Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis (EMPIRE) (EMPIRE)
Primary Purpose
Rheumatoid Arthritis, Inflammatory Arthritis
Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Etanercept (ETN)
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid arthritis, Inflammatory arthritis, Undifferentiated arthritis, Etanercept, Combination Therapy
Eligibility Criteria
Inclusion Criteria:
- Is age 18 -80 years old
- Patients have articular synovitis, within 3 months of diagnosis
- Either RF antibody (+) or anti-CCP antibody (+) or SE (+)
- Demonstrates a negative urine pregnancy test at screening if female of childbearing potential
- Agrees to use a medically accepted form of contraception during the study and for 3 months after the last dose of study drug, if sexually active male
- Is capable of understanding and signing an informed consent form
- Is able and willing to self-inject study drug or have a designee who can do so
- Is able and willing to take oral medication
- Is able to store injectable test article at 2° C to 8° C
- Demonstrates a negative tuberculosis screening test
Exclusion Criteria:
- Received previous treatment with any DMARDS
- Received previous treatment with ETN or other tumour necrosis factor (TNF) antagonist (e.g. a TNF monoclonal antibody or a soluble TNF-receptor)
- Previous treatment with IL-1 receptor antagonist
- Chronic arthritis diagnosed before 16 years old
- Received any investigational "biological" agent within 3 months of screening visit
- Received treatment with any investigational drug of "chemical" nature within one month prior to study screening
- Known Human Immunodeficiency Virus (HIV)
- Presence of any contraindication to ETN or MTX
- Has significant concurrent medical diseases
- Has cancer or a history of cancer within 5 years of entering the screening period
- Current crystal or infective arthritis
- Chronic infection of the upper respiratory tract, chest, urinary tract or skin
- Any ongoing or active infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within the preceding 30 days and/or orally administered antibiotics in the preceding 15 days
- Demonstrates liver function abnormality
- Has renal disease
- Has leukopenia
- Has thrombocytopenia
- Has a hemoglobin level of < 9g/L for males and < 85 g/L for females
- Is pregnant or breast-feeding
- Joint surgery within preceding 2 months (at joints to be assessed within this study)
- Received anti-CD4, diphtheria interleukin-2 fusion protein, anti-interleukin-6 (anti-IL-6), rituximab or other immunosuppressive biologic during the last 6 months before screening, and treatment with such agents more than 6 months before screening if there are persistent signs of immunosuppression (with a subsequent abnormal absolute T-cell count) at screening visit
- Received any live (attenuated) vaccines within 4 weeks of screening visit
- Received cyclophosphamide within 6 months of screening visit
- Any corticosteroids within 28days prior to screening
- Uses a dose of NSAID greater than the maximum recommended dose in the product information at the screening visit
- Has a history of confirmed blood dyscrasia
- Has any condition judged by the physician to cause this study to be detrimental to the subject
- Has a history of drug abuse or psychiatric disease that would interfere with the ability to comply with the study protocol
- Has a history of alcohol abuse or excessive alcohol beverage consumption
- Has a history of known liver cirrhosis, fibrosis, or fatty liver
- Has a history of any viral hepatitis within 1 year of screening
Sites / Locations
- Leeds Teaching Hospital HNS Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Combination Therapy
Single-agent therapy
Arm Description
Methotrexate & Etanercept
Methotrexate (MTX)
Outcomes
Primary Outcome Measures
clinical remission
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)
Secondary Outcome Measures
clinical remission
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
Conventional disease activity measures (VAS pain/fatigue/global/physician, EMS, TJC, SJC, CRP, ESR)
Functional, work and quality of life assessments
Functional, work and quality of life assessments (HAQ, WIS, WDA, EQ-5d, SF-36)
remission
Proportion of patients achieving 26 weeks of remission
DAS 44
Disease Activity Score (DAS) 44
drug-free remission
The number of patients in drug-free remission at 12 18 months
etanercept-free remission
The number of patients in etanercept-free remission at 12 and 18 months (ETN arm)
Remission by ACR Criteria
Remission by ACR Criteria
effects of the combination of ETN and MTX to MTX alone on radiographic change
To compare the effects of the combination of ETN and MTX to MTX alone on radiographic change at 12 months and 18 months
Full Information
NCT ID
NCT01303874
First Posted
February 24, 2011
Last Updated
October 30, 2019
Sponsor
University of Leeds
1. Study Identification
Unique Protocol Identification Number
NCT01303874
Brief Title
Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis (EMPIRE)
Acronym
EMPIRE
Official Title
A Multicentre Randomised Trial Of Etanercept And Methotrexate To Induce Remission In Early Inflammatory Arthritis
Study Type
Interventional
2. Study Status
Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
September 2006 (undefined)
Primary Completion Date
November 5, 2010 (Actual)
Study Completion Date
November 5, 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Leeds
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
TRIAL DESIGN
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis, Inflammatory Arthritis
Keywords
Rheumatoid arthritis, Inflammatory arthritis, Undifferentiated arthritis, Etanercept, Combination Therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
112 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
Methotrexate & Etanercept
Arm Title
Single-agent therapy
Arm Type
Placebo Comparator
Arm Description
Methotrexate (MTX)
Intervention Type
Drug
Intervention Name(s)
Etanercept (ETN)
Other Intervention Name(s)
Enbrel
Intervention Description
ETN 50 mg subcutaneous (SC) injections once weekly and MTX orally once weekly.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Maxtrex
Intervention Description
ETN-matching placebo SC injections once weekly and MTX orally once weekly.
Primary Outcome Measure Information:
Title
clinical remission
Description
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)
Time Frame
12 months
Secondary Outcome Measure Information:
Title
clinical remission
Description
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)
Time Frame
18 months
Title
Conventional disease activity measures
Description
Conventional disease activity measures (VAS pain/fatigue/global/physician, EMS, TJC, SJC, CRP, ESR)
Time Frame
week 78
Title
Functional, work and quality of life assessments
Description
Functional, work and quality of life assessments (HAQ, WIS, WDA, EQ-5d, SF-36)
Time Frame
Week 78
Title
remission
Description
Proportion of patients achieving 26 weeks of remission
Time Frame
Week 26
Title
DAS 44
Description
Disease Activity Score (DAS) 44
Time Frame
Week 78
Title
drug-free remission
Description
The number of patients in drug-free remission at 12 18 months
Time Frame
12 & 18 mths
Title
etanercept-free remission
Description
The number of patients in etanercept-free remission at 12 and 18 months (ETN arm)
Time Frame
12 and 18 months
Title
Remission by ACR Criteria
Description
Remission by ACR Criteria
Time Frame
Week 78
Title
effects of the combination of ETN and MTX to MTX alone on radiographic change
Description
To compare the effects of the combination of ETN and MTX to MTX alone on radiographic change at 12 months and 18 months
Time Frame
12 months and 18 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Is age 18 -80 years old
Patients have articular synovitis, within 3 months of diagnosis
Either RF antibody (+) or anti-CCP antibody (+) or SE (+)
Demonstrates a negative urine pregnancy test at screening if female of childbearing potential
Agrees to use a medically accepted form of contraception during the study and for 3 months after the last dose of study drug, if sexually active male
Is capable of understanding and signing an informed consent form
Is able and willing to self-inject study drug or have a designee who can do so
Is able and willing to take oral medication
Is able to store injectable test article at 2° C to 8° C
Demonstrates a negative tuberculosis screening test
Exclusion Criteria:
Received previous treatment with any DMARDS
Received previous treatment with ETN or other tumour necrosis factor (TNF) antagonist (e.g. a TNF monoclonal antibody or a soluble TNF-receptor)
Previous treatment with IL-1 receptor antagonist
Chronic arthritis diagnosed before 16 years old
Received any investigational "biological" agent within 3 months of screening visit
Received treatment with any investigational drug of "chemical" nature within one month prior to study screening
Known Human Immunodeficiency Virus (HIV)
Presence of any contraindication to ETN or MTX
Has significant concurrent medical diseases
Has cancer or a history of cancer within 5 years of entering the screening period
Current crystal or infective arthritis
Chronic infection of the upper respiratory tract, chest, urinary tract or skin
Any ongoing or active infection or any major episode of infection requiring hospitalization or treatment with IV antibiotics within the preceding 30 days and/or orally administered antibiotics in the preceding 15 days
Demonstrates liver function abnormality
Has renal disease
Has leukopenia
Has thrombocytopenia
Has a hemoglobin level of < 9g/L for males and < 85 g/L for females
Is pregnant or breast-feeding
Joint surgery within preceding 2 months (at joints to be assessed within this study)
Received anti-CD4, diphtheria interleukin-2 fusion protein, anti-interleukin-6 (anti-IL-6), rituximab or other immunosuppressive biologic during the last 6 months before screening, and treatment with such agents more than 6 months before screening if there are persistent signs of immunosuppression (with a subsequent abnormal absolute T-cell count) at screening visit
Received any live (attenuated) vaccines within 4 weeks of screening visit
Received cyclophosphamide within 6 months of screening visit
Any corticosteroids within 28days prior to screening
Uses a dose of NSAID greater than the maximum recommended dose in the product information at the screening visit
Has a history of confirmed blood dyscrasia
Has any condition judged by the physician to cause this study to be detrimental to the subject
Has a history of drug abuse or psychiatric disease that would interfere with the ability to comply with the study protocol
Has a history of alcohol abuse or excessive alcohol beverage consumption
Has a history of known liver cirrhosis, fibrosis, or fatty liver
Has a history of any viral hepatitis within 1 year of screening
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Emery, Prof
Organizational Affiliation
University of Leeds
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leeds Teaching Hospital HNS Trust
City
Leeds
State/Province
West Yorkshire
ZIP/Postal Code
LS7 4SA
Country
United Kingdom
12. IPD Sharing Statement
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Etanercept and Methotrexate in Patients to Induce Remission in Early Arthritis (EMPIRE)
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