, Chang BH, Brophy MT, Soe Thwin S, Hannagan K, O'Dell JR. Rheumatoid arthritis triple therapy compared with etanercept: difference in infectious and gastrointestinal adverse events. Rheumatology (Oxford). 2017 Mar 1;56(3):378-383. doi: 10.1093/rheumatology/kew412.
- Derived from this study: PubMed 26712327Bansback N, Keystone E, O'Dell J, Phibbs CS, Hannagan K, Brophy M, Anis A. Making smart investment decisions in clinical research. Trials. 2015 Dec 29;16:590. doi: 10.1186/s13063-015-1123-1.
Related trials for Rheumatoid Arthritis
RecruitingPhase 2
Study of PTC844 in Participants With Active Rheumatoid Arthritis
Rheumatoid Arthritis
Not yet recruitingPhase 1
An Ascending Dose Study of DKB903 in Participants With Rheumatoid Arthritis (RA) and Participants With Systemic Lupus Erythematosus (SLE)
Rheumatoid Arthritis and Systemic Lupus Erythematosus
Not yet recruitingPhase 1
R-2487 in Patients With Sjogren's Syndrome (SjD)
Sjogren's Syndrome, Sjögren
RecruitingPhase 1
A Trial in Healthy Adult Participants and Adults With Autoimmune Diseases to Test How HBM7020 is Tolerated and How it Behaves in the Body
Rheumatoid Arthritis, Systemic Lupus Erythematosus
Active, not recruitingPhase 2
A Study Evaluating the Safety and Efficacy of Inhaled AP01 in Participants With Progressive Pulmonary Fibrosis
Pulmonary Fibrosis, Progressive Pulmonary Fibrosis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
James R. O'Dell study chair
VA Medical Center, Omaha
37 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Etanercept, methotrexate and Sulfasalazine in people with Rheumatoid Arthritis, run by US Department of Veterans Affairs at 37 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Dec 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 37 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Dec 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean 48-week Change in DAS28 (time frame: 48 weeks after baseline assessment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00405275, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Dec 2013.