Trial Outcomes & Findings for Study of Etanercept Monotherapy vs Methotrexate Monotherapy for Maintenance of Rheumatoid Arthritis Remission (NCT NCT02373813)

NCT ID: NCT02373813

Last Updated: 2023-01-11

Results Overview

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 371 participants
• Primary outcome timeframe: Week 48
• Results posted on: 2023-01-11

Participant Flow

This study was conducted at 97 centers in Canada, United States, Argentina, Bulgaria, Czech Republic, Spain, France, Germany, Greece, Hungary, Italy, Mexico, Poland, Portugal, and South Africa. The first participant enrolled on 20 February 2015; the last participant enrolled on 26 June 2018.

After a 24-week open label run-in period, participants were randomly assigned in a 2:2:1 ratio to one of three treatment groups: methotrexate monotherapy, etanercept monotherapy, or etanercept plus methotrexate.

Participant milestones

Measure	Open Label Run-In: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care.	Double-Blind Treatment: Methotrexate Monotherapy Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Run-In Period STARTED	371	0	0	0
Run-In Period Treated	368	0	0	0
Run-In Period COMPLETED	255	0	0	0
Run-In Period NOT COMPLETED	116	0	0	0
Double-Blind Treatment Period STARTED	0	101	101	51
Double-Blind Treatment Period Received Investigational Product (IP)	0	101	100	51
Double-Blind Treatment Period Received Rescue Treatment	0	52	36	15
Double-Blind Treatment Period COMPLETED	0	88	92	47
Double-Blind Treatment Period NOT COMPLETED	0	13	9	4

Reasons for withdrawal

Measure	Open Label Run-In: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care.	Double-Blind Treatment: Methotrexate Monotherapy Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Run-In Period Other, Not Specified	5	0	0	0
Run-In Period Withdrawal by Subject	16	0	0	0
Run-In Period Decision by Sponsor	11	0	0	0
Run-In Period Protocol Violation	75	0	0	0
Run-In Period Lost to Follow-up	2	0	0	0
Run-In Period Adverse Event	3	0	0	0
Run-In Period Noncompliance	1	0	0	0
Run-In Period Ineligibility Determined	3	0	0	0
Double-Blind Treatment Period Decision by Sponsor	0	1	2	0
Double-Blind Treatment Period Protocol Violation	0	2	0	0
Double-Blind Treatment Period Lost to Follow-up	0	0	1	1
Double-Blind Treatment Period Withdrawal by Subject	0	10	6	3

Baseline Characteristics

Study of Etanercept Monotherapy vs Methotrexate Monotherapy for Maintenance of Rheumatoid Arthritis Remission

Baseline characteristics by cohort

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).	Total n=253 Participants Total of all reporting groups
Age, Continuous	56.2 years STANDARD_DEVIATION 11.4 • n=5 Participants	54.8 years STANDARD_DEVIATION 12.8 • n=7 Participants	55.9 years STANDARD_DEVIATION 12.6 • n=5 Participants	55.6 years STANDARD_DEVIATION 12.2 • n=4 Participants
Sex: Female, Male Female	76 Participants n=5 Participants	77 Participants n=7 Participants	40 Participants n=5 Participants	193 Participants n=4 Participants
Sex: Female, Male Male	25 Participants n=5 Participants	24 Participants n=7 Participants	11 Participants n=5 Participants	60 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	13 Participants n=5 Participants	19 Participants n=7 Participants	8 Participants n=5 Participants	40 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	88 Participants n=5 Participants	82 Participants n=7 Participants	43 Participants n=5 Participants	213 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	4 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	9 Participants n=4 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Black	3 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	15 Participants n=4 Participants
Race/Ethnicity, Customized White	92 Participants n=5 Participants	86 Participants n=7 Participants	42 Participants n=5 Participants	220 Participants n=4 Participants
Race/Ethnicity, Customized Other, Not Specified	0 Participants n=5 Participants	5 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 48

Population: Primary Analysis Set: all randomized participants. Nonresponder imputation.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants With Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy	28.7 percentage of participants	49.5 percentage of participants	—

SECONDARY outcome

Timeframe: Week 48

Population: Primary Analysis Set: all randomized participants. Nonresponder imputation.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants With SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy	28.7 percentage of participants	52.9 percentage of participants	—

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoints.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
SDAI Score at All Measured Timepoints Baseline	1.29 score on a scale Standard Error 0.10	1.26 score on a scale Standard Error 0.14	1.18 score on a scale Standard Error 0.17
SDAI Score at All Measured Timepoints Week 12	7.01 score on a scale Standard Error 1.01	4.37 score on a scale Standard Error 0.75	4.39 score on a scale Standard Error 1.22
SDAI Score at All Measured Timepoints Week 24	5.61 score on a scale Standard Error 0.98	4.98 score on a scale Standard Error 0.92	3.28 score on a scale Standard Error 0.77
SDAI Score at All Measured Timepoints Week 36	4.03 score on a scale Standard Error 0.62	2.25 score on a scale Standard Error 0.36	2.41 score on a scale Standard Error 0.40
SDAI Score at All Measured Timepoints Week 48	3.41 score on a scale Standard Error 0.40	2.33 score on a scale Standard Error 0.23	2.86 score on a scale Standard Error 0.92

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3. A negative change from baseline indicates improvement.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Change From Baseline in SDAI Score at All Measured Timepoints Change at Week 12	5.67 score on a scale Standard Error 1.00	3.14 score on a scale Standard Error 0.75	3.21 score on a scale Standard Error 1.19
Change From Baseline in SDAI Score at All Measured Timepoints Change at Week 24	4.42 score on a scale Standard Error 0.98	3.78 score on a scale Standard Error 0.91	2.14 score on a scale Standard Error 0.78
Change From Baseline in SDAI Score at All Measured Timepoints Change at Week 36	2.90 score on a scale Standard Error 0.63	1.06 score on a scale Standard Error 0.38	1.30 score on a scale Standard Error 0.43
Change From Baseline in SDAI Score at All Measured Timepoints Change at Week 48	2.27 score on a scale Standard Error 0.39	1.16 score on a scale Standard Error 0.24	1.77 score on a scale Standard Error 0.94

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints Baseline	1.80 score on a scale Standard Error 0.06	1.88 score on a scale Standard Error 0.07	1.84 score on a scale Standard Error 0.09
Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints Week 12	2.78 score on a scale Standard Error 0.14	2.37 score on a scale Standard Error 0.12	2.32 score on a scale Standard Error 0.16
Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints Week 24	2.41 score on a scale Standard Error 0.13	2.54 score on a scale Standard Error 0.14	2.17 score on a scale Standard Error 0.12
Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints Week 36	2.32 score on a scale Standard Error 0.11	2.17 score on a scale Standard Error 0.08	2.16 score on a scale Standard Error 0.12
Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints Week 48	2.22 score on a scale Standard Error 0.10	2.21 score on a scale Standard Error 0.08	2.11 score on a scale Standard Error 0.13

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given time point.

The DAS28-ESR is a modified composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, ESR in mm/hr, and a 100 mm VAS measuring the participant's general health, from 0 (best) to 100 (worst). DAS28-ESR scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Change From Baseline in DAS28-ESR at All Measured Timepoints Change at Week 12	0.96 score on a scale Standard Error 0.13	0.50 score on a scale Standard Error 0.10	0.48 score on a scale Standard Error 0.18
Change From Baseline in DAS28-ESR at All Measured Timepoints Change at Week 24	0.65 score on a scale Standard Error 0.12	0.69 score on a scale Standard Error 0.13	0.34 score on a scale Standard Error 0.11
Change From Baseline in DAS28-ESR at All Measured Timepoints Change at Week 36	0.53 score on a scale Standard Error 0.10	0.31 score on a scale Standard Error 0.08	0.35 score on a scale Standard Error 0.12
Change From Baseline in DAS28-ESR at All Measured Timepoints Change at Week 48	0.43 score on a scale Standard Error 0.09	0.34 score on a scale Standard Error 0.07	0.32 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given time point.

The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints Baseline	1.50 score on a scale Standard Error 0.03	1.50 score on a scale Standard Error 0.04	1.54 score on a scale Standard Error 0.05
Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints Week 12	2.36 score on a scale Standard Error 0.13	1.91 score on a scale Standard Error 0.09	1.94 score on a scale Standard Error 0.15
Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints Week 24	2.15 score on a scale Standard Error 0.11	2.00 score on a scale Standard Error 0.11	1.77 score on a scale Standard Error 0.09
Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints Week 36	1.96 score on a scale Standard Error 0.09	1.67 score on a scale Standard Error 0.06	1.72 score on a scale Standard Error 0.08
Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints Week 48	1.87 score on a scale Standard Error 0.07	1.67 score on a scale Standard Error 0.05	1.72 score on a scale Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

The DAS28-CRP is a composite index that was designed to measure disease activity using the number of tender and swollen joints based upon a 28-joint count, CRP in mg/L, and a 100 mm VAS measuring the participant's general health from 0 (best) to 100 (worst). DAS28-CRP scores range from 0 to 9.4, where higher scores represent higher disease activity. A negative change from baseline indicates improvement.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Change From Baseline in DAS28-CRP at All Measured Timepoints Change at Week 12	0.84 score on a scale Standard Error 0.12	0.42 score on a scale Standard Error 0.09	0.41 score on a scale Standard Error 0.15
Change From Baseline in DAS28-CRP at All Measured Timepoints Change at Week 24	0.67 score on a scale Standard Error 0.11	0.52 score on a scale Standard Error 0.11	0.25 score on a scale Standard Error 0.08
Change From Baseline in DAS28-CRP at All Measured Timepoints Change at Week 36	0.49 score on a scale Standard Error 0.09	0.18 score on a scale Standard Error 0.06	0.20 score on a scale Standard Error 0.08
Change From Baseline in DAS28-CRP at All Measured Timepoints Change at Week 48	0.40 score on a scale Standard Error 0.07	0.19 score on a scale Standard Error 0.04	0.21 score on a scale Standard Error 0.11

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Clinical Disease Activity Index (CDAI) at All Measured Timepoints Week 12	6.42 score on a scale Standard Error 0.98	4.08 score on a scale Standard Error 0.74	3.95 score on a scale Standard Error 1.20
Clinical Disease Activity Index (CDAI) at All Measured Timepoints Week 48	3.06 score on a scale Standard Error 0.38	2.00 score on a scale Standard Error 0.23	2.61 score on a scale Standard Error 0.91
Clinical Disease Activity Index (CDAI) at All Measured Timepoints Baseline	1.01 score on a scale Standard Error 0.10	0.92 score on a scale Standard Error 0.13	0.71 score on a scale Standard Error 0.12
Clinical Disease Activity Index (CDAI) at All Measured Timepoints Week 24	5.07 score on a scale Standard Error 0.95	4.63 score on a scale Standard Error 0.91	2.35 score on a scale Standard Error 0.60
Clinical Disease Activity Index (CDAI) at All Measured Timepoints Week 36	3.60 score on a scale Standard Error 0.63	1.93 score on a scale Standard Error 0.36	2.04 score on a scale Standard Error 0.41

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

The CDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, and Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable. The CDAI score ranges from 0 to 76, where a higher score represents worse disease. A negative change from baseline indicates improvement.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Change From Baseline in CDAI at All Measured Timepoints Change at Week 12	5.39 score on a scale Standard Error 0.97	3.15 score on a scale Standard Error 0.73	3.24 score on a scale Standard Error 1.17
Change From Baseline in CDAI at All Measured Timepoints Change at Week 24	4.09 score on a scale Standard Error 0.95	3.75 score on a scale Standard Error 0.90	1.70 score on a scale Standard Error 0.61
Change From Baseline in CDAI at All Measured Timepoints Change at Week 36	2.69 score on a scale Standard Error 0.63	1.07 score on a scale Standard Error 0.37	1.41 score on a scale Standard Error 0.40
Change From Baseline in CDAI at All Measured Timepoints Change at Week 48	2.17 score on a scale Standard Error 0.37	1.15 score on a scale Standard Error 0.23	2.00 score on a scale Standard Error 0.92

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given time point.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints Baseline	96.0 percentage of participants	92.1 percentage of participants	96.1 percentage of participants
Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints Week 12	50.0 percentage of participants	64.0 percentage of participants	74.5 percentage of participants
Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints Week 24	38.8 percentage of participants	56.6 percentage of participants	62.0 percentage of participants
Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints Week 36	36.1 percentage of participants	55.6 percentage of participants	55.1 percentage of participants
Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints Week 48	30.5 percentage of participants	52.1 percentage of participants	56.3 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

A participant achieves Boolean remission (66/68-joint count) if all of the following criteria are met at a single timepoint:

• 68-joint tender joint count ≤ 1
• 66-joint swollen joint count ≤ 1
• CRP (mg/dL) ≤ 1
• Patient's Global Assessment of Disease Activity using a VAS (where 0=no arthritis activity at all and 10=worst arthritis activity imaginable) ≤ 1.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants With Boolean Remission at All Measured Timepoints Baseline	34.0 percentage of participants	34.7 percentage of participants	45.1 percentage of participants
Percentage of Participants With Boolean Remission at All Measured Timepoints Week 12	18.0 percentage of participants	23.0 percentage of participants	19.6 percentage of participants
Percentage of Participants With Boolean Remission at All Measured Timepoints Week 24	15.2 percentage of participants	16.7 percentage of participants	26.5 percentage of participants
Percentage of Participants With Boolean Remission at All Measured Timepoints Week 36	14.6 percentage of participants	20.4 percentage of participants	27.1 percentage of participants
Percentage of Participants With Boolean Remission at All Measured Timepoints Week 48	20.2 percentage of participants	13.3 percentage of participants	25.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 24, Week 36 and Week 48

Population: Primary Analysis Set: all randomized participants. Observed cases at given timepoint.

Percentage of participants who fulfilled disease-worsening criteria for the first time is presented. Disease worsening is defined as any of the following:

• an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart
• SDAI > 3.3 and ≤ 11 on 3 or more separate visits
• SDAI > 11 after randomization.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=101 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=101 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=51 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants With Disease Worsening Baseline	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With Disease Worsening Week 48	4.8 percentage of participants	0.0 percentage of participants	4.3 percentage of participants
Percentage of Participants With Disease Worsening Week 12	42.0 percentage of participants	23.0 percentage of participants	17.6 percentage of participants
Percentage of Participants With Disease Worsening Week 24	8.7 percentage of participants	14.6 percentage of participants	6.1 percentage of participants
Percentage of Participants With Disease Worsening Week 36	10.1 percentage of participants	3.2 percentage of participants	8.3 percentage of participants

SECONDARY outcome

Timeframe: up to Week 48

Population: Primary Analysis Set: all randomized participants. Participants with disease worsening.

Disease worsening is defined as any of the following:

• an SDAI > 3.3 and ≤ 11 during 2 consecutive visits at least 2 weeks apart
• SDAI > 3.3 and ≤ 11 on 3 or more separate visits
• SDAI > 11 after randomization.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=63 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=40 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=18 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Time to Disease Worsening	12.14 weeks Interval 2.3 to 48.7	13.21 weeks Interval 3.0 to 36.1	18.93 weeks Interval 7.0 to 48.1

SECONDARY outcome

Timeframe: Between rescue and remission or Week 48, whichever comes first.

Population: Rescue Analysis Set: randomized participants who met the definition of disease-worsening and received both at least 1 dose of active rescue therapy etanercept and at least 1 dose of active rescue therapy methotrexate. Participants who recaptured SDAI remission. Observed cases.

In participants who receive rescue treatment during the double-blind treatment period.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=37 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=27 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=12 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Time to Recapture SDAI Remission After Starting Rescue Treatment	11.00 weeks Interval 0.6 to 41.1	12.00 weeks Interval 6.0 to 32.0	11.36 weeks Interval 6.0 to 35.1

SECONDARY outcome

Timeframe: Week 48

Population: Rescue Analysis Set: randomized participants who met the definition of disease-worsening and received both at least 1 dose of active rescue therapy etanercept and at least 1 dose of active rescue therapy methotrexate. Observed cases.

The SDAI is a composite score that is based on the number of tender and swollen joints using a 28-joint count, Physician's Global Assessment of Disease Activity using a visual analog scale (VAS) where 0=no activity at all and 100=worst activity imaginable, Patient's Global Assessment of Disease Activity using a VAS where 0=no arthritis activity at all and 100=worst arthritis activity imaginable, and C-reactive protein (CRP) in mg/dL. The SDAI score ranges from 0 to 86, with higher scores representing worse disease. SDAI remission was defined as a score of ≤ 3.3.

Outcome measures

Measure	Double-Blind Treatment: Methotrexate Monotherapy n=48 Participants Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=34 Participants Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=15 Participants Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).
Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48	54.2 percentage of participants	55.9 percentage of participants	66.7 percentage of participants

Adverse Events

Open Label Run-In: Etanercept Plus Methotrexate

Serious events: 14 serious events

Other events: 29 other events

Deaths: 0 deaths

Double-Blind Treatment: Methotrexate Monotherapy

Serious events: 3 serious events

Other events: 21 other events

Deaths: 0 deaths

Double-Blind Treatment: Etanercept Monotherapy

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Double-Blind Treatment: Etanercept Plus Methotrexate

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Open Label Rescue: Etanercept Plus Methotrexate

Serious events: 4 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Measure	Open Label Run-In: Etanercept Plus Methotrexate n=368 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care.	Double-Blind Treatment: Methotrexate Monotherapy n=100 participants at risk Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=99 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=53 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).	Open Label Rescue: Etanercept Plus Methotrexate n=103 participants at risk After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).
Gastrointestinal disorders Gastric ulcer haemorrhage	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Hepatobiliary disorders Cholecystitis	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Herpes zoster	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Pneumonia	0.54% 2/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Respiratory syncytial virus infection	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.9% 1/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Injury, poisoning and procedural complications Aortic pseudoaneurysm	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Injury, poisoning and procedural complications Concussion	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Musculoskeletal and connective tissue disorders Arthritis reactive	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.9% 1/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary tumour benign	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Psychiatric disorders Alcoholism	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Psychiatric disorders Confusional state	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.97% 1/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Vascular disorders Deep vein thrombosis	0.00% 0/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.0% 1/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Cardiac disorders Atrial fibrillation	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Gastrointestinal disorders Duodenal perforation	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Abscess intestinal	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Abscess of salivary gland	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Cellulitis	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Injury, poisoning and procedural complications Foot fracture	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer stage III	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Nervous system disorders Carotid artery stenosis	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Nervous system disorders Carpal tunnel syndrome	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Nervous system disorders Cerebrovascular accident	0.54% 2/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Renal and urinary disorders Nephrolithiasis	0.27% 1/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.

Other adverse events

Measure	Open Label Run-In: Etanercept Plus Methotrexate n=368 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 24 weeks. Participants also receive folic acid as standard of care.	Double-Blind Treatment: Methotrexate Monotherapy n=100 participants at risk Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Monotherapy n=99 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).	Double-Blind Treatment: Etanercept Plus Methotrexate n=53 participants at risk Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. Participants also receive folic acid as standard of care. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment).	Open Label Rescue: Etanercept Plus Methotrexate n=103 participants at risk After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).
Infections and infestations Bronchitis	1.6% 6/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	3.0% 3/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	7.5% 4/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	0.00% 0/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Infections and infestations Upper respiratory tract infection	5.4% 20/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	3.0% 3/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	3.0% 3/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.9% 1/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	6.8% 7/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.82% 3/368 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	18.0% 18/100 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	7.1% 7/99 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	5.7% 3/53 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.	1.9% 2/103 • Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: medinfo@amgen.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
• Publication restrictions are in place

Restriction type: OTHER