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

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

Interventions

DRUG

Etanercept

etanercept, subcutaneous injection

DRUG

methotrexate

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

DRUG

Sulfasalazine

sulfasalazine, oral

DRUG

Hydroxychloroquine

hydroxychloroquine, oral

DRUG

Placebo, triple

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

DRUG

Placebo, etanercept

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

Sponsors & Collaborators

• Canadian Institutes of Health Research (CIHR)

  collaborator OTHER_GOV

• Rheumatoid Arthritis Investigational Network (RAIN)

  collaborator UNKNOWN

• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

  collaborator NIH

• US Department of Veterans Affairs

  lead FED

Principal Investigators

• James R. O'Dell · VA Medical Center, Omaha

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2007-07-31

Primary Completion

2011-12-31

Completion

2012-05-31

Countries

• United States
• Canada

Study Locations