Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis (EMPIRE)
Condition: Rheumatoid Arthritis; Inflammatory Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 4

Summary: 
      TRIAL DESIGN

        1. Description This is a 18-month, double-blind, randomized, multicentre, outpatient study.
           The approximate duration of subject participation will be 18 months and the approximate
           total duration of the study will be 42 months. The duration of subject enrollment will
           be approximately 24 months.

        2. Discussion of Trial Design The study is designed to directly compare the effectiveness
           of combination therapy with MTX + ETN versus

        3. Principal research question/objective To determine the number of patients in clinical
           remission at 12 months of follow-up, as defined as the absence of symptoms and signs of
           inflammatory arthritis.
    

Detailed description: 
      Early arthritis is frequently undifferentiated. It is well recognised that a substantial
      proportion of patients with an undifferentiated inflammatory arthritis will go on to develop
      persistent synovitis, with the strongest predictor of persistence being disease duration > 12
      weeks (1-4). Studies have shown that patients with early oligoarthritis who fail to respond
      within 2 weeks to corticosteroid injections have a high likelihood of persistent disease (2).
      It is therefore clear that these patients with early inflammatory arthritis need definitive
      treatment, but the optimal therapeutic strategy is yet to be determined.

      Tumor Necrosis Factor (TNF) is a naturally occurring cytokine that is involved in normal
      inflammatory and immune responses. It plays an important role in the inflammatory process of
      rheumatoid and other arthritis, and the resulting joint pathology. Elevated levels of TNF are
      found in the synovial fluid of patients with RA. Two distinct receptors for TNF exist
      naturally as monomeric molecules on the cell surfaces and in soluble forms. Biological
      activity of TNF is dependent upon binding to either cell surface TNF receptors (TNFR).
      Etanercept (ETN) is a dimeric fusion protein consisting of the p75 TNFR linked to the Fc
      portion of human IgG1, and is capable of binding two TNF molecules. Etanercept inhibits
      binding of both TNF-alpha and TNF-beta to cell surface TNFRs, rendering TNF biologically
      inactive. Agents that block TNF are effective in all types of arthritis (with the exclusion
      of connective tissue diseases).

      It is generally agreed that there is a window of opportunity in active early inflammatory
      arthritis in which definitive treatment may give a disproportionate improvement compared to
      treatment at a later time, and may well be able to induce remission in a subgroup of
      patients.

      Studies in early rheumatoid arthritis (< 12 months) have shown that remission-induction with
      the TNF-antagonist infliximab provides a significant reduction in MRI-evidence of synovitis
      and erosions at 12 months with evidence of sustained functional and quality of life benefits
      at 2 years, despite withdrawal of infliximab at 12 months (5). Results from the TEMPO study
      show that treatment of established rheumatoid arthritis with ETN+MTX achieves remission in
      about 40% patients (6). TNF antagonists also have the therapeutic benefit of rapid and
      sustained suppression of inflammation.

      Treatment of patients with early undifferentiated arthritis with ETN+MTX is hypothesised to
      prevent progression of persistent disabling disease in a significant number of patients.
      Induction of remission at this time in the disease course may result in sustained remission,
      reduce the need for further treatment, and be most cost effective therapeutic strategy.
    

Intervention name(s): Etanercept (ETN); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): ETN 50 mg subcutaneous (SC) injections once weekly and MTX orally once weekly.; ETN-matching placebo SC injections once weekly and MTX orally once weekly.
Other intervention name(s): Enbrel; Maxtrex
Intervention MeSH terms: Etanercept
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Rheumatoid arthritis; Inflammatory arthritis; Undifferentiated arthritis; Etanercept; Combination Therapy