Study Comparing Etanercept in Combination With Methotrexate in Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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To compare the efficacy of the combination of etanercept 50 mg once weekly plus methotrexate with that of methotrexate monotherapy in the treatment of rheumatoid arthritis over 88 weeks.

Official Title
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A Randomized, Double-Blind Study Comparing the Safety & Efficacy of Once-Weekly Etanercept 50 mg, Etanercept 25 mg, & Placebo in Combination With Methotrexate in Subjects With Active Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Etanercept
* Drug: Methotrexate
* Drug: Etanercept
* Drug: Methotrexate
* Drug: Placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis. Currently receiving an optimal dose of oral Methotrexate (MTX)(at least 15 mg/week but no more than 25 mg/week) for the treatment of rheumatoid arthritis. Active rheumatoid arthritis at the time of screening. Exclusion Criteria: Previous or current treatment with etanercept, other tumor necrosis factor-alpha (TNF) inhibitors, or other biologic agents. Concurrent treatment with any disease-modifying anti-rheumatoid drugs (DMARD), other than MTX within 28 days before baseline. Concurrent treatment with more than 1 non-steroid anti-inflammatory drug (NSAID) at 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Etanercept<br>* Subcutaneous (SC), 50 mg, once weekly for 88 weeks<br>* Other names: Enbrel;Drug: Methotrexate<br>* Oral, 15 to 25 mg (varying based on dosage the subject is receiving at the time of screening and may be increased at the discretion of the investigator through Week 28 to a maximum of 25 mg/week), once weekly for 88 weeks. If a subject experiences an adverse event (AE) during the study, Methotrexate may be decreased by 2.5 or 5.0 mg weekly (the minimum dose to stay in the study is 10 mg/week).<br>|
| Active Comparator: 2<br> | Drug: Etanercept<br>* Subcutaneous (SC), 25 mg, once weekly from week 36 to week 88.<br>Drug: Methotrexate<br>* Oral, 15 to 25 mg (varying based on dosage the subject is receiving at the time of screening and may be increased at the discretion of the investigator through Week 28 to a maximum of 25 mg/week), once weekly for 88 weeks. If a subject experiences an adverse event (AE) during the study, Methotrexate may be decreased by 2.5 or 5.0 mg weekly (the minimum dose to stay in the study is 10 mg/week).<br>|
| Placebo Comparator: 3<br> | Drug: Placebo<br>* Subcutaneous (SC), once weekly from week 36 to week 88.<br>Drug: Methotrexate<br>* Oral, 15 to 25 mg (varying based on dosage the subject is receiving at the time of screening and may be increased at the discretion of the investigator through Week 28 to a maximum of 25 mg/week), once weekly for 88 weeks. If a subject experiences an adverse event (AE) during the study, Methotrexate may be decreased by 2.5 or 5.0 mg weekly (the minimum dose to stay in the study is 10 mg/week).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 28 Joint Disease Activity Score (DAS28) Less Than or Equal to (≤) 3.2 at Week 88 | DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joint count (less than [<]20 percent [%] missing SJC or PJC was prorated), erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and Patient's General Health Visual Analog Scale (VAS). VAS is a line 0-100 millimeters (mm) in length; ranged from 0 (very well)-100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. DAS28 ≤ 3.2 units equals (=) low disease activity. | Week 88 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving DAS28 Low Disease Activity or Remission at Baseline, Weeks 4, 8, 12, 20, 28 and 36 | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR mm/hour and and Patient's General Health VAS. VAS consisted of a line 0 to 100 mm in length; ranged from 0 (very well) to 100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. DAS28 ≤ 3.2 units = low disease activity, DAS28 < 2.6 units = remission. | Baseline, Weeks 4, 8, 12, 20, 28, 36 | 
| Percentage of Participants Achieving DAS28 Low Disease Activity or Remission | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR mm/hour and and Patient's General Health VAS. VAS consisted of a line 0 to 100 mm in length; ranged from 0 (very well) to 100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. DAS28 ≤ 3.2 units = low disease activity, DAS28 < 2.6 units = remission. | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Change From Baseline in DAS28 at Weeks 4, 8, 12, 20, 28 and 36 | The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables (the number of tender joints out of 28, the number of swollen joints out of 28 joints, erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity measured on a visual analogue scale (VAS) of 100 mm). Change equals (=) Week X observation minus (-) Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| Change From Week 36 in DAS28 at Weeks 40, 48, 56, 64, 72, 80 and 88 | The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables (the number of tender joints out of 28, the number of swollen joints out of 28 joints, ESR mm/hour and PGA of disease activity measured on a VAS of 100 mm). Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Time to Loss of Low Disease Activity DAS28 and a Change of ≥ 0.6 Units in the DAS28 | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR mm/hour and Patient's General Health VAS. VAS consisted of a line 0 to 100 mm in length; ranged from 0 (very well) to 100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. Low disease activity = DAS28 ≤ 3.2 units. DAS28 > 3.2 to 5.1 units = moderate to high disease activity. | Week 36 up to Week 88 | 
| Time to Loss of Low Disease Activity DAS28 | DAS28 calculated from the number of SJC and PJC using the 28 joints count, the ESR mm/hour and Patient's General Health VAS. VAS consisted of a line 0 to 100 mm in length; ranged from 0 (very well) to 100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. DAS28 ≤ 3.2 units = low disease activity, DAS28 greater than (>)3.2 to 5.1 units = moderate to high disease activity. | Week 36 up to Week 88 | 
| Proportion of Time Participants Had Low Disease Activity DAS28 Week 36 to Week 88 | DAS28 calculated from the number of SJC and PJC using the 28 joints, the ESR mm/hour and Patient's General Health VAS. VAS consisted of a line 0 to 100 mm in length; ranged from 0 (very well) to 100mm (extremely bad). Participants placed a mark indicating their health over the previous 2-3 weeks. Higher scores indicated greater affectation due to disease activity. DAS28 < 3.2 units = low disease activity. Cumulative proportion calculated as time-averaged Area Under the Curve (AUC) (AUC divided by number of weeks at that time point), with AUC calculated from Week 36 and Week 88. | Week 36 up to Week 88 | 
| Change From Baseline in Prorated Swollen Joint Count at Weeks 4, 8, 12, 20, 28 and 36 | American College of Rheumatology (ACR), swollen joint count were an assessment of 28 joints. Joints are classified as either swollen or not swollen. If < 20% of swollen joints missing then total swollen joint prorated (multiplied by 28 divided by (/) number of non-missing swollen joints). Total possible score ranged from -28 to 28. An increase in swollen joints from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression and a decrease represented improvement. Change = Week X observation - baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| Prorated Swollen Joint Count at Week 36 | ACR, swollen joint count was an assessment of 28 joints. Joints were classified as either swollen or not swollen. If < 20% of swollen joints missing then total swollen joint prorated (multiplied by 28 divided by number of non-missing swollen joints). Total possible score of swollen joints ranged from 0-28. | Week 36 | 
| Change From Week 36 in Prorated Swollen Joint Count at Weeks 40, 48, 56, 64, 72, 80 and 88 | ACR, swollen joint count was an assessment of 28 joints. Joints were classified as either swollen or not swollen. If < 20% of swollen joints missing then total swollen joint prorated (multiplied by 28 divided by (/) number of non-missing swollen joints). Total possible score ranged from -28 to 28. An increase in swollen joints from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression and a decrease represented improvement. Change = Week X observation - Week 36 observation. | Week 36, Weeks 40, 48, 56, 64, 72, 80 and 88 | 
| Change From Baseline in the Painful Joint Count at Weeks 4, 8, 12, 20, 28 and 36 | A total of 28 joints were assessed by the investigator using criteria based on pressure and joint manipulation. Total possible scores ranged from -28 to 28. An increase in joint pain count from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression and a decrease represented improvement. Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| Painful Joint Count at Week 36 | A total of 28 joints were assessed by the investigator using criteria based on pressure and joint manipulation. Total possible score ranged form 0-28. | Week 36 | 
| Change From Week 36 in Painful Joint Count at Weeks 40, 48, 56, 64, 72, 80 and 88 | Total of 28 joints were assessed by the investigator using criteria based on pressure and joint manipulation. Total possible scores ranged from -28 to 28. An increase in joint pain count from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression and a decrease represented improvement. Change = Week X observation - Week 36 observation. | Weeks 36 40, 48, 56, 64, 72, 80 and 88 | 
| Change From Baseline in the Physician Global Assessment (PGA) at Weeks 4, 8, 12, 20, 28 and 36 | PGA of Disease Activity was measured on a 0 to 10 Scale, with 0 = no disease activity and 10 = extreme disease activity. Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| PGA Score at Week 36 | PGA of Disease Activity was measured on a 0 to 10 Scale, with 0 = no disease activity and 10 = extreme disease activity. | Week 36 | 
| Change From Week 36 in the PGA Score at Weeks 40, 48, 56, 64, 72, 80 and 88 | PGA of Disease Activity was measured on a 0 to 10 Scale, with 0 = no disease activity and 10 = extreme disease activity. Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Change From Baseline in Patient's Global Assessment (PtGA) of Arthritis Pain at Weeks 4, 8, 12, 20, 28 and 36 | Participants asked to rate their overall arthritis activity by circling a number ranging from 0 (no disease activity) to 10 (extreme disease activity). Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| PtGA of Arthritis Pain at Week 36 | PtGA asked the participant to assess their overall arthritis activity. Participants responded by circling a number ranging from 0 (no disease activity) to 10 (extreme disease activity). | Week 36 | 
| Change From Week 36 in PtGA of Arthritis Pain at Weeks 40, 48, 56, 64, 72, 80, 88 | PtGA asked the participant to assess their overall arthritis activity. Participants responded by circling a number ranging from 0 (no disease activity) to 10 (extreme disease activity). Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80, 88 | 
| Change From Baseline in Duration of Morning Stiffness at Weeks 4, 8, 12, 20, 28 and 36 | Duration of morning stiffness was defined as the time elapsed when participant woke up in the morning and when the participants were able to resume normal activities without stiffness. No stiffness present = 0; stiffness persisted the entire day = 1440 minutes (24 hour times [*] 60 min) was recorded. Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| Duration of Morning Stiffness at Week 36 | Duration of morning stiffness was defined as the time elapsed when participant woke up in the morning and when the participants were able to resume normal activities without stiffness. No stiffness present = 0; stiffness persisted the entire day = 1440 minutes (24 hour * 60 min) was recorded. | Week 36 | 
| Change From Week 36 in Duration of Morning Stiffness at Weeks 40, 48, 56, 64, 72, 80, 88 | Duration of morning stiffness was defined as the time elapsed when participant woke up in the morning and was able to resume normal activities without stiffness. No stiffness present = 0; stiffness persisted the entire day = 1440 minutes (24 hour * 60 min) was recorded. Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80, 88 | 
| Change From Baseline in General Health at Weeks 4, 8, 12, 20, 28 and 36 | General Health VAS is a 100 millimeter (mm) line marked by the participant. Participants were asked, In general how would you rate your health over the last 2 to 3 weeks? Scores ranged from 0 mm = very well to 100 mm = extremely bad. Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| General Health at Week 36 | General Health VAS is a 100 mm line marked by the participant. Participants are asked, In general how would you rate your health over the last 2 to 3 weeks? Scores ranged from 0 mm = very well to 100 mm = extremely bad. | Week 36 | 
| Change From Week 36 in General Health at Weeks 40, 48, 56, 64, 72, 80, 88 | General Health VAS is a 100 mm line marked by the participant. Participants were asked, In general how would you rate your health over the last 2 to 3 weeks? Scores ranged from 0 mm = very well to 100 mm = extremely bad. Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80, 88 | 
| Change From Baseline in Pain at Weeks 4, 8, 12, 20, 28 and 36 | 100 mm line (Visual Analog Scale) marked by participant. Intensity of pain range (over past 2 to 3 days): 0 = no pain to 100 = worst possible pain. Change = Week X observation - Baseline observation. | Baseline, Weeks 4, 8, 12, 20, 28 and 36 | 
| Pain at Week 36 | 100 mm line (Visual Analog Scale) marked by participant. Intensity of pain range (over past 2 to 3 days): 0 = no pain to 100 = pain as bad as it could be. Change = Week x observation minus (-) Baseline observation. | Week 36 | 
| Change From Week 36 in Pain at Weeks 40, 48, 56, 64, 72, 80 and 88 | 100 mm line (Visual Analog Scale) marked by participant. Intensity of pain range (over past 2 to 3 days): 0 = no pain to 100 = worst possible pain. Change = Week X observation - Week 36 observation. | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Percentage of Participants Achieving an Acceptable State on the Patient Acceptable Symptom State (PASS) at Baseline and Week 36 | PASS was a 1 question assessment of how rheumatoid arthritis has affected the participant in the last 2 days (If you were to remain in the next few months as you were during the last 2 days, would this be acceptable or unacceptable to you?). | Baseline, Week 36 | 
| Percentage of Participants Achieving an Acceptable State on the PASS at Week 36 and Weeks 64 and 88 | PASS was a 1 question assessment of how rheumatoid arthritis has affected the participant in the last 2 days (If you were to remain in the next few months as you were during the last 2 days, would this be acceptable or unacceptable to you?). | Weeks 36, 64 and 88 | 
| Percentage of Participants Achieving European League Against Rheumatism (EULAR) Good or Moderate Response at Weeks 4, 8, 12, 20, 28 and 36 | EULAR Response Criteria: Good response was defined as >1.2 units improvement in DAS28 from Baseline and DAS28 attained up to Week 88 of <=3.2 units. Non responders were participants with improvement of <0.6 units or participants with improvement of 0.6 to 1.2 units and DAS28 attained up to Week 88 of > 5.1 units. Remaining participants were defined as having a moderate response. Scores of good and moderate were considered to have therapeutic response. | Weeks 4, 8, 12, 20, 28 and 36 | 
| Percentage of Participants Achieving EULAR Good or Moderate Response at Week 36, 40, 48, 56, 64, 72, 80 and 88 | EULAR Response Criteria: Good response was defined as >1.2 units improvement in DAS28 from Baseline and DAS28 attained up to Week 88 of <=3.2 units. Non responders were participants with improvement of <0.6 units or participants with improvement of 0.6 to 1.2 units and DAS28 attained up to Week 88 of > 5.1 units. Remaining participants were defined as having a moderate response. Scores of good and moderate were considered to have therapeutic response. | Week 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Percentage of Participants With an American College of Rheumatology 20 Percent (%) (ACR20) Response at Weeks 4, 8, 12, 20, 28 and 36 | ACR20 response, ≥ 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and = at least 20% improvement in at least 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and acute phase reactant (ESR). | Weeks 4, 8, 12, 20, 28 and 36 | 
| Percentage of Participants With an ACR20 Response at Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | ACR20 response: ≥ 20% improvement in tender joint count; ≥20% improvement in swollen joint count; and = at least 20% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Percentage of Participants With an ACR50 Response at Weeks 4, 8, 12, 20, 28 and 36 | ACR50 response: ≥ 50% improvement in tender joint count; = ≥50% improvement in swollen joint count; and = at least 50% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 4, 8, 12, 20, 28 and 36 | 
| Percentage of Participants With an ACR50 Response at Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | ACR50 response: ≥ 50% improvement in tender joint count; = ≥50% improvement in swollen joint count; and = at least 50% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Percentage of Participants With an ACR70 Response at Weeks 4, 8, 12, 20, 28 and 36 | ACR70 response: ≥ 70% improvement in tender joint count; = ≥70% improvement in swollen joint count; and = at least 70% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 4, 8, 12, 20, 28 and 36 | 
| Percentage of Participants With an ACR70 Response at Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | ACR70 response: ≥ 70% improvement in tender joint count; = ≥70% improvement in swollen joint count; and = at least 70% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and C-Reactive Protein CRP. | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| Percentage of Participants With an ACR90 Response at Weeks 4, 8, 12, 20, 28 and 36 | ACR90 response: ≥ 90% improvement in tender joint count; = ≥90% improvement in swollen joint count; and = at least 90% improvement in 3 of the following 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 4, 8, 12, 20, 28 and 36 | 
| Percentage of Participants With an ACR90 Response at Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | ACR90 response: ≥ 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: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and acute phase reactant (ESR). | Weeks 36, 40, 48, 56, 64, 72, 80 and 88 | 
| DAS28 at Week 36 | The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables (the number of tender joints out of 28, the number of swollen joints out of 28 joints, ESR mm/hour and PGA of disease activity measured on a VAS of 100 mm). | Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Active Rheumatoid Arthritis