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.