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

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.

Time frame: Week 88

Population: Modified Intent to Treat population (mITT): all participants who took at least 1 dose of double-blind test article and had at least 1 post-randomization DAS28 evaluation

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; Last observation carried forward (LOCF); N=Number of participants with evaluable data

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF; N=number of participants with evaluable data

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80, 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80, 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF

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.

Time frame: Weeks 36 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Week 36, Weeks 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80, 88

Population: P2 mITT; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF

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).

Time frame: Week 36

Population: P2 mITT; LOCF

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.

Time frame: Week 36

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Week 36

Population: P2 mITT; LOCF

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.

Time frame: Week 36

Population: P2 mITT; LOCF

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.

Time frame: Week 36

Population: P2 mITT; LOCF

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?).

Time frame: Weeks 36, 64 and 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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?).

Time frame: Baseline, Week 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: Period 2 (P2) mITT

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.

Time frame: Baseline, Weeks 4, 8, 12, 20, 28, 36

Population: Period 1 Modified Intent to Treat population (P1 mITT): all participants who took at least 1 dose of open-label test article; N=number of participants with evaluable data; Last observation carried forward (LOCF)

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.

Time frame: Week 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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).

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF; N=number of participants with evaluable data

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).

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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).

Time frame: Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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.

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; N=number of participants with evaluable data; LOCF

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).

Time frame: Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

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).

Time frame: Weeks 36, 40, 48, 56, 64, 72, 80 and 88

Population: P2 mITT; LOCF

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).

Time frame: Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; LOCF

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).

Time frame: Weeks 4, 8, 12, 20, 28 and 36

Population: P1 mITT; N=number of participants with evaluable data; LOCF

PGA of Disease Activity was measured on a 0 to 10 Scale, with 0 = no disease activity and 10 = extreme disease activity.

Time frame: Week 36

Population: P2 mITT; LOCF

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.

Time frame: Week 36 up to Week 88

Population: P2 mITT; LOCF

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.

Time frame: Week 36

Population: P2 mITT; LOCF

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).

Time frame: Week 36

Population: P2 mITT; LOCF

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.

Time frame: Week 36 up to Week 88

Population: P2 mITT;

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.

Time frame: Week 36 up to Week 88

Population: P2 mITT;Imputation of failure; observed cases