Study Evaluating Etanercept Plus Methotrexate in Early Rheumatoid Arthritis

• ClinicalTrials.gov Identifier: NCT00913458
• Recruitment Status: Completed
• First Posted: June 4, 2009
• Results First Posted: July 17, 2014
• Last Update Posted: July 17, 2014
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Active Rheumatoid Arthritis; Arthritis, Rheumatoid; Rheumatoid Arthritis
• Intervention: Drug: etanercept
• Enrollment: 306

Participant Flow

Recruitment Details	This report presents the results of open-label 52-week treatment period (Phase 1), 39 week, double blind randomized (Phase 2) and 26 week observational period (Phase 3) part of a 121 week Phase 4 study program. Responders in Phase 1 were randomized to 3 arms (1:1:1 ratio) in Phase 2. Responders in Phase 2, continued to Phase 3 observational period
Pre-assignment Details	Phase 1 responders, defined as subjects with Disease Activity Score based on 28-joints count (DAS28) ≤ 3.2 at Week 39 and DAS28 <2.6 at Week 52, were randomized to Phase 2. The responders of Phase 2 were observed for 26-weeks in Phase 3 study that include 2 to 4 week period of double blind treatment taper of MTX followed by observational period

Arm/Group Title	ETN 50 QW + MTX (Phase 1)	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)	E25+MTX (Phase 3)	MTX (Phase 3)	Placebo (PBO) (Phase 3)
Arm/Group Description	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	Phase 3 was a 26-week observational period in which Phase 2 responders progressively stopped treatment. It included a 2 to 4 week period of double blind MTX tapering (depending on the optimized MTX dose), followed by an observational period until Week 117.	Phase 3 was a 26-week observational period in which Phase 2 responders progressively stopped treatment. It included a 2 to 4 week period of double blind MTX tapering (depending on the optimized MTX dose), followed by an observational period until Week 117.	Phase 3 was a 26-week observational period in which Phase 2 responders progressively stopped treatment. It included a 2 to 4 week period of double blind MTX tapering (depending on the optimized MTX dose), followed by an observational period until Week 117.
Period Title: Phase 1
Started	306	0 [1]	0 [1]	0 [1]	0 [2]	0 [2]	0 [2]
Completed	194 [3]	0 [1]	0 [1]	0 [1]	0 [2]	0 [2]	0 [2]
Not Completed	112	0	0	0	0	0	0
Reason Not Completed
Non-Responder	54	0	0	0	0	0	0
Subject Request	17	0	0	0	0	0	0
Adverse Event	20	0	0	0	0	0	0
Lost to Follow-up	2	0	0	0	0	0	0
Protocol Violation	10	0	0	0	0	0	0
Sponsor	2	0	0	0	0	0	0
Unsatisfactory Response per Investigator	7	0	0	0	0	0	0
[1] This arm is part of Phase 2 study; [2] This arm is part of Phase 3 study; [3] 194 continued to Phase 2 but 1 was randomized in error leaving 193 in the phase 2 analysis.
Period Title: Phase 2
Started	0 [1]	63	65	65	0	0	0
Completed	0 [1]	53 [2]	46 [2]	32 [2]	0	0	0
Not Completed	0	10	19	33	0	0	0
Reason Not Completed
Non-Responder	0	5	7	12	0	0	0
Subject Request	0	0	1	2	0	0	0
Adverse Event	0	3	0	1	0	0	0
Lost to Follow-up	0	0	0	1	0	0	0
Protocol Violation	0	2	0	0	0	0	0
Unsatisfactory Response per Investigator	0	0	11	17	0	0	0
[1] This arm is part of Phase 1 of the study.; [2] Participants randomized into Phase 3 of study.
Period Title: Phase 3
Started	0 [1]	0	0	0	53 [2]	46 [2]	32 [2]
Completed	0 [1]	0	0	0	31	28	24
Not Completed	0	0	0	0	22	18	8
Reason Not Completed
Adverse Event	0	0	0	0	5	4	1
Lost to Follow-up	0	0	0	0	2	0	0
Non-Responder	0	0	0	0	0	1	3
Withdrawal by Subject	0	0	0	0	1	2	0
Unsatisfactory Response per Investigator	0	0	0	0	14	11	4
[1] This arm is part of Phase 1 of the study.; [2] Participants who completed Phase 2 study

Baseline Characteristics

Arm/Group Title		ETN 50 QW + MTX (Phase 1)
Arm/Group Description		Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Baseline Participants		306
Baseline Analysis Population Description		A total of 306 participants were enrolled in the study (Phase 1). Out of the 306 participants, 193 were eligible and were randomized at a ratio of 1:1:1 to Phase 2 study. Of the 193 participants from Phase 2, a total of 131 participants were eligible and were randomized to Phase 3 study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	306 participants
		49.94 (13.70)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	306 participants
	Female	213 69.6%
	Male	93 30.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score
Description	Sustained remission was defined as a DAS28 <2.6 at the Week 76 and Week 91 visits without requiring a corticosteroid boost between the Week 52 and Week 64 visits, where the requirement for a corticosteroid boost was defined as a value of DAS28 >3.2 at either the Week 56 or Week 64 visit. DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity. The participants who met sustained remission in both Week 76 and 91 are presented here.
Time Frame	76 and 91 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all participants who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: Participants
	40	26	15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The rate of sustained remission was analyzed using a logistic regression model with a 2-sided significance level of 5%.
	Method	Regression, Logistic
	Comments	Values are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; 2.7 to 12.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0085
	Comments	The rate of sustained remission was analyzed using a logistic regression model with a 2-sided significance level of 5%.
	Method	Regression, Logistic
	Comments	Values are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.61
	Confidence Interval	(2-Sided) 95%; 1.3 to 5.3
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0397
	Comments	The rate of sustained remission was analyzed using a logistic regression model with a 2-sided significance level of 5%.
	Method	Regression, Linear
	Comments	Values are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.22
	Confidence Interval	(2-Sided) 95%; 1.0 to 4.8
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Number of Participants Achieving Complete Response (Using Disease Activity Score Based on 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)
Description	The composite measure of complete response over the last 3 months of Phase 1 was defined as: DAS28 <2.6 at the week 39 and 52 visits and,; No radiographic progression during Phase 1, defined as mean change in modified total Sharp score (mTSS) ≤0.5 and,; Health Assessment Questionnaire (HAQ) ≤ 0.5 at the week 39 and week 52 visits
Time Frame	End of Phase 1

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
	89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. End of Phase 1
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy
Description	mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time Frame	52 week and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: Units on a scale
Week 52 (N = 200)	0.3 (3.0)
Final on Therapy (N = 269)	0.4 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1183
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0286
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem
Description	WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 13 (N = 100)	-27.6 (27.4)
Week 26 (N = 94)	-32.2 (28.0)
Week 39 (N = 97)	-35.9 (27.0)
Week 52 (N = 81)	-37.3 (30.7)
Final on Therapy (N = 124)	-35.5 (31.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem
Description	WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 13 (N = 140)	-27.1 (27.8)
Week 26 (N = 138)	-31.5 (28.0)
Week 39 (N = 129)	-35.3 (27.3)
Week 52 (N = 116)	-36.6 (31.5)
Final on Therapy (N = 169)	-33.7 (30.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

6. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem
Description	WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 13 (N = 116)	-8.9 (34.5)
Week 26 (N = 110)	-8.8 (32.5)
Week 39 (N = 110)	-9.0 (30.7)
Week 52 (N = 93)	-12.9 (32.4)
Final on Therapy (N = 138)	-10.7 (35.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 13
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0063
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 26
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0053
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 39
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0027
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 52
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0002
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

7. Secondary Outcome

Title	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem
Description	WPAI:6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived:percentage of absenteeism, percentage of presenteeism (reduced productivity while at work),overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw scores (0-10) are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 13 (N = 244)	-30.3 (26.0)
Week 26 (N = 241)	-34.7 (27.5)
Week 39 (N = 224)	-39.9 (27.0)
Week 52 (N = 194)	-41.3 (28.6)
Final on Therapy (N = 270)	-36.4 (29.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

8. Secondary Outcome

Title	Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response
Description	ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	139
Week 4 (N = 295)	195
Week 8 (N = 290)	225
Week 13 (N = 280)	232
Week 26 (N = 272)	232
Week 39 (N = 256)	235
Week 52 (N = 221)	212
Final on Therapy (N = 301)	258

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

9. Secondary Outcome

Title	Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response
Description	ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	52
Week 4 (N = 295)	114
Week 8 (N = 290)	144
Week 13 (N = 280)	169
Week 26 (N = 272)	190
Week 39 (N = 256)	218
Week 52 (N = 221)	202
Final on Therapy (N = 301)	229

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 week and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

10. Secondary Outcome

Title	Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response
Description	ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	17
Week 4 (N = 295)	49
Week 8 (N = 290)	80
Week 13 (N = 280)	115
Week 26 (N = 272)	146
Week 39 (N = 256)	178
Week 52 (N = 221)	176
Final on Therapy (N = 301)	198

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

11. Secondary Outcome

Title	Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response
Description	ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	2
Week 4 (N = 295)	11
Week 8 (N = 290)	22
Week 13 (N = 280)	34
Week 26 (N = 272)	70
Week 39 (N = 256)	85
Week 52 (N = 221)	97
Final on Therapy (N = 301)	105

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

12. Secondary Outcome

Title	Change From Baseline in Physician's Global Assessment of Disease Activity
Description	Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: Units on a scale
Week 2 (N = 300)	-21.1 (18.2)
Week 4 (N = 299)	-29.9 (19.7)
Week 8 (N = 294)	-34.8 (19.9)
Week 13 (N = 284)	-38.7 (20.0)
Week 26 (N = 277)	-42.4 (18.9)
Week 39 (N = 260)	-46.5 (18.5)
Week 52 (N = 223)	-49.2 (17.2)
Final on Therapy (N = 305)	-45.0 (19.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 2, 4, 8, 13, 26, 39, 52 week and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

13. Secondary Outcome

Title	Change From Baseline in Participant's Global Assessment of Disease Activity
Description	Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 2 (N = 301)	-23.4 (24.4)
Week 4 (N = 299)	-27.4 (26.2)
Week 8 (N = 294)	-31.8 (26.0)
Week 13 (N = 285)	-34.6 (26.8)
Week 26 (N = 277)	-40.1 (28.1)
Week 39 (N = 260)	-44.8 (26.6)
Week 52 (N = 233)	-48.6 (26.2)
Final on Therapy (N = 305)	-42.8 (28.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

14. Secondary Outcome

Title	Change From Baseline in DAS44 Score at All Visits
Description	DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 <1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 2 (N = 297)	-1.3 (0.9)
Week 4 (N = 293)	-1.9 (1.1)
Week 8 (N = 293)	-2.3 (1.1)
Week 13 (N = 282)	-2.5 (1.2)
Week 26 (N = 276)	-2.9 (1.2)
Week 39 (N = 259)	-3.2 (1.2)
Week 52 (N = 221)	-3.4 (1.2)
Final on Therapy (N = 305)	-3.0 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Significance tests were based on paired t-tests using a 2-sided α=0.05. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Paired t-test
	Comments	[Not Specified]

15. Secondary Outcome

Title	Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission
Description	DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 <1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	13
Week 4 (N = 293)	48
Week 8 (N = 293)	81
Week 13 (N = 282)	95
Week 26 (N = 276)	142
Week 39 (N = 259)	174
Week 52 (N = 221)	193
Final on Therapy (N = 305)	211

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

16. Secondary Outcome

Title	Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity
Description	DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 <1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participant who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: participants
Week 2 (N = 297)	67
Week 4 (N = 293)	122
Week 8 (N = 293)	157
Week 13 (N = 282)	194
Week 26 (N = 276)	210
Week 39 (N = 259)	236
Week 52 (N = 221)	214
Final on Therapy (N = 305)	249

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	Binomial test-value tests the null hypothesis that the proportion is significantly different from 0. Week 2, 4, 8, 13, 26, 39, 52 week and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Binomial test
	Comments	[Not Specified]

17. Secondary Outcome

Title	Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit
Description	The PASS is defined as a symptom state that the participants consider acceptable.
Time Frame	2, 4, 8, 13, 26, 39, 52 weeks and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Efficacy data were analyzed in the modified intent-to-treat (mITT) population, which included all participants who took at least 1 dose of open-label investigational product

Arm/Group Title	ETN 50 QW + MTX (Phase 1)
Arm/Group Description:	Phase 1 was a 52-week open-label, single-arm period in which all subjects were treated with etanercept (ETN) 50 mg once weekly plus methotrexate (MTX). MTX starting dose was 10 mg per week and could increase by 5 mg per week increments up to Week 8, and up to a maximum of 25 mg per week. Participants with Disease Activity Score based on 28-joints count [DAS28] ≤3.2 at Week 39 and DAS28 <2.6 at Week 52 classified as a phase 1 responder, and will continue to Phase 2 study.
Overall Number of Participants Analyzed	306
Measure Type: Number; Unit of Measure: Participants
Week 2 (N = 297)	151
Week 4 (N = 292)	180
Week 8 (N = 288)	189
Week 13 (N = 279)	197
Week 26 (N = 268)	213
Week 39 (N = 257)	219
Week 52 (N = 220)	206
Final on Therapy (N = 305)	250

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ETN 50 QW + MTX (Phase 1)
	Comments	P-value is from McNemar's test for no change from baseline in response rate. Week 2, 4, 8, 13, 26, 39, 52 week and final on therapy
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	McNemar
	Comments	[Not Specified]

18. Secondary Outcome

Title	Number of Participants With an American College of Rheumatology 20% (ACR20) Response
Description	ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% 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 Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP).
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: participants
Week 52 (N = 63, 63, 65)	61	63	64
Week 56 (N = 63, 63, 63)	59	59	56
Week 64 (N = 62, 61, 62)	61	51	44
Week 76 (N = 60, 55, 46)	57	51	40
Week 91 (N = 57, 50, 38)	55	48	31
Final on Therapy (N = 63, 63, 65)	58	52	37

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4075
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.83
	Confidence Interval	(2-Sided) 95%; 0.4 to 7.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0011
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	8.88
	Confidence Interval	(2-Sided) 95%; 2.4 to 33.1
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0031
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.87
	Confidence Interval	(2-Sided) 95%; 1.7 to 13.9
	Estimation Comments	[Not Specified]

19. Secondary Outcome

Title	Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response
Description	ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: participants
Week 52 (N = 63, 63, 65)	58	61	62
Week 56 (N = 63, 63, 63)	55	58	48
Week 64 (N = 62, 61, 62)	59	47	33
Week 76 (N = 60, 55, 46)	54	48	33
Week 91 (N = 57, 50, 38)	48	45	29
Final on Therapy (N = 63, 63, 65)	50	47	32

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5951
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.3 to 2.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0934
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.19
	Confidence Interval	(2-Sided) 95%; 0.9 to 5.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0314
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.85
	Confidence Interval	(2-Sided) 95%; 1.1 to 7.4
	Estimation Comments	[Not Specified]

20. Secondary Outcome

Title	Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response
Description	ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: participants
Week 52 (N = 63, 63, 65)	52	56	52
Week 56 (N = 63, 63, 63)	46	51	37
Week 64 (N = 62, 61, 62)	49	42	24
Week 76 (N = 60, 55, 46)	47	41	25
Week 91 (N = 57, 50, 38)	44	39	25
Final on Therapy (N = 63, 63, 65)	46	39	26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6152
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.5 to 2.8
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0432
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.36
	Confidence Interval	(2-Sided) 95%; 1.0 to 5.4
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1189
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95%; 0.8 to 4.3
	Estimation Comments	[Not Specified]

21. Secondary Outcome

Title	Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response
Description	ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and 90% improvement in 3 of the following 5 criteria: 1) physician's global assessment of disease activity, 2) subject's assessment of disease activity, 3) subject's assessment of pain, 4) subject's assessment of functional disability via a health assessment questionnaire, and 5) C-reactive protein at each visit.
Time Frame	52, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: participants
Week 52 (N = 63, 63, 65)	32	31	25
Week 56 (N = 63, 63, 63)	32	31	20
Week 64 (N = 62, 61, 62)	29	22	11
Week 76 (N = 60, 55, 46)	25	18	13
Week 91 (N = 57, 50, 38)	30	19	12
Final on Therapy (N = 63, 63, 65)	31	19	12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0535
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 95%; 1.0 to 4.7
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0064
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.22
	Confidence Interval	(2-Sided) 95%; 1.4 to 7.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3696
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.6 to 3.6
	Estimation Comments	[Not Specified]

22. Secondary Outcome

Title	Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission
Description	DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 <1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: Participants
Week 52 (N = 63, 65, 65)	60	62	60
Week 56 (N = 63, 65, 63)	52	52	47
Week 64 (N = 62, 63, 60)	54	44	25
Week 76 (N = 60, 57, 46)	51	42	24
Week 91 (N = 57, 52, 38)	48	39	23
Final on Therapy (N = 63, 65, 65)	51	40	24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0788
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.17
	Confidence Interval	(2-Sided) 95%; 0.9 to 5.2
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0007
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.57
	Confidence Interval	(2-Sided) 95%; 1.9 to 11.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0676
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.10
	Confidence Interval	(2-Sided) 95%; 0.9 to 4.7
	Estimation Comments	[Not Specified]

23. Secondary Outcome

Title	Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity
Description	DAS44 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 44 joints count, the erythrocyte sedimentation rate (ESR) (millimeters per hour [mm/hour]) and patient's global assessment (PGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). DAS44 <1.6 = clinical remission, DAS44 ≤2.4 = low disease activity.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: Participants
Week 52 (N = 63, 65, 65)	63	65	65
Week 56 (N = 63, 65, 63)	62	60	54
Week 64 (N = 62, 63, 60)	61	52	38
Week 76 (N = 60, 57, 46)	57	54	37
Week 91 (N = 57, 52, 38)	56	47	33
Final on Therapy (N = 63, 65, 65)	60	50	35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0548
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	7.56
	Confidence Interval	(2-Sided) 95%; 1.0 to 59.5
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0166
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	12.18
	Confidence Interval	(2-Sided) 95%; 1.6 to 94.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3619
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Odds ratios and p-values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.6 to 4.5
	Estimation Comments	[Not Specified]

24. Secondary Outcome

Title	Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)
Description	The composite measure of complete response over the last 3 months of Phase 2 was defined as: DAS28 <2.6 at the Week 76 and Week 91 visits and; No radiographic progression during Phase 2, defined as mean change from Week 52 in mTSS of ≤0.5.; Participant must achieve HAQ score ≤0.5 at Week 76 and 91 visits. HAQ is self-reported, valid assessment of functional disability in rheumatoid arthritis. Assessed based on ability of participants to perform daily activities in 8 categories: dressing, arising, eating, walking, reaching, gripping, hygiene, and carrying out daily activities. HAQ score range: 0-3: without any difficulty=0, with some difficulty=1, with much difficulty=2, unable to do=3. HAQ total scores expressed as overall mean score with range 0-3: 0-0.25=normal functioning; 0.25-0.5=mild functional limitation; 0.5-1=moderate functional limitation; more than 1=significant functional limitation.A subject had to satisfy all 3 criteria at thevisits to be defined as a responder
Time Frame	52 and 91 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe.Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study.The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 = DAS28 = 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe.All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe.Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 = DAS28 = 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: Participants
	36	19	7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0017
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Odds ratios, p-values, and 95% CIs are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.23
	Confidence Interval	(2-Sided) 95%; 1.6 to 6.7
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Odds ratios, p-values, and 95% CIs are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	11.05
	Confidence Interval	(2-Sided) 95%; 4.4 to 28.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0111
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Odds ratios, p-values, and 95% CIs are based on a logistic regression model with treatment as the only factor.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.42
	Confidence Interval	(2-Sided) 95%; 1.3 to 8.8
	Estimation Comments	[Not Specified]

25. Secondary Outcome

Title	Physician's Global Assessment of Disease Activity
Description	Physician Global Assessment of Disease Activity was measured on a 0 to 100 Visual Analog Scale (VAS), with 0 = no disease activity and 100 = extreme disease activity.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Mean (Standard Deviation); Unit of Measure: Units on a scale
Week 52 (N = 63, 65, 65)	5.0 (5.3)	4.2 (4.9)	6.3 (8.0)
Week 56 (N = 63, 65, 65)	5.5 (6.2)	7.7 (12.6)	12.2 (15.1)
Week 64 (N = 62, 63, 62)	6.0 (7.4)	11.6 (16.7)	23.6 (26.0)
Week 76 (N = 60, 57, 46)	5.5 (7.1)	9.0 (13.6)	14.6 (18.1)
Week 91 (N = 57, 52, 38)	5.8 (9.8)	10.3 (16.8)	15.9 (21.7)
Final on Therapy (N = 63, 65, 65)	6.9 (10.8)	16.7 (21.7)	30.7 (28.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0328
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.66
	Confidence Interval	(2-Sided) 95%; -16.6 to -0.7
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.64
	Confidence Interval	(2-Sided) 95%; -30.1 to -13.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0035
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.98
	Confidence Interval	(2-Sided) 95%; -21.5 to -4.5
	Estimation Comments	[Not Specified]

26. Secondary Outcome

Title	Participant's Global Assessment of Disease Activity
Description	Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no disease activity and 100 = extreme disease activity
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Mean (Standard Deviation); Unit of Measure: Units on a scale
Week 52 (N = 63, 65, 65)	5.8 (6.3)	5.7 (7.7)	9.3 (14.1)
Week 56 (N = 63, 65, 65)	10.3 (14.8)	9.7 (16.3)	17.3 (22.1)
Week 64 (N = 62, 63, 62)	7.6 (9.1)	17.8 (25.5)	31.0 (31.4)
Week 76 (N = 60, 56, 46)	8.9 (12.1)	11.7 (17.9)	18.3 (18.7)
Week 91 (N = 56, 52, 38)	9.6 (14.1)	12.3 (17.5)	18.8 (25.7)
Final on Therapy (N = 63, 65, 65)	11.1 (16.2)	20.7 (25.9)	37.1 (33.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2473
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.36
	Confidence Interval	(2-Sided) 95%; -11.8 to 3.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0016
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.19
	Confidence Interval	(2-Sided) 95%; -21.3 to -5.1
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0348
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.83
	Confidence Interval	(2-Sided) 95%; -17.0 to -0.6
	Estimation Comments	[Not Specified]

27. Secondary Outcome

Title	Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS)
Description	100-mm line (Visual Analog Scale) marked by the participant to measure their degree of pain over past 2-3 weeks. Range: 0 = no pain to 100 = pain as bad as it could be.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Mean (Standard Deviation); Unit of Measure: mm
Week 52 (N = 63, 65, 65)	7.3 (7.7)	6.9 (8.6)	9.9 (14.8)
Week 56 (N = 63, 65, 65)	10.9 (15.0)	10.2 (16.9)	18.8 (23.1)
Week 64 (N = 62, 63, 62)	8.0 (9.8)	18.0 (25.1)	31.7 (31.3)
Week 76 (N = 60, 56, 46)	9.8 (12.9)	12.3 (19.2)	17.6 (18.1)
Week 91 (N = 57, 52, 38)	9.5 (12.7)	13.3 (16.4)	19.7 (26.1)
Final on Therapy (N = 63, 65, 65)	11.4 (15.4)	21.4 (24.8)	37.8 (33.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1248
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.51
	Confidence Interval	(2-Sided) 95%; -12.6 to 1.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.14
	Confidence Interval	(2-Sided) 95%; -21.8 to -6.5
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0306
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for Week 52 value, treatment, visit, and interaction of treatment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.63
	Confidence Interval	(2-Sided) 95%; -16.4 to -0.8
	Estimation Comments	[Not Specified]

28. Secondary Outcome

Title	Number of Participants Achieving Patient Acceptable Symptom State (PASS)
Description	The PASS is defined as a symptom state that the subjects consider acceptable.
Time Frame	52, 56, 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Measure Type: Number; Unit of Measure: Participants
Week 52 (N = 61, 65, 64)	57	64	61
Week 56 (N = 63, 63, 64)	57	58	53
Week 64 (N = 61, 60, 60)	58	51	42
Week 76 (N = 60, 56, 45)	57	48	38
Week 91 (N = 57, 52, 38)	52	46	33
Final on Therapy (N = 63, 65, 65)	56	50	38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4717
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 0.5 to 4.6
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0551
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.77
	Confidence Interval	(2-Sided) 95%; 1.0 to 7.8
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2141
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a longitudinal statistical model with factors for treatment, visit, and interaction of treatment and visit.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; 0.7 to 4.8
	Estimation Comments	[Not Specified]

29. Secondary Outcome

Title	Modified Total Sharp Score (mTSS) at Week 52
Description	mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	58	56	49
Mean (Standard Deviation); Unit of Measure: Units on a scale
	8.4 (13.5)	8.4 (15.1)	8.6 (12.8)

30. Secondary Outcome

Title	Change From Baseline mTSS at Week 91 and Final on Therapy
Description	mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time Frame	91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 91 (N = 51, 45, 30)	0.0 (0.16)	0.0 (0.17)	0.5 (0.21)
Final on Therapy (N = 58, 56, 49)	0.1 (0.14)	-0.0 (0.15)	0.4 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9652
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	P-values for between-treatment comparisons are based on ANCOVA on ranks of change in score with ranks of Week 52 value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.4
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2168
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	P-values for between-treatment comparisons are based on ANCOVA on ranks of change in score with ranks of Week 52 value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2131
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	P-values for between-treatment comparisons are based on ANCOVA on ranks of change in score with ranks of Week 52 value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.0
	Estimation Comments	[Not Specified]

31. Secondary Outcome

Title	Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	29	43	25
Mean (Standard Deviation); Unit of Measure: units on a scale
	0.2 (1.2)	0.1 (0.6)	0.0 (0.0)

32. Secondary Outcome

Title	Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem
Description	WPAI is a 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 64 (N = 30, 44, 26)	1.9 (2.78)	2.6 (2.29)	6.1 (3.04)
Week 76 (N = 28, 33, 18)	-0.1 (2.38)	2.9 (2.19)	2.6 (3.09)
Week 91 (N = 29, 32, 14)	4.4 (3.78)	4.0 (3.63)	7.0 (5.79)
Final on Therapy (N = 34, 48, 29)	3.6 (3.65)	5.3 (3.07)	10.2 (4.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hyothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9338
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.44
	Confidence Interval	(2-Sided) 95%; -10.0 to 10.9
	Estimation Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7130
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.55
	Confidence Interval	(2-Sided) 95%; -16.4 to 11.2
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6628
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.99
	Confidence Interval	(2-Sided) 95%; -16.6 to 10.6
	Estimation Comments	[Not Specified]

33. Secondary Outcome

Title	WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	63	65	65
Mean (Standard Deviation); Unit of Measure: units on a scale
	6.2 (9.2)	8.9 (15.5)	14.2 (17.9)

34. Secondary Outcome

Title	Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 64 (N = 37, 49, 31)	-2.5 (3.57)	9.6 (3.16)	18.2 (3.96)
Week 76 (N = 38, 38, 23)	-0.6 (2.16)	2.3 (2.01)	12.2 (2.54)
Week 91 (N = 37, 35, 18)	1.8 (3.16)	8.6 (3.06)	18.4 (4.23)
Final on Therapy (N = 45, 50, 40)	1.1 (3.51)	11.1 (3.10)	19.9 (3.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1303
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.74
	Confidence Interval	(2-Sided) 95%; -15.5 to 2.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0024
	Comments	[Not Specified]
	Method	Longitudinal statisitical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.59
	Confidence Interval	(2-Sided) 95%; -27.1 to -6.0
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0621
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.85
	Confidence Interval	(2-Sided) 95%; -20.2 to 0.5
	Estimation Comments	[Not Specified]

35. Secondary Outcome

Title	WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	27	42	24
Mean (Standard Deviation); Unit of Measure: units on a scale
	5.3 (9.8)	6.7 (15.0)	9.2 (12.8)

36. Secondary Outcome

Title	Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 64 (N = 29, 43, 25)	0.1 (4.49)	11.5 (3.75)	22.4 (2.01)
Week 76 (N = 27, 30, 18)	-0.9 (2.40)	2.6 (2.18)	16.6 (2.95)
Week 91 (N = 28, 30, 13)	5.4 (3.98)	9.5 (3.74)	22.0 (5.75)
Final on Therapy (N = 34, 48, 28)	4.4 (4.32)	13.3 (3.60)	25.1 (4.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4664
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.01
	Confidence Interval	(2-Sided) 95%; -15.0 to 6.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0210
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.57
	Confidence Interval	(2-Sided) 95%; -30.6 to -2.6
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0713
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.56
	Confidence Interval	(2-Sided) 95%; -26.2 to 1.1
	Estimation Comments	[Not Specified]

37. Secondary Outcome

Title	WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire to determine the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Four scores are derived: percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment score that combined absenteeism and presenteeism and percentage of impairment in activities performed outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores indicated greater impairment and less productivity. The raw (0-10) scores are converted to percents (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study
Overall Number of Participants Analyzed	56	60	60
Mean (Standard Deviation); Unit of Measure: Units on a scale
	8.6 (11.0)	10.0 (15.9)	16.8 (20.0)

38. Secondary Outcome

Title	Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem
Description	WPAI: 6 question participant rated questionnaire determined the degree to which rheumatoid arthritis affected work productivity while at work and affected activities outside of work. Scores scaled as 0 (not affected/no impairment) to 10 (completely affected/impaired). Higher scores = greater impairment and less productivity. The raw (0-10) scores were converted to percent (the variable is named "Percent impairment While Working") and as such range from 0 to 100.
Time Frame	64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat (mITT) population, which included all subjects who had taken at least 1 dose of double-blind investigational product and had at least 1 post-randomization DAS28 evaluation.

Arm/Group Title	E25 + MTX (Phase 2)	MTX + PBO (Phase 2)	Placebo (PBO) (Phase 2)
Arm/Group Description:	In Phase 2 E25 + MTX arm, Etanercept 25 milligram (mg) was administered once weekly as a subcutaneous injection using the 25 mg pre filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 MTX + PBO arm, the weekly dose of etanercept was tapered from the 50 mg dosage. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept matching placebo injection using a pre-filled syringe. Methotrexate was administered once weekly as oral capsules. All subjects received a dose of methotrexate during this Phase 2 study that was equal to their optimal methotrexate dose in earlier Phase 1 study. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.	In Phase 2 Placebo (PBO) arm, the weekly dose of etanercept was tapered from the 50 mg dosage to a placebo injection. At Week 52, subjects assigned to this arm received a double blinded 25 mg dose of etanercept as a subcutaneous injection using a pre filled syringe. All weekly doses thereafter (ie, Weeks 53 to 90) were administered as an etanercept-matching placebo injection using a pre-filled syringe. Methotrexate-matching placebo was administered once weekly as oral capsules. The subjects received the study treatment for 39 weeks, unless the subject was evaluated as non-responder at Week 64 or Week 76 and discontinued the study. Participants in sustained remission (Disease Activity Score based on 28-joints count [DAS28] <2.6) or with low disease activity (2.6 ≤ DAS28 ≤ 3.2) at Week 91 were classified as Phase 2 responder, and will continue to Phase 3 study.
Overall Number of Participants Analyzed	63	65	65
Least Squares Mean (Standard Error); Unit of Measure: Units on a scale
Week 64 (N = 56, 60, 57)	-0.5 (3.21)	9.9 (3.10)	19.1 (3.18)
Week 76 (N = 57, 55, 41)	2.9 (2.94)	7.1 (2.96)	13.9 (3.35)
Week 91 (N = 53, 49, 37)	-1.8 (2.83)	7.3 (2.87)	17.9 (3.20)
Final on Therapy (N = 60, 64, 64)	-0.9 (3.24)	12.2 (3.13)	24.2 (3.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), MTX + PBO (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0256
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.11
	Confidence Interval	(2-Sided) 95%; -17.1 to -1.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	E25 + MTX (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.62
	Confidence Interval	(2-Sided) 95%; -28.1 to -11.1
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	MTX + PBO (Phase 2), Placebo (PBO) (Phase 2)
	Comments	Change from Week 52 to Week 91. The hypothesis of primary interest was the superiority of E25+MTX compared with PBO.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0161
	Comments	[Not Specified]
	Method	Longitudinal statistical model
	Comments	Values are based on a model with factors for Week 52 value, treatment, visit, and interaction of treatment and Week 52 value and treatment and visit.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.51
	Confidence Interval	(2-Sided) 95%; -19.0 to -2.0
	Estimation Comments