Study Conducted in Subjects With Rheumatoid Arthritis Who Have Moderate to Severe Disease Activity Despite Methotrexate Therapy With or Without Other Non Biologic Disease Modifying Antirheumatic Drugs (DMARDs)for at Least 12 Weeks Prior to Screening

Study Overview
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Brief Summary
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To compare the maintenance of efficacy of the combination of etanercept 50 mg once weekly plus methotrexate with or without other disease modifying antirheumatic drugs therapy with that of methotrexate with or without other disease modifying antirheumatic drugs therapy at Week 52 in subjects with moderately to severely active rheumatoid arthritis who have achieved low disease activity after 24 weeks of therapy with open label etanercept 50 mg once weekly plus MTX with or without other disease modifying antirheumatic drugs therapy.

Official Title
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A Randomized, Double-blind Placebo-controlled Study Of The Maintenance Of Efficacy Of Etanercept Plus Dmard(s) Compared With Dmard(s) Alone In Subjects With Rheumatoid Arthritis After Achieving An Adequate Response With Etanercept Plus Dmard(s)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Etanercept
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has a minimum 1 year history/diagnosis of rheumatoid arthritis based on the 1987 American College of Rheumatology (ACR) Revised criteria for RA. Subject must have active rheumatoid arthritis despite methotrexate (MTX) therapy of ≥10 mg/wk for at least 12 weeks. The MTX dose must be stable for at least 4 weeks immediately prior to screening. Exclusion Criteria: Subjects who used any of the following systemic treatments during the washout periods given below: Oral corticosteroid dose of prednisone >7.5 mg/day (or equivalent) or a change in dose within 28 days of baseline. Treatment with more than 1 NSAID within 14 days at baseline. Methotrexate dose greater than 25 mg/week, or change in the dose of methotrexate within 28 days of baseline. Subjects will be allowed to continue the following non biologic DMARDs: sulfasalazine, hydroxychloroquine, and leflumomide. All other non-biologic DMARDs (including but not limited to gold, penicillamine, azathioprine, cyclophospamide), and biologic DMARDs must have been discontinued at least 2 months prior to Week 1. Any biologic B cell depleting agent (eg, rituximab) within 2 years of Week 1. Receipt of any live (attenuated) vaccine within 4 weeks prior to baseline. Receipt of any live (attenuated) vaccine within 4 weeks prior to baseline.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br> | Drug: Etanercept<br>* etanercept 50mg once weekly + methotrexate with or without other DMARDs<br>|
| Placebo Comparator: Group B<br> | Drug: placebo<br>* etanercept placebo once weekly + methotrexate with or without other DMARDs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Remained in Low Disease Activity (LDA) (Disease Activity Score in 28 Joints-erythrocyte Sedimentation Rate [DAS28-ESR] <3.2) at Week 52. | Proportion of participants who remained in LDA DAS28-ESR <3.2 at Week 52 is presented below. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Remained in Remission at Week 52 (DAS28-ESR) | Proportion of participants who remained in Remission (DAS28-ESR <2.6) at Week 52. | Baseline and Week 52 | 
| Percentage of Participants Achieving LDA (DAS28-ESR and DAS28-C-reactive Protein [CRP]) at Each Visit During Period 1 | Proportion of participants who achieved LDA (DAS28-ESR and DAS28-CRP at each visit during period 1 is presented below. | Baseline, Weeks 4, 8, 16 and 24 | 
| Percentage of Participants Achieving LDA (DAS28-ESR and DAS28-CRP) at Each Visit During Period 2 | Proportion of participants who achieved LDA (DAS28-ESR and DAS28-CRP at each visit during period 2 is presented below. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Percentage of Participants Achieving Remission (DAS28-ESR and DAS28-CRP) at Each Visit During Period 1 | Proportion of participants who achieved remission (DAS28-ESR and DAS28-CRP at each visit during period 1 is presented below. | Baseline, Weeks 4, 8, 16 and 24 | 
| Percentage of Participants Achieving Remission (DAS28-ESR and DAS28-CRP) at Each Visit During Period 2 | Proportion of participants who achieved LDA (DAS28-ESR and DAS28-CRP at each visit during period 2 is presented below. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change From Baseline in DAS28-CRP and DAS28-ESR in Period 1 | The DAS assessment is a derived measurement with differential weight given to each component. The DAS28-ESR and DAS28-CRP was calculated at every visit within the clinical database in period 1. The components of the DAS28 ESR score assessment are: Tender/ Painful Joint Count (28), Swollen Joint Count (28); ESR, Subject General Health VAS assessment. The components of the DAS28 CRP score assessment were: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement was made at every study visit. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change From Baseline in DAS28-CRP and DAS28-ESR in Period 2 | The DAS assessment is a derived measurement with differential weight given to each component. The DAS28-ESR and DAS28-CRP was calculated at every visit within the clinical database in period 2. The components of the DAS28 ESR score assessment are: Tender/ Painful Joint Count (28), Swollen Joint Count (28); ESR, Subject General Health VAS assessment. The components of the DAS28 CRP score assessment were: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement was made at every study visit. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Percentage of Participants Who Had a Recurrence of Disease Symptoms During Period 2, Based on the Protocol Criteria | Flare is defined as the criteria of loss of LDA plus ≥0.6 unit worsening in DAS28-ESR score during period 2. | Baseline and Week 52 | 
| Percentage of Participants Achieving European League Against Rheumatism (EULAR) Good and or Moderate Responses (by Both DAS28-ESR and DAS28-CRP Scores) at Each Visit During Period 1. | EULAR response is based on DAS28-ESR scores. The following good and moderate response is defined based on DAS28-ESR at endpoint (DAS28-ESR improvement at from Baseline in parenthesis): ≤3.2 units (>1.2 units) is good response; ≤3.2 units (0.6-1.2 units) are moderate response; ≤3.2 units (≤0.6 units) are no response. | Baseline, Weeks 4, 8, 16 and 24 | 
| Percentage of Participants Achieving EULAR Good and or Moderate Responses (by Both DAS28-ESR and DAS28-CRP Scores) at Each Visit During Period 2. | EULAR response is based on DAS28-ESR scores. The following good and moderate response is defined based on DAS28-ESR at endpoint (DAS28-ESR improvement at from Baseline in parenthesis): ≤3.2 units (>1.2 units) is good response; ≤3.2 units (0.6-1.2 units) are moderate response; ≤3.2 units (≤0.6 units) are no response. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Percentage of Participants Achieving LDA or Remission Based on Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) at Each Visit During Period 1. | SDAI and CDAI are defined as: 1) SDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0-28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) + hs CRP (in mg/dL) in Period 1. 2) CDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0 28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) in Period 1. | Baseline, Weeks 4, 8, 16 and 24 | 
| Percentage of Participants Achieving LDA or Remission Based on CDAI and SDAI at Each Visit During Period 2. | SDAI and CDAI are defined as: 1) SDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0-28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) + hs CRP (in mg/dL) in Period 2. 2) CDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0 28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) in Period 2. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change of CDAI and SDAI at Each Visit During Period 1. | SDAI and CDAI are defined as: 1) SDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0-28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) + hs CRP (in mg/dL) in Period 1. 2) CDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0 28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) in Period 1. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change of CDAI and SDAI at Each Visit During Period 2 | SDAI and CDAI are defined as: 1) SDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0-28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) + hs CRP (in mg/dL) in Period 2. 2) CDAI = DAS28 prorated Swollen Joint Count (0-28) + DAS28 prorated Tender Joint Count (0 28) + Physician Global Assessment of arthritis (0-10) + Subject Global Assessment of arthritis (0-10) in Period 2. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Percentage of Participants Achieving American College of Rheumatology (ACR) ACR20, ACR50, ACR70 and ACR90 (by 66/68 Joint Counts) During Period 1 at Each Visit. | A 66 swollen and 68 tender joint count was used for calculating ACR responses. The ACR's definition for calculating improvement in RA (ACR20) was calculated as a 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: subject and physician global assessments of arthritis, pain, disability, and an acute phase reactant. Similarly, ACR50, ACR70 and ACR90 were calculated with the respective percent improvement. This efficacy measurement was made at every study visit. | Baseline, Weeks 4, 8, 16 and 24 | 
| Percentage of Participants Achieving ACR20, ACR50, ACR70 and ACR90 (by 66/68 Joint Counts) During Period 2 at Each Visit. | A 66 swollen and 68 tender joint count was used for calculating ACR responses. The ACR's definition for calculating improvement in RA (ACR20) was calculated as a 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: subject and physician global assessments of arthritis, pain, disability, and an acute phase reactant. Similarly, ACR50, ACR70 and ACR90 were calculated with the respective percent improvement. This efficacy measurement was made at every study visit. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in the Tender and Swollen Joint Counts at Each Visit During Period 1 (Using 28 Joint Count as Well as 66/68 Joint Counts). | A total of 66 swollen and 68 tender joints were assessed for tenderness/pain and swelling by the same qualified personnel (when possible) at each visit. For ACR responses, a 66/68 joint count was used. For DAS28-ESR, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) calculations, the 28 joint count was used, which included: shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and knees. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in the Tender and Swollen Joint Counts at Each Visit During Period 2 (Using 28 Joint Count as Well as 66/68 Joint Counts). | A total of 66 swollen and 68 tender joints were assessed for tenderness/pain and swelling by the same qualified personnel (when possible) at each visit. For ACR responses, a 66/68 joint count was used. For DAS28-ESR, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) calculations, the 28 joint count was used, which included: shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and knees. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in the Physician Global Assessment of Arthritis at Each Visit During Period 1 | The investigator estimated the subject's overall disease activity over the last 2 to 3 days (independent of the Subject Global Assessment of arthritis) using a scale between 0 (no disease activity) and 10 (extreme disease activity) and marking one number with an 'X'. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in the Physician Global Assessment of Arthritis at Each Visit During Period 2 | The investigator estimated the subject's overall disease activity over the last 2 to 3 days (independent of the Subject Global Assessment of arthritis) using a scale between 0 (no disease activity) and 10 (extreme disease activity) and marking one number with an 'X'. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in the Subject Global Assessment of Arthritis in Period 1 | Subjects assessed their overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity), which corresponded to the magnitude of their pain) and marked one number with an 'X'. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in the Subject Global Assessment of Arthritis in Period 2 | Subjects assessed their overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity), which corresponded to the magnitude of their pain) and marked one number with an 'X'. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in Morning Stiffness (Measured in Minutes) at Each Visit During Period 1 | Morning stiffness was defined as stiffness in and around the joints, lasting at least 1 hour before maximal improvement. Participants assessed their overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity), which corresponded to the magnitude of their pain) and marked one number with an 'X'. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in Morning Stiffness (Measured in Minutes) at Each Visit During Period 2 | Morning stiffness was defined as stiffness in and around the joints, lasting at least 1 hour before maximal improvement. Participants assessed their overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity), which corresponded to the magnitude of their pain) and marked one number with an 'X'. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in the Subject General Health Visual Analog Scale (VAS) and Pain VAS at Each Visit During Period 1 | Participants were asked to answer the question In general how would you rate your health over the last 2 3 weeks? by marking a vertical line at the appropriate position through the 100 mm VAS. The length on the line was measured from the left (in mm). For Pain VAS, participants assessed the severity of their arthritis pain during the last 2 to 3 days using a 100 mm VAS by marking a vertical line at the appropriate position on the scale between 0 (no pain) and 100 (most severe pain), which corresponded to the magnitude of their pain. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in the Subject General Health VAS and Pain VAS at Each Visit During Period 2 | Participants were asked to answer the question In general how would you rate your health over the last 2-3 weeks? by marking a vertical line at the appropriate position through the 100 mm VAS. The length on the line was measured from the left (in mm). For Pain VAS, participants assessed the severity of their arthritis pain during the last 2 to 3 days using a 100 mm VAS by marking a vertical line at the appropriate position on the scale between 0 (no pain) and 100 (most severe pain), which corresponded to the magnitude of their pain. | Baseline, Weeks 24, 28, 36, 44 and 52 | 
| Change in CRP and ESR at Each Visit During Period 1 | The DAS assessment is a derived measurement with differential weight given to each component. The DAS28-ESR and DAS28-CRP was calculated at every visit within the clinical database in period 1. The components of the DAS28 ESR score assessment are: Tender/ Painful Joint Count (28), Swollen Joint Count (28); ESR, Subject General Health VAS assessment. The components of the DAS28 CRP score assessment were: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement was made at every study visit. | Baseline, Weeks 4, 8, 16 and 24 | 
| Change in CRP and ESR at Each Visit During Period 2 | The DAS assessment is a derived measurement with differential weight given to each component. The DAS28-ESR and DAS28-CRP was calculated at every visit within the clinical database in period 1. The components of the DAS28 ESR score assessment are: Tender/ Painful Joint Count (28), Swollen Joint Count (28); ESR, Subject General Health VAS assessment. The components of the DAS28 CRP score assessment were: Tender/Painful Joint Count (28); Swollen Joint Count (28), hsCRP, and the Subject General Health VAS assessment. This efficacy measurement was made at every study visit. | Baseline, Weeks 24, 28, 36, 44 and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, etanercept, methotrexate, DMARDs