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

18 Years
Not Enrolling
Rheumatoid Arthritis

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Trial Information

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

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.

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

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.

13. 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:

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

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 de

Type of Study:


Study Design:

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

Outcome Measure:

Change of DAS28 score between baseline and week 48

Outcome Time Frame:

Week 48

Safety Issue:


Principal Investigator

James R. O'Dell

Investigator Role:

Study Chair

Investigator Affiliation:

VA Medical Center, Omaha


United States: Federal Government

Study ID:




Start Date:

July 2007

Completion Date:

May 2012

Related Keywords:

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



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