Trial Outcomes & Findings for Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects With Rheumatoid Arthritis (NCT NCT00445770)

Last Updated: 2011-08-15

Results Overview

mTSS = sum of erosion and 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 represents improvement.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

550 participants

Primary outcome timeframe

Week 52

Results posted on

2011-08-15

Participant Flow

Participant milestones

Participant milestones
Measure	Methotrexate Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Overall Study STARTED	176	192	182
Overall Study COMPLETED	123	157	151
Overall Study NOT COMPLETED	53	35	31

Reasons for withdrawal

Reasons for withdrawal
Measure	Methotrexate Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Overall Study Adverse Event	9	15	19
Overall Study Lack of Efficacy	38	13	6
Overall Study Lost to Follow-up	0	2	0
Overall Study Other	6	5	6

Baseline Characteristics

Study Evaluating the Efficacy and Safety of Etanercept and Methotrexate in Japanese Subjects With Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks	Total n=550 Participants Total of all reporting groups
Age Continuous	50.40 years STANDARD_DEVIATION 11.91 • n=5 Participants	51.46 years STANDARD_DEVIATION 12.21 • n=7 Participants	51.81 years STANDARD_DEVIATION 11.07 • n=5 Participants	51.24 years STANDARD_DEVIATION 11.74 • n=4 Participants
Sex: Female, Male Female	140 Participants n=5 Participants	154 Participants n=7 Participants	145 Participants n=5 Participants	439 Participants n=4 Participants
Sex: Female, Male Male	36 Participants n=5 Participants	38 Participants n=7 Participants	37 Participants n=5 Participants	111 Participants n=4 Participants
modified Total Sharp Score (mTSS)	43.01 scores on a scale STANDARD_DEVIATION 46.78 • n=5 Participants	45.17 scores on a scale STANDARD_DEVIATION 38.75 • n=7 Participants	41.98 scores on a scale STANDARD_DEVIATION 41.51 • n=5 Participants	43.42 scores on a scale STANDARD_DEVIATION 42.28 • n=4 Participants
Erosion Score	25.09 scores on a scale STANDARD_DEVIATION 26.30 • n=5 Participants	26.66 scores on a scale STANDARD_DEVIATION 22.1 • n=7 Participants	25.23 scores on a scale STANDARD_DEVIATION 23.88 • n=5 Participants	25.69 scores on a scale STANDARD_DEVIATION 24.05 • n=4 Participants
Joint Space Narrowing (JSN) Score	17.92 scores on a scale STANDARD_DEVIATION 21.93 • n=5 Participants	18.50 scores on a scale STANDARD_DEVIATION 19.14 • n=7 Participants	16.75 scores on a scale STANDARD_DEVIATION 19.11 • n=5 Participants	17.73 scores on a scale STANDARD_DEVIATION 20.03 • n=4 Participants

PRIMARY outcome

Timeframe: Week 52

Population: Radiographic intent-to-treat (rITT) population: all participants who received at least 1 dose of the assigned test article and provided radiographic data for baseline and at least 1 post-baseline visit

Outcome measures

Outcome measures
Measure	Methotrexate n=171 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=190 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=181 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 52	9.82 Scores on a scale Standard Error 1.16	5.19 Scores on a scale Standard Error 0.93	3.33 Scores on a scale Standard Error 0.73

SECONDARY outcome

Timeframe: Week 24

Population: rITT

Outcome measures

Outcome measures
Measure	Methotrexate n=171 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=190 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=181 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Modified Total Sharp Score (mTSS) at Week 24	5.11 Scores on a scale Standard Error 0.58	2.42 Scores on a scale Standard Error 0.48	1.74 Scores on a scale Standard Error 0.45

SECONDARY outcome

Timeframe: Baseline, Week 24, and Week 52

Population: rITT

Joint erosion score: erosion severity in 44 joints (16 per hand, 6 per foot). Each joint scored according to surface area involved, from 0 (no erosion) to 5 (extensive bone loss from more than one half of articulating bone). Because each side of foot joint was graded, maximum erosion score for foot joint was 10. Thus, maximum erosion score was 280. Change = score at observation minus score at Baseline. An increase in score 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	Methotrexate n=171 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=190 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=181 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Erosion Score at Weeks 24 and 52 Change at Week 24	2.90 Scores on a scale Standard Error 0.33	1.25 Scores on a scale Standard Error 0.29	1.12 Scores on a scale Standard Error 0.30
Change From Baseline in Erosion Score at Weeks 24 and 52 Change at Week 52	5.43 Scores on a scale Standard Error 0.64	2.75 Scores on a scale Standard Error 0.57	2.03 Scores on a scale Standard Error 0.48

SECONDARY outcome

Timeframe: Baseline, Week 24, and Week 52

Population: rITT

JSN score: severity of JSN in 42 joints (15 per hand and 6 per foot), including subluxation, scored from 0 (no/normal JSN) to 4 (complete loss of joint space, bony ankylosis, or luxation). Maximum JSN score was 168. Change = scores at observation minus score at Baseline. An increase in score 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	Methotrexate n=171 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=190 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=181 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Joint Space Narrowing (JSN) Score at Weeks 24 and 52 Change at Week 24	2.21 Scores on a scale Standard Error 0.34	1.18 Scores on a scale Standard Error 0.23	0.62 Scores on a scale Standard Error 0.20
Change From Baseline in Joint Space Narrowing (JSN) Score at Weeks 24 and 52 Change at Week 52	4.39 Scores on a scale Standard Error 0.66	2.44 Scores on a scale Standard Error 0.42	1.31 Scores on a scale Standard Error 0.33

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: rITT

Absence of joint destruction defined by 3 categories (mTSS change \<=0.5, \<=3.0, and \<smallest detectable difference \[SDD\] where SDDs were scores \>3.0). mTSS = sum of erosion and JSN scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score).

Outcome measures

Outcome measures
Measure	Methotrexate n=171 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=190 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=181 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Percentage of Participants With no Progression of Joint Destruction at Week 52 Progression ≤0.5	25.7 Percentage of participants	45.3 Percentage of participants	49.2 Percentage of participants
Percentage of Participants With no Progression of Joint Destruction at Week 52 Progression ≤3.0	46.8 Percentage of participants	64.2 Percentage of participants	68.0 Percentage of participants
Percentage of Participants With no Progression of Joint Destruction at Week 52 Progression ≤SDD	81.9 Percentage of participants	88.9 Percentage of participants	94.5 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: Modified ITT (mITT) population: participants who received at least 1 dose of the assigned test article; Last Observation Carried Forward (LOCF)

American College of Rheumatology (ACR) swollen joint count was an assessment of 68 joints. Joints classified as either swollen or not swollen. Change = scores at observation minus score at Baseline, and total possible scores ranged from -68 to 68. An increase in swollen joints from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	13.84 Swollen Joints Standard Deviation 7.81	14.23 Swollen Joints Standard Deviation 8.97	14.00 Swollen Joints Standard Deviation 8.80
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-7.93 Swollen Joints Standard Deviation 7.83	-9.97 Swollen Joints Standard Deviation 8.53	-10.05 Swollen Joints Standard Deviation 8.02
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-3.39 Swollen Joints Standard Deviation 6.59	-5.96 Swollen Joints Standard Deviation 6.94	-5.02 Swollen Joints Standard Deviation 5.66
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-4.31 Swollen Joints Standard Deviation 6.68	-7.03 Swollen Joints Standard Deviation 7.57	-6.95 Swollen Joints Standard Deviation 6.35
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-5.76 Swollen Joints Standard Deviation 6.41	-8.38 Swollen Joints Standard Deviation 7.77	-7.91 Swollen Joints Standard Deviation 6.71
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-6.36 Swollen Joints Standard Deviation 6.97	-9.05 Swollen Joints Standard Deviation 7.79	-8.55 Swollen Joints Standard Deviation 6.72
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-6.59 Swollen Joints Standard Deviation 6.77	-9.29 Swollen Joints Standard Deviation 7.93	-8.78 Swollen Joints Standard Deviation 6.89
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-7.21 Swollen Joints Standard Deviation 7.47	-9.68 Swollen Joints Standard Deviation 7.92	-9.43 Swollen Joints Standard Deviation 7.45
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-7.06 Swollen Joints Standard Deviation 7.52	-9.58 Swollen Joints Standard Deviation 7.98	-9.57 Swollen Joints Standard Deviation 7.51
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-7.47 Swollen Joints Standard Deviation 7.74	-9.89 Swollen Joints Standard Deviation 8.51	-9.79 Swollen Joints Standard Deviation 7.62
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-7.53 Swollen Joints Standard Deviation 8.26	-9.87 Swollen Joints Standard Deviation 8.51	-10.30 Swollen Joints Standard Deviation 8.41
Change From Baseline in Swollen Joint Count at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-7.53 Swollen Joints Standard Deviation 8.09	-9.79 Swollen Joints Standard Deviation 8.58	-10.49 Swollen Joints Standard Deviation 8.14

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

71 joints assessed by the investigator using criteria based on pressure and joint manipulation. Change = scores at observation minus score at Baseline, and total possible scores ranged from -71 to 71. An increase in tender joint count 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	17.12 Tender Joints Standard Deviation 10.78	16.30 Tender Joints Standard Deviation 10.56	17.48 Tender Joints Standard Deviation 11.21
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-3.41 Tender Joints Standard Deviation 7.48	-6.81 Tender Joints Standard Deviation 7.67	-7.73 Tender Joints Standard Deviation 7.81
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-5.58 Tender Joints Standard Deviation 8.34	-7.74 Tender Joints Standard Deviation 9.21	-8.65 Tender Joints Standard Deviation 7.75
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-6.83 Tender Joints Standard Deviation 8.30	-9.27 Tender Joints Standard Deviation 9.50	-10.86 Tender Joints Standard Deviation 9.07
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-8.42 Tender Joints Standard Deviation 9.08	-9.94 Tender Joints Standard Deviation 9.63	-11.36 Tender Joints Standard Deviation 9.20
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-8.82 Tender Joints Standard Deviation 9.44	-10.70 Tender Joints Standard Deviation 9.79	-11.81 Tender Joints Standard Deviation 9.29
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-9.15 Tender Joints Standard Deviation 9.93	-10.86 Tender Joints Standard Deviation 9.85	-12.38 Tender Joints Standard Deviation 10.10
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-9.47 Tender Joints Standard Deviation 10.30	-10.94 Tender Joints Standard Deviation 9.64	-12.48 Tender Joints Standard Deviation 9.81
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-9.91 Tender Joints Standard Deviation 10.56	-10.93 Tender Joints Standard Deviation 9.75	-12.97 Tender Joints Standard Deviation 10.14
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-9.97 Tender Joints Standard Deviation 10.43	-11.07 Tender Joints Standard Deviation 10.32	-12.73 Tender Joints Standard Deviation 10.87
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-10.45 Tender Joints Standard Deviation 10.69	-10.78 Tender Joints Standard Deviation 9.84	-13.17 Tender Joints Standard Deviation 11.20
Change From Baseline in Number of Painful Joints on Pressure or on Motion at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-10.27 Tender Joints Standard Deviation 10.60	-10.75 Tender Joints Standard Deviation 9.99	-13.23 Tender Joints Standard Deviation 11.13

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

Physician Global Assessment of symptoms, assessed using a 11-point rating scale, where 0=asymptomatic and 10=severe symptoms. Change = scores at observation minus score at Baseline. An increase in score 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	6.34 Scores on a scale Standard Deviation 1.98	6.23 Scores on a scale Standard Deviation 1.79	6.20 Scores on a scale Standard Deviation 1.86
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 2	-1.23 Scores on a scale Standard Deviation 1.67	-2.20 Scores on a scale Standard Deviation 1.71	-2.25 Scores on a scale Standard Deviation 1.71
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 4	-1.66 Scores on a scale Standard Deviation 1.81	-2.65 Scores on a scale Standard Deviation 1.91	-2.67 Scores on a scale Standard Deviation 1.90
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 8	-2.13 Scores on a scale Standard Deviation 2.05	-3.02 Scores on a scale Standard Deviation 1.89	-3.14 Scores on a scale Standard Deviation 1.89
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 12	-2.43 Scores on a scale Standard Deviation 2.13	-3.30 Scores on a scale Standard Deviation 2.04	-3.34 Scores on a scale Standard Deviation 1.94
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 16	-2.51 Scores on a scale Standard Deviation 2.21	-3.46 Scores on a scale Standard Deviation 2.02	-3.53 Scores on a scale Standard Deviation 1.99
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 20	-2.54 Scores on a scale Standard Deviation 2.29	-3.51 Scores on a scale Standard Deviation 2.07	-3.76 Scores on a scale Standard Deviation 2.01
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 24	-2.60 Scores on a scale Standard Deviation 2.43	-3.52 Scores on a scale Standard Deviation 2.22	-3.76 Scores on a scale Standard Deviation 2.07
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 32	-2.70 Scores on a scale Standard Deviation 2.36	-3.54 Scores on a scale Standard Deviation 2.24	-3.94 Scores on a scale Standard Deviation 2.09
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 40	-2.63 Scores on a scale Standard Deviation 2.41	-3.62 Scores on a scale Standard Deviation 2.28	-3.97 Scores on a scale Standard Deviation 2.27
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 48	-2.70 Scores on a scale Standard Deviation 2.52	-3.59 Scores on a scale Standard Deviation 2.45	-4.03 Scores on a scale Standard Deviation 2.20
Change From Baseline in Physician's Global Assessment of Symptoms at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Week 52	-2.72 Scores on a scale Standard Deviation 2.40	-3.68 Scores on a scale Standard Deviation 2.42	-4.07 Scores on a scale Standard Deviation 2.11

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

Patient's Global Assessment of symptoms, assessed using a 11-point rating scale, where 0=asymptomatic and 10=severe symptoms. Change = scores at observation minus score at Baseline. An increase in score 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	6.01 Scores on a scale Standard Deviation 2.28	6.12 Scores on a scale Standard Deviation 2.17	5.95 Scores on a scale Standard Deviation 2.01
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-0.65 Scores on a scale Standard Deviation 1.95	-1.81 Scores on a scale Standard Deviation 1.86	-1.79 Scores on a scale Standard Deviation 1.82
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-1.11 Scores on a scale Standard Deviation 1.99	-1.89 Scores on a scale Standard Deviation 2.06	-1.91 Scores on a scale Standard Deviation 2.04
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-1.34 Scores on a scale Standard Deviation 2.31	-2.37 Scores on a scale Standard Deviation 2.05	-2.27 Scores on a scale Standard Deviation 2.13
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-1.63 Scores on a scale Standard Deviation 2.52	-2.57 Scores on a scale Standard Deviation 2.22	-2.38 Scores on a scale Standard Deviation 2.29
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-1.71 Scores on a scale Standard Deviation 2.45	-2.55 Scores on a scale Standard Deviation 2.37	-2.54 Scores on a scale Standard Deviation 2.40
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-1.85 Scores on a scale Standard Deviation 2.42	-2.59 Scores on a scale Standard Deviation 2.36	-2.69 Scores on a scale Standard Deviation 2.34
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-1.85 Scores on a scale Standard Deviation 2.66	-2.65 Scores on a scale Standard Deviation 2.45	-2.79 Scores on a scale Standard Deviation 2.45
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-1.89 Scores on a scale Standard Deviation 2.71	-2.84 Scores on a scale Standard Deviation 2.44	-2.92 Scores on a scale Standard Deviation 2.58
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-1.88 Scores on a scale Standard Deviation 2.68	-2.89 Scores on a scale Standard Deviation 2.44	-2.82 Scores on a scale Standard Deviation 2.67
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-1.97 Scores on a scale Standard Deviation 2.77	-2.95 Scores on a scale Standard Deviation 2.46	-2.98 Scores on a scale Standard Deviation 2.52
Change From Baseline in Patient's Global Assessment at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-1.97 Scores on a scale Standard Deviation 2.70	-3.04 Scores on a scale Standard Deviation 2.58	-2.91 Scores on a scale Standard Deviation 2.60

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

Morning stiffness in and around the joints lasting at least 1 hour before maximal improvement. Change = scores at observation minus score at Baseline. An increase in stiffness duration 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	204.74 Minutes Standard Deviation 338.70	203.80 Minutes Standard Deviation 304.92	223.48 Minutes Standard Deviation 344.75
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-46.39 Minutes Standard Deviation 250.13	-98.73 Minutes Standard Deviation 259.91	-108.37 Minutes Standard Deviation 256.49
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-34.43 Minutes Standard Deviation 249.33	-94.87 Minutes Standard Deviation 280.56	-107.09 Minutes Standard Deviation 255.06
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-52.53 Minutes Standard Deviation 247.74	-122.13 Minutes Standard Deviation 304.33	-127.55 Minutes Standard Deviation 279.88
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-73.48 Minutes Standard Deviation 236.69	-128.02 Minutes Standard Deviation 309.89	-129.74 Minutes Standard Deviation 284.58
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-78.60 Minutes Standard Deviation 252.64	-136.18 Minutes Standard Deviation 318.85	-148.13 Minutes Standard Deviation 304.03
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-87.11 Minutes Standard Deviation 276.35	-137.18 Minutes Standard Deviation 320.34	-153.01 Minutes Standard Deviation 314.41
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-89.94 Minutes Standard Deviation 295.48	-137.72 Minutes Standard Deviation 317.24	-143.03 Minutes Standard Deviation 332.16
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-95.32 Minutes Standard Deviation 330.07	-137.26 Minutes Standard Deviation 332.50	-163.64 Minutes Standard Deviation 320.36
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-97.76 Minutes Standard Deviation 332.93	-142.06 Minutes Standard Deviation 335.44	-157.52 Minutes Standard Deviation 336.53
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-99.38 Minutes Standard Deviation 306.33	-136.23 Minutes Standard Deviation 333.45	-163.03 Minutes Standard Deviation 326.06
Change From Baseline in Mean Duration of Morning Stiffness at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-98.98 Minutes Standard Deviation 303.71	-124.86 Minutes Standard Deviation 361.03	-171.36 Minutes Standard Deviation 322.43

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

100 millimeter (mm) line (VAS) marked by participant. Intensity of pain range (over past week): 0mm = no pain to 100mm = worst possible pain. Change = scores at observation minus score at Baseline. An increase in score 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	54.91 mm Standard Deviation 23.62	54.37 mm Standard Deviation 23.10	52.63 mm Standard Deviation 21.54
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-5.98 mm Standard Deviation 19.11	-18.85 mm Standard Deviation 19.76	-18.67 mm Standard Deviation 20.32
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-10.64 mm Standard Deviation 21.45	-18.18 mm Standard Deviation 22.95	-19.16 mm Standard Deviation 21.86
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-13.48 mm Standard Deviation 25.21	-23.09 mm Standard Deviation 22.37	-22.46 mm Standard Deviation 22.34
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-16.95 mm Standard Deviation 25.09	-24.70 mm Standard Deviation 22.74	-24.01 mm Standard Deviation 22.70
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-17.97 mm Standard Deviation 26.61	-24.41 mm Standard Deviation 24.53	-25.63 mm Standard Deviation 25.04
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-19.53 mm Standard Deviation 24.67	-25.39 mm Standard Deviation 24.01	-26.52 mm Standard Deviation 24.58
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-19.53 mm Standard Deviation 27.02	-26.86 mm Standard Deviation 24.37	-26.73 mm Standard Deviation 24.99
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-19.72 mm Standard Deviation 27.01	-28.68 mm Standard Deviation 25.00	-28.10 mm Standard Deviation 25.85
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-19.68 mm Standard Deviation 27.35	-28.81 mm Standard Deviation 26.09	-27.17 mm Standard Deviation 25.26
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-20.85 mm Standard Deviation 28.08	-28.28 mm Standard Deviation 25.04	-28.77 mm Standard Deviation 25.50
Change From Baseline in Visual Analogue Scale for Pain (VAS-pain) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-20.03 mm Standard Deviation 27.74	-29.08 mm Standard Deviation 25.85	-28.34 mm Standard Deviation 25.92

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

100mm line (VAS) marked by participant. Participants asked, "In general how would you rate your health over the last 2-3 weeks?" 0mm=very well to 100mm=extremely bad. Change = scores at observation minus score at Baseline. An increase in score 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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	58.37 mm Standard Deviation 24.04	58.71 mm Standard Deviation 23.08	55.70 mm Standard Deviation 21.68
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-8.06 mm Standard Deviation 19.00	-21.07 mm Standard Deviation 20.39	-20.27 mm Standard Deviation 22.08
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-13.51 mm Standard Deviation 21.35	-20.65 mm Standard Deviation 23.18	-20.69 mm Standard Deviation 22.47
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-15.59 mm Standard Deviation 24.92	-26.16 mm Standard Deviation 23.39	-25.57 mm Standard Deviation 22.59
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-20.05 mm Standard Deviation 25.50	-28.08 mm Standard Deviation 24.87	-26.34 mm Standard Deviation 23.27
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-20.89 mm Standard Deviation 27.29	-28.37 mm Standard Deviation 26.15	-27.30 mm Standard Deviation 24.73
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-22.35 mm Standard Deviation 25.37	-29.51 mm Standard Deviation 25.05	-29.16 mm Standard Deviation 24.79
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-21.78 mm Standard Deviation 27.55	-30.23 mm Standard Deviation 25.23	-29.52 mm Standard Deviation 25.39
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-22.87 mm Standard Deviation 27.60	-31.92 mm Standard Deviation 24.91	-31.11 mm Standard Deviation 25.86
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-22.69 mm Standard Deviation 28.18	-31.49 mm Standard Deviation 27.26	-30.36 mm Standard Deviation 25.54
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-23.76 mm Standard Deviation 29.21	-32.15 mm Standard Deviation 26.01	-31.27 mm Standard Deviation 25.42
Change From Baseline in VAS for Participant General Health at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-23.34 mm Standard Deviation 28.48	-32.25 mm Standard Deviation 27.02	-31.08 mm Standard Deviation 26.60

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

HAQ-DI: participant-reported assessment of ability to perform tasks: 1) dress/groom; 2) arise; 3) eat; 4) walk; 5) reach; 6) grip; 7) hygiene; and 8) common activities over past week. Each item scored on 4-point Likert scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Change = scores at observation minus score at Baseline and total possible scores ranged from -3 to 3. An increase in score from baseline represented disease progression and/or joint worsening and a decrease represented improvement.

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	1.01 Scores on a scale Standard Deviation 0.65	1.17 Scores on a scale Standard Deviation 0.66	1.06 Scores on a scale Standard Deviation 0.67
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-0.06 Scores on a scale Standard Deviation 0.36	-0.30 Scores on a scale Standard Deviation 0.34	-0.34 Scores on a scale Standard Deviation 0.41
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-0.12 Scores on a scale Standard Deviation 0.44	-0.33 Scores on a scale Standard Deviation 0.39	-0.40 Scores on a scale Standard Deviation 0.43
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-0.21 Scores on a scale Standard Deviation 0.49	-0.46 Scores on a scale Standard Deviation 0.45	-0.48 Scores on a scale Standard Deviation 0.46
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-0.29 Scores on a scale Standard Deviation 0.54	-0.51 Scores on a scale Standard Deviation 0.48	-0.52 Scores on a scale Standard Deviation 0.49
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-0.30 Scores on a scale Standard Deviation 0.55	-0.52 Scores on a scale Standard Deviation 0.51	-0.54 Scores on a scale Standard Deviation 0.52
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-0.32 Scores on a scale Standard Deviation 0.58	-0.49 Scores on a scale Standard Deviation 0.53	-0.57 Scores on a scale Standard Deviation 0.54
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-0.33 Scores on a scale Standard Deviation 0.62	-0.54 Scores on a scale Standard Deviation 0.52	-0.59 Scores on a scale Standard Deviation 0.55
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-0.33 Scores on a scale Standard Deviation 0.64	-0.56 Scores on a scale Standard Deviation 0.52	-0.59 Scores on a scale Standard Deviation 0.59
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-0.35 Scores on a scale Standard Deviation 0.64	-0.56 Scores on a scale Standard Deviation 0.55	-0.60 Scores on a scale Standard Deviation 0.60
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-0.34 Scores on a scale Standard Deviation 0.65	-0.57 Scores on a scale Standard Deviation 0.57	-0.59 Scores on a scale Standard Deviation 0.57
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-0.35 Scores on a scale Standard Deviation 0.64	-0.56 Scores on a scale Standard Deviation 0.56	-0.58 Scores on a scale Standard Deviation 0.59

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

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	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 16	51.7 Percentage of participants	73.8 Percentage of participants	75.3 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 20	58.5 Percentage of participants	75.4 Percentage of participants	78.6 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 24	56.3 Percentage of participants	77.0 Percentage of participants	77.5 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 32	58.0 Percentage of participants	79.1 Percentage of participants	80.8 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 40	59.7 Percentage of participants	78.5 Percentage of participants	75.3 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 48	59.1 Percentage of participants	76.4 Percentage of participants	79.7 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 52	62.5 Percentage of participants	75.9 Percentage of participants	78.6 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 2	16.1 Percentage of participants	54.0 Percentage of participants	49.4 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 4	27.3 Percentage of participants	55.5 Percentage of participants	56.9 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 8	43.2 Percentage of participants	68.1 Percentage of participants	68.7 Percentage of participants
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response Week 12	48.3 Percentage of participants	70.2 Percentage of participants	77.5 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

ACR50 response: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Percentage of Participants With an ACR50 Response Week 16	26.1 Percentage of participants	50.0 Percentage of participants	44.0 Percentage of participants
Percentage of Participants With an ACR50 Response Week 2	2.3 Percentage of participants	14.7 Percentage of participants	16.0 Percentage of participants
Percentage of Participants With an ACR50 Response Week 4	4.0 Percentage of participants	28.1 Percentage of participants	22.5 Percentage of participants
Percentage of Participants With an ACR50 Response Week 8	15.3 Percentage of participants	38.5 Percentage of participants	35.7 Percentage of participants
Percentage of Participants With an ACR50 Response Week 12	23.9 Percentage of participants	47.4 Percentage of participants	42.3 Percentage of participants
Percentage of Participants With an ACR50 Response Week 20	30.7 Percentage of participants	50.0 Percentage of participants	50.5 Percentage of participants
Percentage of Participants With an ACR50 Response Week 24	32.4 Percentage of participants	53.6 Percentage of participants	54.4 Percentage of participants
Percentage of Participants With an ACR50 Response Week 32	34.7 Percentage of participants	60.4 Percentage of participants	59.3 Percentage of participants
Percentage of Participants With an ACR50 Response Week 40	36.9 Percentage of participants	60.4 Percentage of participants	58.8 Percentage of participants
Percentage of Participants With an ACR50 Response Week 48	39.2 Percentage of participants	57.3 Percentage of participants	57.7 Percentage of participants
Percentage of Participants With an ACR50 Response Week 52	36.9 Percentage of participants	59.4 Percentage of participants	62.1 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

ACR70 response: ≥ 70% improvement in tender joint count; ≥ 70% improvement in swollen joint count; and ≥ 70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Percentage of Participants With an ACR70 Response Week 8	2.8 Percentage of participants	15.1 Percentage of participants	11.0 Percentage of participants
Percentage of Participants With an ACR70 Response Week 2	0 Percentage of participants	4.2 Percentage of participants	3.8 Percentage of participants
Percentage of Participants With an ACR70 Response Week 32	11.9 Percentage of participants	28.1 Percentage of participants	31.3 Percentage of participants
Percentage of Participants With an ACR70 Response Week 4	0.6 Percentage of participants	7.8 Percentage of participants	8.2 Percentage of participants
Percentage of Participants With an ACR70 Response Week 12	9.7 Percentage of participants	21.9 Percentage of participants	15.4 Percentage of participants
Percentage of Participants With an ACR70 Response Week 16	9.7 Percentage of participants	17.7 Percentage of participants	18.7 Percentage of participants
Percentage of Participants With an ACR70 Response Week 20	13.1 Percentage of participants	25.0 Percentage of participants	25.3 Percentage of participants
Percentage of Participants With an ACR70 Response Week 24	11.9 Percentage of participants	25.5 Percentage of participants	25.8 Percentage of participants
Percentage of Participants With an ACR70 Response Week 40	14.8 Percentage of participants	31.3 Percentage of participants	35.7 Percentage of participants
Percentage of Participants With an ACR70 Response Week 48	18.2 Percentage of participants	34.4 Percentage of participants	36.3 Percentage of participants
Percentage of Participants With an ACR70 Response Week 52	15.9 Percentage of participants	33.9 Percentage of participants	36.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

DAS: weighted calculation of joint tenderness score (Ritchie Articular Index\[RAI\]), swollen joint count of 44 joints, natural logarithm (ln) of erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/hr), and general health (GH) using VAS. RAI defined as sum of 26 possible 0 to 3 tender scores. DAS = 0.53938 square root (√) (RAI) + 0.06465 (swollen joint count) + 0.330 (ln ESR) + 0.00722 (GH). Change from baseline = DAS at Week x minus Baseline DAS. Total DAS scores could range from 10 (worse outcome) to 0 (better outcome).

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	4.07 Scores on a scale Standard Deviation 0.95	4.03 Scores on a scale Standard Deviation 0.89	4.05 Scores on a scale Standard Deviation 0.88
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-0.48 Scores on a scale Standard Deviation 0.64	-1.09 Scores on a scale Standard Deviation 0.72	-1.05 Scores on a scale Standard Deviation 0.70
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-0.69 Scores on a scale Standard Deviation 0.67	-1.26 Scores on a scale Standard Deviation 0.90	-1.26 Scores on a scale Standard Deviation 0.80
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-0.93 Scores on a scale Standard Deviation 0.79	-1.48 Scores on a scale Standard Deviation 0.88	-1.54 Scores on a scale Standard Deviation 0.86
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-1.12 Scores on a scale Standard Deviation 0.93	-1.66 Scores on a scale Standard Deviation 0.97	-1.65 Scores on a scale Standard Deviation 0.83
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-1.19 Scores on a scale Standard Deviation 0.98	-1.69 Scores on a scale Standard Deviation 0.98	-1.72 Scores on a scale Standard Deviation 0.88
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-1.28 Scores on a scale Standard Deviation 1.00	-1.74 Scores on a scale Standard Deviation 0.97	-1.80 Scores on a scale Standard Deviation 0.93
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-1.31 Scores on a scale Standard Deviation 1.09	-1.77 Scores on a scale Standard Deviation 1.03	-1.87 Scores on a scale Standard Deviation 0.98
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-1.37 Scores on a scale Standard Deviation 1.08	-1.80 Scores on a scale Standard Deviation 1.02	-1.95 Scores on a scale Standard Deviation 1.01
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-1.36 Scores on a scale Standard Deviation 1.08	-1.90 Scores on a scale Standard Deviation 1.10	-1.97 Scores on a scale Standard Deviation 1.02
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-1.46 Scores on a scale Standard Deviation 1.17	-1.86 Scores on a scale Standard Deviation 1.13	-2.02 Scores on a scale Standard Deviation 1.04
Change From Baseline in Disease Activity Score (DAS) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-1.42 Scores on a scale Standard Deviation 1.14	-1.86 Scores on a scale Standard Deviation 1.14	-2.01 Scores on a scale Standard Deviation 1.06

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

DAS based on 28 painful joint counts, 28 swollen joint counts, ESR, and GH. DAS28 score calculated as 0.56 √ (28 painful joint count) + 0.28 √ (28 swollen joint count) + 0.70 (ln ESR mm/hr) + 0.014 GH. Change from baseline = DAS at Week x minus Baseline DAS. Total DAS scores could range from 10 (worse outcome) to 0 (better outcome).

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-1.54 Scores on a scale Standard Deviation 1.34	-2.20 Scores on a scale Standard Deviation 1.31	-2.36 Scores on a scale Standard Deviation 1.27
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	5.84 Scores on a scale Standard Deviation 1.13	5.75 Scores on a scale Standard Deviation 1.17	5.82 Scores on a scale Standard Deviation 1.02
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-0.52 Scores on a scale Standard Deviation 0.75	-1.32 Scores on a scale Standard Deviation 0.86	-1.38 Scores on a scale Standard Deviation 0.88
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-0.77 Scores on a scale Standard Deviation 0.83	-1.51 Scores on a scale Standard Deviation 1.05	-1.60 Scores on a scale Standard Deviation 1.02
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-1.08 Scores on a scale Standard Deviation 0.99	-1.79 Scores on a scale Standard Deviation 1.05	-1.96 Scores on a scale Standard Deviation 1.11
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-1.33 Scores on a scale Standard Deviation 1.16	-2.00 Scores on a scale Standard Deviation 1.15	-2.09 Scores on a scale Standard Deviation 1.13
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-1.42 Scores on a scale Standard Deviation 1.24	-2.08 Scores on a scale Standard Deviation 1.22	-2.20 Scores on a scale Standard Deviation 1.17
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-1.54 Scores on a scale Standard Deviation 1.28	-2.13 Scores on a scale Standard Deviation 1.24	-2.31 Scores on a scale Standard Deviation 1.21
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-1.63 Scores on a scale Standard Deviation 1.34	-2.22 Scores on a scale Standard Deviation 1.29	-2.45 Scores on a scale Standard Deviation 1.31
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-1.61 Scores on a scale Standard Deviation 1.36	-2.31 Scores on a scale Standard Deviation 1.44	-2.45 Scores on a scale Standard Deviation 1.33
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-1.75 Scores on a scale Standard Deviation 1.48	-2.28 Scores on a scale Standard Deviation 1.51	-2.51 Scores on a scale Standard Deviation 1.37
Change From Baseline in Disease Activity Score in 28 Joints (DAS28) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-1.71 Scores on a scale Standard Deviation 1.44	-2.25 Scores on a scale Standard Deviation 1.55	-2.50 Scores on a scale Standard Deviation 1.38

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

CRP: marker of inflammation. Higher level consistent with inflammation. Normal CRP range: 0 to 1.0 milligrams per deciliter (mg/dL).

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	21.13 mg/dL Standard Deviation 22.30	22.86 mg/dL Standard Deviation 29.77	22.09 mg/dL Standard Deviation 24.17
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-3.08 mg/dL Standard Deviation 13.08	-13.41 mg/dL Standard Deviation 19.53	-15.62 mg/dL Standard Deviation 17.70
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-3.25 mg/dL Standard Deviation 15.82	-11.05 mg/dL Standard Deviation 17.73	-13.33 mg/dL Standard Deviation 16.58
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-4.19 mg/dL Standard Deviation 17.81	-13.18 mg/dL Standard Deviation 20.74	-15.17 mg/dL Standard Deviation 19.05
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-7.30 mg/dL Standard Deviation 18.00	-13.04 mg/dL Standard Deviation 20.48	-14.87 mg/dL Standard Deviation 20.36
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-6.51 mg/dL Standard Deviation 19.28	-13.31 mg/dL Standard Deviation 20.73	-15.15 mg/dL Standard Deviation 20.82
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-7.18 mg/dL Standard Deviation 21.29	-12.21 mg/dL Standard Deviation 22.31	-15.86 mg/dL Standard Deviation 20.23
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-6.31 mg/dL Standard Deviation 21.74	-13.69 mg/dL Standard Deviation 21.26	-16.28 mg/dL Standard Deviation 21.25
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-6.41 mg/dL Standard Deviation 21.68	-13.45 mg/dL Standard Deviation 21.76	-16.10 mg/dL Standard Deviation 21.38
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-6.23 mg/dL Standard Deviation 22.16	-13.13 mg/dL Standard Deviation 22.47	-15.38 mg/dL Standard Deviation 21.80
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-6.34 mg/dL Standard Deviation 22.18	-13.01 mg/dL Standard Deviation 22.03	-15.73 mg/dL Standard Deviation 22.44
Change From Baseline in C-reactive Protein (CRP) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-5.20 mg/dL Standard Deviation 22.55	-12.90 mg/dL Standard Deviation 22.96	-15.08 mg/dL Standard Deviation 22.29

SECONDARY outcome

Timeframe: Baseline and Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52

Population: mITT; LOCF

ESR: laboratory test that provided a non-specific measure of inflammation. The test assessed the rate at which red blood cells fell in a test tube and was measured in mm/hour. Normal range: 0-30mm/h. Higher rate consistent with inflammation.

Outcome measures

Outcome measures
Measure	Methotrexate n=176 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 Participants Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Baseline	42.55 mm/hr Standard Deviation 28.24	42.00 mm/hr Standard Deviation 29.44	43.66 mm/hr Standard Deviation 27.64
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 2	-1.86 mm/hr Standard Deviation 10.65	-13.67 mm/hr Standard Deviation 13.07	-16.91 mm/hr Standard Deviation 15.01
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 4	-2.92 mm/hr Standard Deviation 11.78	-13.26 mm/hr Standard Deviation 14.94	-16.62 mm/hr Standard Deviation 16.03
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 8	-5.50 mm/hr Standard Deviation 16.89	-13.99 mm/hr Standard Deviation 17.39	-18.01 mm/hr Standard Deviation 17.83
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 12	-8.89 mm/hr Standard Deviation 17.38	-15.18 mm/hr Standard Deviation 17.63	-18.98 mm/hr Standard Deviation 19.04
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 16	-8.56 mm/hr Standard Deviation 18.73	-15.45 mm/hr Standard Deviation 18.54	-19.78 mm/hr Standard Deviation 20.32
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 20	-10.56 mm/hr Standard Deviation 20.45	-15.68 mm/hr Standard Deviation 19.15	-19.40 mm/hr Standard Deviation 20.18
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 24	-9.88 mm/hr Standard Deviation 20.15	-16.52 mm/hr Standard Deviation 20.09	-20.01 mm/hr Standard Deviation 20.86
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 32	-9.92 mm/hr Standard Deviation 20.51	-16.06 mm/hr Standard Deviation 21.14	-20.16 mm/hr Standard Deviation 21.54
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 40	-9.33 mm/hr Standard Deviation 20.50	-15.93 mm/hr Standard Deviation 21.47	-18.28 mm/hr Standard Deviation 21.81
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 48	-10.70 mm/hr Standard Deviation 20.93	-15.61 mm/hr Standard Deviation 23.07	-19.25 mm/hr Standard Deviation 21.77
Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 Change at Week 52	-10.22 mm/hr Standard Deviation 21.69	-14.79 mm/hr Standard Deviation 23.06	-18.85 mm/hr Standard Deviation 21.67

OTHER_PRE_SPECIFIED outcome

Timeframe: Weeks 12, 24, 52

Population: mITT; n = evaluable participants at the specified time point.

Outcome measures

Outcome measures
Measure	Methotrexate n=179 Participants Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=171 Participants Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Comparison of Etanercept Serum Concentrations Between the 10 mg and 25 mg Etanercept Doses Week 12 (n=179, 164)	1012 nanograms per milliliter (ng/mL) Standard Error 30.3	2490 nanograms per milliliter (ng/mL) Standard Error 79.6	—
Comparison of Etanercept Serum Concentrations Between the 10 mg and 25 mg Etanercept Doses Week 24 (n=171, 171)	1094 nanograms per milliliter (ng/mL) Standard Error 32.2	2500 nanograms per milliliter (ng/mL) Standard Error 79.3	—
Comparison of Etanercept Serum Concentrations Between the 10 mg and 25 mg Etanercept Doses Week 52 (n=158, 149)	1097 nanograms per milliliter (ng/mL) Standard Error 34.4	2754 nanograms per milliliter (ng/mL) Standard Error 136	—

Adverse Events

Methotrexate

Serious events: 10 serious events

Other events: 92 other events

Deaths: 0 deaths

Etanercept 10 mg

Serious events: 8 serious events

Other events: 106 other events

Deaths: 0 deaths

Etanercept 25 mg

Serious events: 11 serious events

Other events: 102 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Wyeth 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.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Methotrexate n=176 participants at risk Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 participants at risk Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 participants at risk Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Ear and labyrinth disorders Sudden hearing loss	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Vertigo positional	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Endocrine disorders Thyroiditis subacute	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Retinal detachment	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Food poisoning	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Ankle fracture	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Fracture	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Spinal compression fracture	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Ulna fracture	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Pain in extremity	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 2/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Depressed level of consciousness	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Occipital neuralgia	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Pregnancy, puerperium and perinatal conditions Abortion	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Varicose vein	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Appendicitis	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Other adverse events
Measure	Methotrexate n=176 participants at risk Participants received 4 milligrams (mg) up to 8 mg orally (2.0 mg capsules), once weekly for 52 weeks and subcutaneous (SC) placebo injections twice weekly	Etanercept 10 mg n=192 participants at risk Participants received 10 mg SC twice weekly and oral placebo capsules once weekly for 52 weeks	Etanercept 25 mg n=182 participants at risk Participants received 25 mg twice weekly SC and oral placebo capsules once weekly for 52 weeks
Cardiac disorders Palpitations	2.3% 4/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 2/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Vertigo	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Conjunctivitis allergic	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal discomfort	2.3% 4/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.1% 6/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain upper	2.8% 5/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	5.1% 9/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.1% 6/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.8% 7/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	2.8% 5/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 10/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastritis	3.4% 6/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	4.0% 7/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Stomatitis	4.5% 8/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.2% 8/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	3.4% 6/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.0% 2/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.4% 8/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Hepatobiliary disorders Hepatic function abnormal	3.4% 6/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Injury, poisoning and procedural complications Contusion	2.3% 4/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.4% 8/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Alanine aminotransferase increased	12.5% 22/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	6.2% 12/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 10/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Aspartate aminotransferase increased	10.2% 18/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.2% 8/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.4% 8/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Blood alkaline phosphatase increased	1.7% 3/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.0% 2/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.7% 5/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Blood pressure increased	1.7% 3/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Blood urine present	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 2/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Transaminases increased	4.5% 8/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.7% 5/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	4.0% 7/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.0% 2/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Dizziness	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.1% 6/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	2.3% 4/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.9% 9/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Insomnia	5.1% 9/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.7% 9/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.1% 2/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 6/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	1.7% 3/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.1% 6/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Dermatitis	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.0% 2/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Dermatitis contact	2.3% 4/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.6% 3/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Eczema	4.5% 8/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 7/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.4% 8/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Erythema	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Pruritus	1.7% 3/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	6.2% 12/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.7% 5/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Rash	4.5% 8/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.2% 10/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.5% 10/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Urticaria	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	1.1% 2/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Dental caries	1.7% 3/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.4% 8/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Periodontitis	0.00% 0/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.7% 5/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Bronchitis	2.8% 5/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.6% 5/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 6/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Cystitis	3.4% 6/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.1% 4/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.9% 9/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Gastroenteritis	2.8% 5/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.52% 1/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.55% 1/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Hordeolum	0.57% 1/176 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.0% 2/192 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	2.2% 4/182 The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.