Trial Outcomes & Findings for Study Evaluating Etanercept Plus Methotrexate in Early Rheumatoid Arthritis (NCT NCT00913458)

Last Updated: 2014-07-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

306 participants

Primary outcome timeframe

76 and 91 weeks

Results posted on

2014-07-17

Participant Flow

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

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

Participant milestones

Participant milestones
Measure	ETN 50 QW + MTX (Phase 1) 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.	E25 + MTX (Phase 2) 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.	E25+MTX (Phase 3) 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.	MTX (Phase 3) 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.	Placebo (PBO) (Phase 3) 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 1 STARTED	306	0	0	0	0	0	0
Phase 1 COMPLETED	194	0	0	0	0	0	0
Phase 1 NOT COMPLETED	112	0	0	0	0	0	0
Phase 2 STARTED	0	63	65	65	0	0	0
Phase 2 COMPLETED	0	53	46	32	0	0	0
Phase 2 NOT COMPLETED	0	10	19	33	0	0	0
Phase 3 STARTED	0	0	0	0	53	46	32
Phase 3 COMPLETED	0	0	0	0	31	28	24
Phase 3 NOT COMPLETED	0	0	0	0	22	18	8

Reasons for withdrawal

Reasons for withdrawal
Measure	ETN 50 QW + MTX (Phase 1) 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.	E25 + MTX (Phase 2) 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.	E25+MTX (Phase 3) 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.	MTX (Phase 3) 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.	Placebo (PBO) (Phase 3) 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 1 Non-Responder	54	0	0	0	0	0	0
Phase 1 Subject Request	17	0	0	0	0	0	0
Phase 1 Adverse Event	20	0	0	0	0	0	0
Phase 1 Lost to Follow-up	2	0	0	0	0	0	0
Phase 1 Protocol Violation	10	0	0	0	0	0	0
Phase 1 Sponsor	2	0	0	0	0	0	0
Phase 1 Unsatisfactory Response per Investigator	7	0	0	0	0	0	0
Phase 2 Non-Responder	0	5	7	12	0	0	0
Phase 2 Subject Request	0	0	1	2	0	0	0
Phase 2 Adverse Event	0	3	0	1	0	0	0
Phase 2 Lost to Follow-up	0	0	0	1	0	0	0
Phase 2 Protocol Violation	0	2	0	0	0	0	0
Phase 2 Unsatisfactory Response per Investigator	0	0	11	17	0	0	0
Phase 3 Adverse Event	0	0	0	0	5	4	1
Phase 3 Lost to Follow-up	0	0	0	0	2	0	0
Phase 3 Non-Responder	0	0	0	0	0	1	3
Phase 3 Withdrawal by Subject	0	0	0	0	1	2	0
Phase 3 Unsatisfactory Response per Investigator	0	0	0	0	14	11	4

Baseline Characteristics

Study Evaluating Etanercept Plus Methotrexate in Early Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ETN 50 QW + MTX (Phase 1) n=306 Participants 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.
Age, Continuous	49.94 Years STANDARD_DEVIATION 13.70 • n=5 Participants
Sex: Female, Male Female	213 Participants n=5 Participants
Sex: Female, Male Male	93 Participants n=5 Participants

PRIMARY outcome

Timeframe: 76 and 91 weeks

Population: 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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants That Met Sustained Remission at Week 76 and Week 91 Based on DAS28 Score	40 Participants	26 Participants	15 Participants

SECONDARY outcome

Timeframe: End of Phase 1

Population: 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

The composite measure of complete response over the last 3 months of Phase 1 was defined as: 1. DAS28 \<2.6 at the week 39 and 52 visits and, 2. No radiographic progression during Phase 1, defined as mean change in modified total Sharp score (mTSS) ≤0.5 and, 3. Health Assessment Questionnaire (HAQ) ≤ 0.5 at the week 39 and week 52 visits

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants Achieving Complete Response (Using Disease Activity Score Based on 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)	89 Participants	—	—

SECONDARY outcome

Timeframe: 52 week and Final on Therapy (includes all visits for a participant up to Week 52 or the visit they discontinued at)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy Week 52 (N = 200)	0.3 Units on a scale Standard Deviation 3.0	—	—
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52 and Final on Therapy Final on Therapy (N = 269)	0.4 Units on a scale Standard Deviation 2.8	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem Week 13 (N = 100)	-27.6 units on a scale Standard Deviation 27.4	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem Week 26 (N = 94)	-32.2 units on a scale Standard Deviation 28.0	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem Week 39 (N = 97)	-35.9 units on a scale Standard Deviation 27.0	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem Week 52 (N = 81)	-37.3 units on a scale Standard Deviation 30.7	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Overall Work Impairment Due to Problem Final on Therapy (N = 124)	-35.5 units on a scale Standard Deviation 31.3	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem Week 13 (N = 140)	-27.1 units on a scale Standard Deviation 27.8	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem Week 26 (N = 138)	-31.5 units on a scale Standard Deviation 28.0	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem Week 39 (N = 129)	-35.3 units on a scale Standard Deviation 27.3	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem Week 52 (N = 116)	-36.6 units on a scale Standard Deviation 31.5	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Impairment While Working Due to Problem Final on Therapy (N = 169)	-33.7 units on a scale Standard Deviation 30.3	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem Week 13 (N = 116)	-8.9 units on a scale Standard Deviation 34.5	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem Week 26 (N = 110)	-8.8 units on a scale Standard Deviation 32.5	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem Week 39 (N = 110)	-9.0 units on a scale Standard Deviation 30.7	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem Week 52 (N = 93)	-12.9 units on a scale Standard Deviation 32.4	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed Due to Problem Final on Therapy (N = 138)	-10.7 units on a scale Standard Deviation 35.3	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem Week 13 (N = 244)	-30.3 units on a scale Standard Deviation 26.0	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem Week 26 (N = 241)	-34.7 units on a scale Standard Deviation 27.5	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem Week 39 (N = 224)	-39.9 units on a scale Standard Deviation 27.0	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem Week 52 (N = 194)	-41.3 units on a scale Standard Deviation 28.6	—	—
Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Activity Impairment Due to Problem Final on Therapy (N = 270)	-36.4 units on a scale Standard Deviation 29.4	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 8 (N = 290)	225 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 2 (N = 297)	139 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 4 (N = 295)	195 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 13 (N = 280)	232 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 26 (N = 272)	232 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 39 (N = 256)	235 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Week 52 (N = 221)	212 Participants	—	—
Number of Participants Achieving American College of Rhematology 20% (ACR 20) Response Final on Therapy (N = 301)	258 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 2 (N = 297)	52 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 4 (N = 295)	114 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 8 (N = 290)	144 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 13 (N = 280)	169 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 26 (N = 272)	190 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 39 (N = 256)	218 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Week 52 (N = 221)	202 Participants	—	—
Number of Participants Achieving American College of Rhematology 50% (ACR 50) Response Final on Therapy (N = 301)	229 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 2 (N = 297)	17 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 4 (N = 295)	49 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 8 (N = 290)	80 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 13 (N = 280)	115 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 26 (N = 272)	146 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 39 (N = 256)	178 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Week 52 (N = 221)	176 Participants	—	—
Number of Participants Achieving American College of Rhematology 70% (ACR 70) Response Final on Therapy (N = 301)	198 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 8 (N = 290)	22 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 13 (N = 280)	34 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 26 (N = 272)	70 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 39 (N = 256)	85 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 52 (N = 221)	97 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Final on Therapy (N = 301)	105 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 2 (N = 297)	2 Participants	—	—
Number of Participants Achieving American College of Rhematology 90% (ACR 90) Response Week 4 (N = 295)	11 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Physician's Global Assessment of Disease Activity Week 2 (N = 300)	-21.1 Units on a scale Standard Deviation 18.2	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 4 (N = 299)	-29.9 Units on a scale Standard Deviation 19.7	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 8 (N = 294)	-34.8 Units on a scale Standard Deviation 19.9	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 13 (N = 284)	-38.7 Units on a scale Standard Deviation 20.0	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 26 (N = 277)	-42.4 Units on a scale Standard Deviation 18.9	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 39 (N = 260)	-46.5 Units on a scale Standard Deviation 18.5	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Week 52 (N = 223)	-49.2 Units on a scale Standard Deviation 17.2	—	—
Change From Baseline in Physician's Global Assessment of Disease Activity Final on Therapy (N = 305)	-45.0 Units on a scale Standard Deviation 19.8	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in Participant's Global Assessment of Disease Activity Week 2 (N = 301)	-23.4 units on a scale Standard Deviation 24.4	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 4 (N = 299)	-27.4 units on a scale Standard Deviation 26.2	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 8 (N = 294)	-31.8 units on a scale Standard Deviation 26.0	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 26 (N = 277)	-40.1 units on a scale Standard Deviation 28.1	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 39 (N = 260)	-44.8 units on a scale Standard Deviation 26.6	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 52 (N = 233)	-48.6 units on a scale Standard Deviation 26.2	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Final on Therapy (N = 305)	-42.8 units on a scale Standard Deviation 28.4	—	—
Change From Baseline in Participant's Global Assessment of Disease Activity Week 13 (N = 285)	-34.6 units on a scale Standard Deviation 26.8	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Change From Baseline in DAS44 Score at All Visits Week 2 (N = 297)	-1.3 units on a scale Standard Deviation 0.9	—	—
Change From Baseline in DAS44 Score at All Visits Week 4 (N = 293)	-1.9 units on a scale Standard Deviation 1.1	—	—
Change From Baseline in DAS44 Score at All Visits Week 8 (N = 293)	-2.3 units on a scale Standard Deviation 1.1	—	—
Change From Baseline in DAS44 Score at All Visits Week 13 (N = 282)	-2.5 units on a scale Standard Deviation 1.2	—	—
Change From Baseline in DAS44 Score at All Visits Week 26 (N = 276)	-2.9 units on a scale Standard Deviation 1.2	—	—
Change From Baseline in DAS44 Score at All Visits Week 39 (N = 259)	-3.2 units on a scale Standard Deviation 1.2	—	—
Change From Baseline in DAS44 Score at All Visits Week 52 (N = 221)	-3.4 units on a scale Standard Deviation 1.2	—	—
Change From Baseline in DAS44 Score at All Visits Final on Therapy (N = 305)	-3.0 units on a scale Standard Deviation 1.3	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 2 (N = 297)	13 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 4 (N = 293)	48 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 8 (N = 293)	81 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 13 (N = 282)	95 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 26 (N = 276)	142 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 39 (N = 259)	174 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Week 52 (N = 221)	193 Participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44)-Remission Final on Therapy (N = 305)	211 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 52 (N = 221)	214 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Final on Therapy (N = 305)	249 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 4 (N = 293)	122 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 8 (N = 293)	157 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 13 (N = 282)	194 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 26 (N = 276)	210 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 39 (N = 259)	236 participants	—	—
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 2 (N = 297)	67 participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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

The PASS is defined as a symptom state that the participants consider acceptable.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=306 Participants 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.	MTX + PBO (Phase 2) 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.	Placebo (PBO) (Phase 2) 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.
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 2 (N = 297)	151 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 4 (N = 292)	180 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 8 (N = 288)	189 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 13 (N = 279)	197 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 26 (N = 268)	213 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 39 (N = 257)	219 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Week 52 (N = 220)	206 Participants	—	—
Proportion of Subjects Achieving a Patient Acceptable Symptom State (PASS) at Each Visit Final on Therapy (N = 305)	250 Participants	—	—

SECONDARY outcome

Timeframe: 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)

Population: 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.

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).

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Week 56 (N = 63, 63, 63)	59 participants	59 participants	56 participants
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Week 64 (N = 62, 61, 62)	61 participants	51 participants	44 participants
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Week 76 (N = 60, 55, 46)	57 participants	51 participants	40 participants
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Week 91 (N = 57, 50, 38)	55 participants	48 participants	31 participants
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Final on Therapy (N = 63, 63, 65)	58 participants	52 participants	37 participants
Number of Participants With an American College of Rheumatology 20% (ACR20) Response Week 52 (N = 63, 63, 65)	61 participants	63 participants	64 participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Week 52 (N = 63, 63, 65)	58 participants	61 participants	62 participants
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Week 56 (N = 63, 63, 63)	55 participants	58 participants	48 participants
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Week 64 (N = 62, 61, 62)	59 participants	47 participants	33 participants
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Week 76 (N = 60, 55, 46)	54 participants	48 participants	33 participants
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Week 91 (N = 57, 50, 38)	48 participants	45 participants	29 participants
Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response Final on Therapy (N = 63, 63, 65)	50 participants	47 participants	32 participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Week 52 (N = 63, 63, 65)	52 participants	56 participants	52 participants
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Week 56 (N = 63, 63, 63)	46 participants	51 participants	37 participants
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Week 64 (N = 62, 61, 62)	49 participants	42 participants	24 participants
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Week 76 (N = 60, 55, 46)	47 participants	41 participants	25 participants
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Week 91 (N = 57, 50, 38)	44 participants	39 participants	25 participants
Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response Final on Therapy (N = 63, 63, 65)	46 participants	39 participants	26 participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Week 52 (N = 63, 63, 65)	32 participants	31 participants	25 participants
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Week 56 (N = 63, 63, 63)	32 participants	31 participants	20 participants
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Week 64 (N = 62, 61, 62)	29 participants	22 participants	11 participants
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Week 76 (N = 60, 55, 46)	25 participants	18 participants	13 participants
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Week 91 (N = 57, 50, 38)	30 participants	19 participants	12 participants
Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response Final on Therapy (N = 63, 63, 65)	31 participants	19 participants	12 participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Week 52 (N = 63, 65, 65)	60 Participants	62 Participants	60 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Week 56 (N = 63, 65, 63)	52 Participants	52 Participants	47 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Week 64 (N = 62, 63, 60)	54 Participants	44 Participants	25 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Week 76 (N = 60, 57, 46)	51 Participants	42 Participants	24 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Week 91 (N = 57, 52, 38)	48 Participants	39 Participants	23 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) Remission Final on Therapy (N = 63, 65, 65)	51 Participants	40 Participants	24 Participants

SECONDARY outcome

Timeframe: 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 measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 52 (N = 63, 65, 65)	63 Participants	65 Participants	65 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 56 (N = 63, 65, 63)	62 Participants	60 Participants	54 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 64 (N = 62, 63, 60)	61 Participants	52 Participants	38 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 76 (N = 60, 57, 46)	57 Participants	54 Participants	37 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Week 91 (N = 57, 52, 38)	56 Participants	47 Participants	33 Participants
Number of Participants With Disease Activity Score Based on 44-joints Count (DAS44) - Low Disease Activity Final on Therapy (N = 63, 65, 65)	60 Participants	50 Participants	35 Participants

SECONDARY outcome

Timeframe: 52 and 91 weeks

The composite measure of complete response over the last 3 months of Phase 2 was defined as: 1. DAS28 \<2.6 at the Week 76 and Week 91 visits and 2. No radiographic progression during Phase 2, defined as mean change from Week 52 in mTSS of ≤0.5. 3. 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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants Achieving Complete Response (Using Disease Activity Score Based on a 28-joint Count, Modified Total Sharp Score, Health Assessment Questionnaire)	36 Participants	19 Participants	7 Participants

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Physician's Global Assessment of Disease Activity Week 52 (N = 63, 65, 65)	5.0 Units on a scale Standard Deviation 5.3	4.2 Units on a scale Standard Deviation 4.9	6.3 Units on a scale Standard Deviation 8.0
Physician's Global Assessment of Disease Activity Week 56 (N = 63, 65, 65)	5.5 Units on a scale Standard Deviation 6.2	7.7 Units on a scale Standard Deviation 12.6	12.2 Units on a scale Standard Deviation 15.1
Physician's Global Assessment of Disease Activity Week 64 (N = 62, 63, 62)	6.0 Units on a scale Standard Deviation 7.4	11.6 Units on a scale Standard Deviation 16.7	23.6 Units on a scale Standard Deviation 26.0
Physician's Global Assessment of Disease Activity Week 76 (N = 60, 57, 46)	5.5 Units on a scale Standard Deviation 7.1	9.0 Units on a scale Standard Deviation 13.6	14.6 Units on a scale Standard Deviation 18.1
Physician's Global Assessment of Disease Activity Week 91 (N = 57, 52, 38)	5.8 Units on a scale Standard Deviation 9.8	10.3 Units on a scale Standard Deviation 16.8	15.9 Units on a scale Standard Deviation 21.7
Physician's Global Assessment of Disease Activity Final on Therapy (N = 63, 65, 65)	6.9 Units on a scale Standard Deviation 10.8	16.7 Units on a scale Standard Deviation 21.7	30.7 Units on a scale Standard Deviation 28.4

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Participant's Global Assessment of Disease Activity Week 52 (N = 63, 65, 65)	5.8 Units on a scale Standard Deviation 6.3	5.7 Units on a scale Standard Deviation 7.7	9.3 Units on a scale Standard Deviation 14.1
Participant's Global Assessment of Disease Activity Week 56 (N = 63, 65, 65)	10.3 Units on a scale Standard Deviation 14.8	9.7 Units on a scale Standard Deviation 16.3	17.3 Units on a scale Standard Deviation 22.1
Participant's Global Assessment of Disease Activity Week 64 (N = 62, 63, 62)	7.6 Units on a scale Standard Deviation 9.1	17.8 Units on a scale Standard Deviation 25.5	31.0 Units on a scale Standard Deviation 31.4
Participant's Global Assessment of Disease Activity Week 76 (N = 60, 56, 46)	8.9 Units on a scale Standard Deviation 12.1	11.7 Units on a scale Standard Deviation 17.9	18.3 Units on a scale Standard Deviation 18.7
Participant's Global Assessment of Disease Activity Week 91 (N = 56, 52, 38)	9.6 Units on a scale Standard Deviation 14.1	12.3 Units on a scale Standard Deviation 17.5	18.8 Units on a scale Standard Deviation 25.7
Participant's Global Assessment of Disease Activity Final on Therapy (N = 63, 65, 65)	11.1 Units on a scale Standard Deviation 16.2	20.7 Units on a scale Standard Deviation 25.9	37.1 Units on a scale Standard Deviation 33.9

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Week 91 (N = 57, 52, 38)	9.5 mm Standard Deviation 12.7	13.3 mm Standard Deviation 16.4	19.7 mm Standard Deviation 26.1
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Final on Therapy (N = 63, 65, 65)	11.4 mm Standard Deviation 15.4	21.4 mm Standard Deviation 24.8	37.8 mm Standard Deviation 33.7
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Week 52 (N = 63, 65, 65)	7.3 mm Standard Deviation 7.7	6.9 mm Standard Deviation 8.6	9.9 mm Standard Deviation 14.8
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Week 56 (N = 63, 65, 65)	10.9 mm Standard Deviation 15.0	10.2 mm Standard Deviation 16.9	18.8 mm Standard Deviation 23.1
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Week 64 (N = 62, 63, 62)	8.0 mm Standard Deviation 9.8	18.0 mm Standard Deviation 25.1	31.7 mm Standard Deviation 31.3
Participant's Global Assessment of Pain (Visual Analogue Scale) (VAS) Week 76 (N = 60, 56, 46)	9.8 mm Standard Deviation 12.9	12.3 mm Standard Deviation 19.2	17.6 mm Standard Deviation 18.1

SECONDARY outcome

Timeframe: 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)

The PASS is defined as a symptom state that the subjects consider acceptable.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Week 64 (N = 61, 60, 60)	58 Participants	51 Participants	42 Participants
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Week 52 (N = 61, 65, 64)	57 Participants	64 Participants	61 Participants
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Week 56 (N = 63, 63, 64)	57 Participants	58 Participants	53 Participants
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Week 76 (N = 60, 56, 45)	57 Participants	48 Participants	38 Participants
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Week 91 (N = 57, 52, 38)	52 Participants	46 Participants	33 Participants
Number of Participants Achieving Patient Acceptable Symptom State (PASS) Final on Therapy (N = 63, 65, 65)	56 Participants	50 Participants	38 Participants

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=58 Participants 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.	MTX + PBO (Phase 2) n=56 Participants 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.	Placebo (PBO) (Phase 2) n=49 Participants 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.
Modified Total Sharp Score (mTSS) at Week 52	8.4 Units on a scale Standard Deviation 13.5	8.4 Units on a scale Standard Deviation 15.1	8.6 Units on a scale Standard Deviation 12.8

SECONDARY outcome

Timeframe: 91 weeks and Final on Therapy (includes all visits for a participant up to Week 91 or the visit they discontinued at)

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Change From Baseline mTSS at Week 91 and Final on Therapy Week 91 (N = 51, 45, 30)	0.0 Units on a scale Standard Error 0.16	0.0 Units on a scale Standard Error 0.17	0.5 Units on a scale Standard Error 0.21
Change From Baseline mTSS at Week 91 and Final on Therapy Final on Therapy (N = 58, 56, 49)	0.1 Units on a scale Standard Error 0.14	-0.0 Units on a scale Standard Error 0.15	0.4 Units on a scale Standard Error 0.16

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=29 Participants 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.	MTX + PBO (Phase 2) n=43 Participants 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.	Placebo (PBO) (Phase 2) n=25 Participants 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.
Work Productivity and Activity Impairment (WPAI) Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem	0.2 units on a scale Standard Deviation 1.2	0.1 units on a scale Standard Deviation 0.6	0.0 units on a scale Standard Deviation 0.0

SECONDARY outcome

Timeframe: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem Week 64 (N = 30, 44, 26)	1.9 Units on a scale Standard Error 2.78	2.6 Units on a scale Standard Error 2.29	6.1 Units on a scale Standard Error 3.04
Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem Week 76 (N = 28, 33, 18)	-0.1 Units on a scale Standard Error 2.38	2.9 Units on a scale Standard Error 2.19	2.6 Units on a scale Standard Error 3.09
Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem Week 91 (N = 29, 32, 14)	4.4 Units on a scale Standard Error 3.78	4.0 Units on a scale Standard Error 3.63	7.0 Units on a scale Standard Error 5.79
Change From Baseline in WPAI Questionnaire: Percent Work Time Missed in the Past 7 Days Due to Problem Final on Therapy (N = 34, 48, 29)	3.6 Units on a scale Standard Error 3.65	5.3 Units on a scale Standard Error 3.07	10.2 Units on a scale Standard Error 4.06

SECONDARY outcome

Timeframe: 52 Weeks

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem	6.2 units on a scale Standard Deviation 9.2	8.9 units on a scale Standard Deviation 15.5	14.2 units on a scale Standard Deviation 17.9

SECONDARY outcome

Timeframe: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem Week 64 (N = 37, 49, 31)	-2.5 Units on a scale Standard Error 3.57	9.6 Units on a scale Standard Error 3.16	18.2 Units on a scale Standard Error 3.96
Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem Week 76 (N = 38, 38, 23)	-0.6 Units on a scale Standard Error 2.16	2.3 Units on a scale Standard Error 2.01	12.2 Units on a scale Standard Error 2.54
Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem Week 91 (N = 37, 35, 18)	1.8 Units on a scale Standard Error 3.16	8.6 Units on a scale Standard Error 3.06	18.4 Units on a scale Standard Error 4.23
Change From Baseline in WPAI Questionnaire: Percent Impairment While Working in the Past 7 Days Due to Problem Final on Therapy (N = 45, 50, 40)	1.1 Units on a scale Standard Error 3.51	11.1 Units on a scale Standard Error 3.10	19.9 Units on a scale Standard Error 3.76

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=27 Participants 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.	MTX + PBO (Phase 2) n=42 Participants 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.	Placebo (PBO) (Phase 2) n=24 Participants 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.
WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem	5.3 units on a scale Standard Deviation 9.8	6.7 units on a scale Standard Deviation 15.0	9.2 units on a scale Standard Deviation 12.8

SECONDARY outcome

Timeframe: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem Week 64 (N = 29, 43, 25)	0.1 Units on a scale Standard Error 4.49	11.5 Units on a scale Standard Error 3.75	22.4 Units on a scale Standard Error 2.01
Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem Week 76 (N = 27, 30, 18)	-0.9 Units on a scale Standard Error 2.40	2.6 Units on a scale Standard Error 2.18	16.6 Units on a scale Standard Error 2.95
Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem Week 91 (N = 28, 30, 13)	5.4 Units on a scale Standard Error 3.98	9.5 Units on a scale Standard Error 3.74	22.0 Units on a scale Standard Error 5.75
Change From Baseline in WPAI Questionnaire: Percent Overall Work Impairment in the Past 7 Days Due to Problem Final on Therapy (N = 34, 48, 28)	4.4 Units on a scale Standard Error 4.32	13.3 Units on a scale Standard Error 3.60	25.1 Units on a scale Standard Error 4.84

SECONDARY outcome

Timeframe: 52 weeks

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.

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=56 Participants 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.	MTX + PBO (Phase 2) n=60 Participants 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.	Placebo (PBO) (Phase 2) n=60 Participants 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.
WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem	8.6 Units on a scale Standard Deviation 11.0	10.0 Units on a scale Standard Deviation 15.9	16.8 Units on a scale Standard Deviation 20.0

SECONDARY outcome

Timeframe: 64, 76, 91 weeks and Final on Therapy (includes all visits for a participant upto Week 91 or the visit they discontinued at)

Outcome measures

Outcome measures
Measure	E25 + MTX (Phase 2) n=63 Participants 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.	MTX + PBO (Phase 2) n=65 Participants 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.	Placebo (PBO) (Phase 2) n=65 Participants 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.
Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem Week 76 (N = 57, 55, 41)	2.9 Units on a scale Standard Error 2.94	7.1 Units on a scale Standard Error 2.96	13.9 Units on a scale Standard Error 3.35
Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem Week 91 (N = 53, 49, 37)	-1.8 Units on a scale Standard Error 2.83	7.3 Units on a scale Standard Error 2.87	17.9 Units on a scale Standard Error 3.20
Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem Week 64 (N = 56, 60, 57)	-0.5 Units on a scale Standard Error 3.21	9.9 Units on a scale Standard Error 3.10	19.1 Units on a scale Standard Error 3.18
Change From Baseline in WPAI Questionnaire: Percent Activity Impairment in the Past 7 Days Due to Problem Final on Therapy (N = 60, 64, 64)	-0.9 Units on a scale Standard Error 3.24	12.2 Units on a scale Standard Error 3.13	24.2 Units on a scale Standard Error 3.16

Adverse Events

ETN 50 QW + MTX (Phase 1)

Serious events: 28 serious events

Other events: 130 other events

Deaths: 0 deaths

E25 + MTX (Phase 2)

Serious events: 3 serious events

Other events: 10 other events

Deaths: 0 deaths

MTX + PBO (Phase 2)

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo (PBO) (Phase 2)

Serious events: 2 serious events

Other events: 11 other events

Deaths: 0 deaths

E25+MTX (Phase 3)

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

MTX (Phase 3)

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo (PBO) (Phase 3)

Serious events: 2 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	ETN 50 QW + MTX (Phase 1) n=306 participants at risk 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.	E25 + MTX (Phase 2) n=63 participants at risk 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	MTX + PBO (Phase 2) n=65 participants at risk 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.	Placebo (PBO) (Phase 2) n=65 participants at risk 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.	E25+MTX (Phase 3) n=53 participants at risk 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.	MTX (Phase 3) n=46 participants at risk 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.	Placebo (PBO) (Phase 3) n=32 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Pericarditis	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Ear canal stenosis postoperative	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anal Fissure	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.5% 1/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bacterial pyelonephritis	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.5% 1/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.5% 1/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.5% 1/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Reproductive system and breast disorders Cystocele	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	1.6% 1/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Oral infection	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 1/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Vasculitis	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 1/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Acute Myocardial Infarction	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac Failure	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Cardiac disorders Coronary Artery Disease	0.65% 2/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Eye disorders Cataract	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal Pain	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastritis Erosive	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Inguinal Hernia	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Abscess	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchitis	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Empyema	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Infected Cyst	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Lower Respiratory Tract Infection Viral	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Soft Tissue Infection	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Foot Fracture	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Upper Limb Fracture	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Dehydration	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back Pain	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Intervertebral Disc Protrusion	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Muscle Spasms	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.65% 2/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Systemic Sclerosis	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Tendon Disorder	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian Cancer	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary Tumour Benign	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Cancer	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Cancer	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Loss Of Consciousness	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Pregnancy, puerperium and perinatal conditions Abortion Spontaneous	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Psychiatric Decompensation	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Reproductive system and breast disorders Endometrial Hyperplasia	0.33% 1/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Other adverse events

Other adverse events
Measure	ETN 50 QW + MTX (Phase 1) n=306 participants at risk 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.	E25 + MTX (Phase 2) n=63 participants at risk 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	MTX + PBO (Phase 2) n=65 participants at risk 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.	Placebo (PBO) (Phase 2) n=65 participants at risk 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.	E25+MTX (Phase 3) n=53 participants at risk 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.	MTX (Phase 3) n=46 participants at risk 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.	Placebo (PBO) (Phase 3) n=32 participants at risk 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.
Gastrointestinal disorders Nausea	12.7% 39/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Injection site Erythema	5.6% 17/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
General disorders Injection site reaction	6.2% 19/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Nasopharyngitis	12.7% 39/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	7.9% 5/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.6% 3/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.6% 3/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	5.7% 3/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 1/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Upper Respiratory Tract Infection	5.6% 17/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.3% 4/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.6% 3/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	4.6% 3/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Investigations Alanine Aminotransferase Increased	5.6% 17/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	6.5% 20/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	5.9% 18/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.2% 2/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 2/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	9.2% 6/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	18.9% 10/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	15.2% 7/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	3.1% 1/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary Tract Infection	0.00% 0/306 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/63 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/65 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	0.00% 0/53 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	2.2% 1/46 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.	6.2% 2/32 • Screening to Week 117 (Phase 1, 2, and 3 data) The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
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Restriction type: OTHER