Study Evaluating Efficacy / Safety of Etanercept + Methotrexate Compared to Usual Treatment in Moderate RA Subjects

An Open-Label, Randomized Study to Evaluate the Radiographic Efficacy and Safety of Enbrel™ (Etanercept) Added to Methotrexate in Comparison With Usual Treatment in Subjects With Moderate Rheumatoid Arthritis Disease Activity

To assess comparative radiographic efficacy, clinical efficacy and safety of etanercept (ETN) + methotrexate (MTX) with usual disease-modifying anti-rheumatic drug (DMARD) treatment in subjects with moderate RA who were treated with MTX monotherapy, but continue to have moderate disease activity.

Study Overview

• Status: Terminated
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: methotrexate; Drug: etanercept (EnbrelTM)

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czech Republic
  • Ostrava, Czech Republic, 722 00
  • Prague, Czech Republic, 128-50
  • Prague, Czech Republic, 140-59
• France
  • Amiens, France, 80054
  • Amiens cedex 1, France, 80054
  • Echirolles, France, 38130
  • Metz, France, 57077
  • Montpellier, France, 34295
  • Paris, France, 75651
  • Paris, France, 75679
  • Paris cedex 13, France, 75651
  • Paris cedex 14, France, 75679
  • Rouen, France, 76031
  • Tours, France, 37044
  • Tours cedex 9, France, 37044
• Germany
  • Berlin, Germany, 10117
  • Frankfurt, Germany, 60590
  • Hamburg-Eilbeck, Germany, 22081
  • Homburg, Germany, 66424
  • Koeln, Germany, 50924
  • Mainz, Germany, 55131
• Hungary
  • Budapest, Hungary, 1036
  • Budapest, Hungary, 1023
  • Miskolc, Hungary, 3529
  • Rijeka, Hungary, 51000
  • Split, Hungary, 21000
  • Zagreb, Hungary, 10000
• Italy
  • Jesi (Ancona), Italy, 60035
  • Reggio Calabria, Italy, 89100
• Poland
  • Bytom, Poland, 41-902
  • Krakow, Poland, 31-531
  • Ustron, Poland, 43-450
  • Warszawa, Poland, 02-637
  • Warszawa, Poland, 00-909
  • Wroclaw, Poland, 50-088
• Spain
  • Barcelona, Spain, 08035
  • Madrid, Spain, 28006
  • Madrid, Spain, 28040
  • Madrid, Spain, 28046
  • Valencia, Spain, 46010
  • Cantabria
    • Santander, Cantabria, Spain, 39008
  • Madrid
    • Getafe, Madrid, Spain, 28902
  • Vizcaya
    • Bilbao, Vizcaya, Spain, 48013
• Turkey
  • Izmir, Turkey, 35340
• United Kingdom
  • Aintree, United Kingdom, L9 7AL
  • Newcastle, United Kingdom, NE7 7DN
  • Wirral, United Kingdom, CH49 5PE
  • Cambs
    • Cambridge, Cambs, United Kingdom, CB2 2QQ
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, WS11 5XY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meet the 1987 ACR Revised Criteria for Rheumatoid Arthritis.
• Documented evidence, confirmed by a blinded 3rd party assessor, of at least one erosion observed by X-ray at randomization based on X-ray taken at the screening visit.
• Have received MTX as stable dose for 28 days prior to the screening visit.

Exclusion Criteria:

• Previous treatment with ETN, infliximab, adalimumab, other Tumor necrosis factor (TNF) -a inhibitors, anakinra or other biological agents.
• Receipt of any DMARD, other than MTX, within 28 days before screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Usual care; Utilized Disease-Modifying Antirheumatic Drugs (DMARDs) from a list of the 6 most commonly prescribed in the participating countries (Methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, cyclosporine A and gold).	Drug: methotrexate
ACTIVE_COMPARATOR: ETN + MTX; Etanercept (ETN) 50 milligrams (mg) sub-cutaneous (SC) injection once weekly (pre-filled syringe) plus continuation of current dose of Methotrexate (MTX) either oral (PO), SC, or intramuscular (IM).	Drug: methotrexate; Drug: etanercept (EnbrelTM)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Modified Total Sharp Score (TSS) at Week 52	Modified TSS is a measure of change in joint health. TSS is defined as joint space narrowing score (range 0 [no narrowing] to 168 [high narrowing]) plus (+) erosion score (range is from 0 [no erosion] to 280 [high erosion]). The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Erosions at Week 52	Erosion score (a component of the modified TSS) is a measure of change in joint health. Erosion score range is from 0 (no erosion) to 280 (high erosion). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.	Baseline, Week 52
Change From Baseline in Joint Space Narrowing at Week 52	Joint space narrowing score (a component of the modified TSS) is a measure of change in joint health. Joint space narrowing score range is 0 (no narrowing) to 168 (high narrowing). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.	Baseline, Week 52
Percentage of Participants Showing no Radiographic Progression (TSS Change <0.5) at Week 52	Radiographic non-progression determined based on TSS change <0.5 using the dichotomous response Yes / No. The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement.	Baseline, Week 52, Last observation carried forward (LOCF)
Percentage of Participants Achieving >1.2 Improvement in Disease Activity Score Based on a 28-joint Count (DAS28)	Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) using Visual Analog Scale (VAS); range 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 square root (√) (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score >5.1=higher disease activity; <3.2=low disease activity; <2.6=clinical remission. Achievement of >1.2 improvement defined as decrease in DAS28 >1.2 (change in DAS28 < -1.2).	Baseline, Week 12, Week 24, and Week 52
Percentage of Participants Achieving Remission (DAS28 <2.60)	Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score >5.10=higher disease activity; <3.20=low disease activity; <2.60=clinical remission.	Week 12, Week 24, and Week 52
Percentage of Participants Achieving Low Disease Activity (DAS28 ≤3.20)	Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score >5.10=higher disease activity; <3.20=low disease activity; <2.60=clinical remission.	Week 12, Week 24, and Week 52
Percentage of Participants Achieving a >0.6 Disease Activity Score (DAS)28 Response	Disease activity score based on 28 painful joint counts, 28 swollen joint counts, erythrocyte sedimentation rate (ESR) mm/hr, and participant's assessment of general health (GH) using a visual analog scale (VAS); VAS range: 0 (very well) to 100 (extremely bad). DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH; range 0 to 10. DAS28 score >5.10=higher disease activity; <3.20=low disease activity; <2.60=clinical remission. DAS28 response of >0.6 defined as decrease in DAS28 >0.6 (change in DAS28 < -0.6).	Week 12, Week 24, and Week 52
Percentage of Participants Achieving Moderate or Good Response on European League Against Rheumatism (EULAR) Response Criteria	Response to treatment assessed by EULAR response criteria. Participants were characterized as good, moderate, or non-responders based on both Disease Activity Score (DAS) level attained and change in DAS. Good response defined as >1.2 improvement in DAS from Baseline and DAS attained during follow-up of ≤2.4. Non-responders = participants with improvement of ≤0.6 or participants with improvement of >0.6 but ≤1.2 and DAS attained during follow-up of >5.1. Remaining participants were classified as moderate. Scores of good and moderate were considered to have therapeutic response.	Week 12, Week 24, Week 52
Percentage of Participants With American College of Rheumatology 20% (ACR20) Response	American College of Rheumatology 20% (ACR20) response: responder = ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.	Week 12, Week 24, Week 52
Percentage of Participants With American College of Rheumatology 50% (ACR50) Response	American College of Rheumatology 50% (ACR50) response: responder = ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.	Week 12, Week 24, Week 52
Percentage of Participants With American College of Rheumatology 70% (ACR70) Response	American College of Rheumatology 70% (ACR70) response: responder = ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and erythrocyte sedimentation rate (ESR) . Subjects withdrawing early were non-responders.	Week 12, Week 24, Week 52
Percentage of Participants With American College of Rheumatology 90% (ACR90) Response	American College of Rheumatology 90% (ACR 90) response: responder = ≥ 90% improvement in tender joint count; ≥ 90% improvement in swollen joint count; and ≥ 90% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and erythrocyte sedimentation rate (ESR). Subjects withdrawing early were non-responders.	Week 12, Week 24, Week 52
Change From Baseline in Mean Daily Dose of Corticosteroids to Manage Flare-ups Across the 52-week Treatment Period	Mean daily dose of corticosteroids to manage flare-ups (temporary increases in corticosteroid dose or use of intra-articular steroids) during treatment period. Daily dose of equivalent prednisone derived in mg/day: oral corticosteroids: 5 mg of prednisone = 5 mg of prednisolone = 25 mg of cortisone = 20 mg of hydrocortisone = 4 mg of methylprednisolone = 4 mg of triamcinolone = 2mg of paramethasone = 0.75 mg of betamethasone = 0.75 of dexamethasone = 0.3 of cortivazol.	Week 4, Week 12, Week 24, Week 40, Week 52
Percentage of Participants Achieving a Minimal Clinically Important Improvement (MCII)	Participants were asked how their pain had been during the last 48 hours compared to baseline. Participants that reported improvement assessed how important this improvement was to them; range: very important, moderately important, slightly important, or not at all important. Binary response options: 1=improved very important, or improved moderately important; 2=slightly important, not at all important, no change, or worse-more pain.	Week 12, Week 52
Percentage of Participants Achieving a Patient Acceptable Symptom State (PASS)	Percentage of participants reporting acceptable symptom state: acceptance to remain for the rest of their lives with the level of pain they had during the last 48 hours; and unacceptable symptom state: not able to remain for the rest of their lives with the level of pain they had during the last 48 hours.	Week 4, Week 12, Week 24, Week 40, Week 52
Health Related Quality of Life: EuroQol-5D Health Index	EQ-5D is a self-administered questionnaire to assess health-related quality of life in 5 domains (mobility, self care, usual activities, pain or discomfort, and anxiety or depression). Scores from the 5 domains are used to calculate the Health State Profile Score as a single index value; range: 0.0 (death) to 1.0 (perfect health); higher scores indicate a better health state.	Baseline, Week 12, Week 24, and Week 52
Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS)	EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.	Baseline, Week 12, Week 24, and Week 52

Collaborators and Investigators

• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer

Publications and helpful links

General Publications

• Mandl P, Balint PV, Brault Y, Backhaus M, D'Agostino MA, Grassi W, van der Heijde D, de Miguel E, Wakefield RJ, Logeart I, Dougados M. Clinical and ultrasound-based composite disease activity indices in rheumatoid arthritis: results from a multicenter, randomized study. Arthritis Care Res (Hoboken). 2013 Jun;65(6):879-87. doi: 10.1002/acr.21913.
• Mandl P, Balint PV, Brault Y, Backhaus M, D'Agostino MA, Grassi W, van der Heijde D, de Miguel E, Wakefield RJ, Logeart I, Dougados M. Metrologic properties of ultrasound versus clinical evaluation of synovitis in rheumatoid arthritis: results of a multicenter, randomized study. Arthritis Rheum. 2012 Apr;64(4):1272-82. doi: 10.1002/art.33491. Epub 2011 Nov 30.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (ACTUAL): December 1, 2009
• Study Completion (ACTUAL): May 1, 2010

Study Registration Dates

• First Submitted: June 25, 2008
• First Submitted That Met QC Criteria: June 27, 2008
• First Posted (ESTIMATE): June 30, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): June 21, 2011
• Last Update Submitted That Met QC Criteria: June 16, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: Moderate Rheumatoid Arthritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Etanercept; Methotrexate
• Other Study ID Numbers: 0881X1-4437