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

NCT00405275 | Completed Results DMC

• 2 other identifiers: 551Y1-AR-0048-01
• Study Type: interventional
• Target: 353
• Locations: 2 countries
• Sites: 37

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.

Conditions

Rheumatoid Arthritis

Keywords

antineoplastic; antiparasitics; antirheumatics; chronic diseases; clinical trial; connective tissue; double-blind; drug treatment; gastric medications; joint; multi-site trial; musculoskeletal; randomized; rheumatoid arthritis

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Arm 1

ACTIVE COMPARATOR

Etanercept and Methotrexate. Participants also received placebo hydroxychloroquine and sulfasalazine

Drug: Etanercept; Drug: methotrexate; Drug: Placebo, triple

Arm 2

ACTIVE COMPARATOR

Hydroxychloroquine, sulfasalazine and methotrexate. Participants also received placebo etanercept.

Drug: methotrexate; Drug: Sulfasalazine; Drug: Hydroxychloroquine; Drug: Placebo, etanercept

Interventions

Etanercept DRUG

etanercept, subcutaneous injection

Also known as: Enbrel

Arm 1

methotrexate DRUG

baseline methotrexate is maintained throughout the study and is not provided by the sponsor

Arm 1; Arm 2

Sulfasalazine DRUG

sulfasalazine, oral

Arm 2

Hydroxychloroquine DRUG

hydroxychloroquine, oral

Also known as: Plaquenil

Arm 2

Placebo, triple DRUG

Participants in Etanercept arm (Arm 1) were given placebo hydroxychloroquine and sulfasalazine pills.

Arm 1

Placebo, etanercept DRUG

Participants in triple arm (Arm 2) were given placebo etanercept injections.

Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• US Department of Veterans Affairs: lead
• Canadian Institutes of Health Research (CIHR): collaborator
• Rheumatoid Arthritis Investigational Network (RAIN): collaborator
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (37)

VA Medical Center, Loma Linda

Loma Linda, California, 92357, United States

Location

VA Medical Center, Long Beach

Long Beach, California, 90822, United States

Location

VA Medical Center, San Francisco

San Francisco, California, 94121, United States

Location

Pacific Arthritis Center (RAIN)

Santa Maria, California, 93454-6945, United States

Location

VA Greater Los Angeles HCS, Sepulveda

Sepulveda, California, 91343, United States

Location

VA Medical Center, DC

Washington D.C., District of Columbia, 20422, United States

Location

St. Mary's/ Duluth Clinic Health System (RAIN)

Duluth, Minnesota, 55804, United States

Location

Park Nicollet (RAIN)

Minneapolis, Minnesota, 55417, United States

Location

VA Medical Center, Minneapolis

Minneapolis, Minnesota, 55417, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

VA Medical Center, St Louis

St Louis, Missouri, 63106, United States

Location

Lincoln Medical Center

Lincoln, Nebraska, 68506, United States

Location

VA Medical Center, Omaha

Omaha, Nebraska, 68105-1873, United States

Location

Univesity of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Bone, Spine Sports Clinic (RAIN)

Bismarck, North Dakota, 58501, United States

Location

VA Medical Center, Fargo

Fargo, North Dakota, 58102, United States

Location

VA Medical Center, Portland

Portland, Oregon, 97201, United States

Location

Geisinger Medical Center

Danville, Pennsylvania, 17822, United States

Location

VA Medical Center, Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

VA Pittsburgh Health Care System

Pittsburgh, Pennsylvania, 15240, United States

Location

Geisinger Medical Group - State College

State College, Pennsylvania, 16801, United States

Location

Geisinger Medical Group- Wilkes Barre

Wyoming Valley, Pennsylvania, 18711, United States

Location

Ralph H Johnson VA Medical Center, Charleston

Charleston, South Carolina, 29401-5799, United States

Location

Rapid City Medical Center (RAIN)

Rapid City, South Dakota, 57701, United States

Location

Avera Research Institute (RAIN)

Sioux Falls, South Dakota, 57117-5046, United States

Location

VA North Texas Health Care System, Dallas

Dallas, Texas, 75216, United States

Location

VA Salt Lake City Health Care System, Salt Lake City

Salt Lake City, Utah, 84148, United States

Location

VA Medical & Regional Office Center, White River

White River Junction, Vermont, 05009-0001, United States

Location

University of Calgary (CRRC)

Calgary, Alberta, T2N 4N1, Canada

Location

University of Manitoba (CRRC)

Winnipeg, Manitoba, R3A 1M4, Canada

Location

Brampton (CRRC)

Brampton, Ontario, L6T 3J1, Canada

Location

Credit Valley Rheumatology

Missassauga, Ontario, L5M 2V8, Canada

Location

Newmarket (CRRC)

Newmarket, Ontario, L3Y 3R7, Canada

Location

Mount Sinai Hospital (CRRC)

Toronto, Ontario, M5T 3L9, Canada

Location

Clinical Research and Arthritis Center

Windsor, Ontario, N8X 5A6, Canada

Location

Hopital Notre Dame (CRRC)

Montreal, Quebec, H2L 4M1, Canada

Location

Crc-Chus (Crrc)

Sherbrooke, Quebec, J1H 5N4, Canada

Location

Related Publications (4)

• 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.

  PMID: 23755969 RESULT

• Peper 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.

  PMID: 28388820 DERIVED

• Quach 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.

  PMID: 27994091 DERIVED

• Bansback 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.

  PMID: 26712327 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid; Chronic Disease

Interventions

Etanercept; Methotrexate; Sulfasalazine; Hydroxychloroquine

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Chloroquine; Aminoquinolines; Quinolines

Results Point of Contact

• Title: James R. O'Dell, MD
• Organization: VA Nebraska-Western Iowa Health Care System

jrodell@unmc.edu

402-559-7288

Study Officials

• James R. O'Dell

  VA Medical Center, Omaha

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2006
• First Posted: November 30, 2006
• Study Start: July 1, 2007
• Primary Completion: December 1, 2011
• Study Completion: May 1, 2012
• Last Updated: December 3, 2013
• Results First Posted: December 3, 2013

Record last verified: 2013-11

Locations

CA (9); US (28)