Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis (EMPIRE) (EMPIRE)
- 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.
- Discussion of Trial Design The study is designed to directly compare the effectiveness of combination therapy with MTX + ETN versus
- 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.
Drug: Etanercept (ETN)
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Multicentre Randomised Trial Of Etanercept And Methotrexate To Induce Remission In Early Inflammatory Arthritis|
- clinical remission [ Time Frame: 12 months ] [ Designated as safety issue: No ]To determine the number of patients in clinical remission at 12 months, as defined as the absence of symptoms and signs of inflammatory arthritis (i.e. swollen joint count 0; tender joint count 0)
- clinical remission [ Time Frame: 18 months ] [ Designated as safety issue: No ]The number of patients in clinical remission at 18 months (as defined as absence of symptoms and signs of clinical arthritis i.e. swollen joint count 0 ; tender joint count 0)
- Conventional disease activity measures [ Time Frame: week 78 ] [ Designated as safety issue: No ]Conventional disease activity measures (VAS pain/fatigue/global/physician, EMS, TJC, SJC, CRP, ESR)
- Functional, work and quality of life assessments [ Time Frame: Week 78 ] [ Designated as safety issue: No ]Functional, work and quality of life assessments (HAQ, WIS, WDA, EQ-5d, SF-36)
- remission [ Time Frame: Week 26 ] [ Designated as safety issue: No ]Proportion of patients achieving 26 weeks of remission
- DAS 44 [ Time Frame: Week 78 ] [ Designated as safety issue: No ]Disease Activity Score (DAS) 44
- drug-free remission [ Time Frame: 12 & 18 mths ] [ Designated as safety issue: No ]The number of patients in drug-free remission at 12 18 months
- etanercept-free remission [ Time Frame: 12 and 18 months ] [ Designated as safety issue: No ]The number of patients in etanercept-free remission at 12 and 18 months (ETN arm)
- Remission by ACR Criteria [ Time Frame: Week 78 ] [ Designated as safety issue: No ]Remission by ACR Criteria
- effects of the combination of ETN and MTX to MTX alone on radiographic change [ Time Frame: 12 months and 18 months ] [ Designated as safety issue: No ]To compare the effects of the combination of ETN and MTX to MTX alone on radiographic change at 12 months and 18 months
|Study Start Date:||September 2006|
|Estimated Study Completion Date:||March 2011|
|Primary Completion Date:||February 2011 (Final data collection date for primary outcome measure)|
Experimental: Combination Therapy
Methotrexate & Etanercept
Drug: Etanercept (ETN)
ETN 50 mg subcutaneous (SC) injections once weekly and MTX orally once weekly.
Other Name: Enbrel
Placebo Comparator: Single-agent therapy
ETN-matching placebo SC injections once weekly and MTX orally once weekly.
Other Name: Maxtrex
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01303874
|Leeds Teaching Hospital HNS Trust|
|Leeds, West Yorkshire, United Kingdom, LS7 4SA|
|Principal Investigator:||Paul Emery, Prof||University of Leeds|