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    Clinical Trial Results:
    A Randomized Withdrawal Double-blind Study of Etanercept Monotherapy Compared to Methotrexate Monotherapy for Maintenance of Remission in Subjects With Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2014-004868-38
    Trial protocol
    		 GR   CZ   HU   PT   BG   ES   FR   DE   IT  
    Global end of trial date
    06 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Dec 2020
    First version publication date
    10 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20110186
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02373813
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of etanercept monotherapy compared to methotrexate monotherapy on maintenance of remission in subjects with rheumatoid arthritis (RA) who were on etanercept plus methotrexate combination therapy.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Before a subject’s participation in the clinical study, the investigator was responsible for obtaining written informed consent from the subject after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any investigational product(s) were administered.
    Background therapy
    		 Participants also receive folic acid 5 to 7 mg per week as per investigator judgment or according to local standard of care.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Bulgaria: 21
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 35
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United States: 181
    Worldwide total number of subjects
    371
    EEA total number of subjects
    135
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    266
    From 65 to 84 years
    104
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 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.

    Pre-assignment
    Screening details
    		 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.

    Period 1
    Period 1 title
    Run-In Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open Label Run-In: Etanercept plus Methotrexate
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept dosing in the study followed the recommended label dosing for subjects with RA (subcutaneous injection, 50 mg once weekly).

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate dosing in the study will be 10 to 25 mg weekly, consistent with the participant’s dosing prior to screening.

    Number of subjects in period 1
    		Open Label Run-In: Etanercept plus Methotrexate
    Started
    371
    Treated
    368
    Completed
    254
    Not completed
    117
         Consent withdrawn by subject
    16
         No Case Report Form
    1
         Ineligibility Determined
    3
         Adverse event, non-fatal
    3
         Decision by Sponsor
    11
         Lost to follow-up
    2
         Other, Not Specified
    5
         Protocol deviation
    75
         Noncompliance
    1
    Period 2
    Period 2 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This was a double-blind study; both participants and investigators were blinded to treatment assignments. A participant's treatment assignment was only to be unblinded when knowledge of the treatment was essential for the further management of the participant on this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Treatment: Methotrexate Monotherapy
    Arm description
    		 Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept dosing in the study followed the recommended label dosing for subjects with RA (subcutaneous injection, 50 mg once weekly). Used as rescue treatment in this arm as needed.

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate dosing in the study will be 10 to 25 mg weekly, consistent with the participant’s dosing prior to screening.

    Investigational medicinal product name
    Placebo for etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    During the double-blind treatment period, participants receive 1 dose of etanercept placebo per week (scheduled approximately 7 days apart) for 48 weeks.

    Arm title
    		 Double-Blind Treatment: Etanercept Monotherapy
    Arm description
    		 Etanercept 50 mg weekly by subcutaneous injection plus placebo for methotrexate for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept dosing in the study followed the recommended label dosing for subjects with RA (subcutaneous injection, 50 mg once weekly).

    Investigational medicinal product name
    Placebo for methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    During the double-blind treatment period, methotrexate placebo capsules were taken once weekly by oral administration.

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate dosing in the study will be 10 to 25 mg weekly, consistent with the participant’s dosing prior to screening. Used as rescue treatment in this arm as needed.

    Arm title
    		 Double-Blind Treatment: Etanercept plus Methotrexate
    Arm description
    		 Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment). Participants also receive folic acid as standard of care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Methotrexate dosing in the study will be 10 to 25 mg weekly, consistent with the participant’s dosing prior to screening.

    Investigational medicinal product name
    etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Etanercept dosing in the study followed the recommended label dosing for subjects with RA (subcutaneous injection, 50 mg once weekly).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 was a run-in period.
    Number of subjects in period 2 [2] [3]
    		Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Started
    101
    101
    51
    Received Investigational Product (IP)
    101
    100
    51
    Received Rescue Treatment
    52 [4]
    36 [5]
    15 [6]
    Completed
    88
    92
    47
    Not completed
    13
    9
    4
         Consent withdrawn by subject
    10
    6
    3
         Decision by Sponsor
    1
    2
    -
         Lost to follow-up
    -
    1
    1
         Protocol deviation
    2
    -
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The double-blind treatment period was preceded by a run-in period.
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One participant who completed the run-in period was not randomized.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who received rescue treatment in each arm.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who received rescue treatment in each arm.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who received rescue treatment in each arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Treatment: Methotrexate Monotherapy
    Reporting group description
    		 Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept Monotherapy
    Reporting group description
    		 Etanercept 50 mg weekly by subcutaneous injection plus placebo for methotrexate for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept plus Methotrexate
    Reporting group description
    		 Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment). Participants also receive folic acid as standard of care.

    Reporting group values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate Total
    Number of subjects
    		 101 101 51 253
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.2 ± 11.4 54.8 ± 12.8 55.9 ± 12.6 -
    Sex: Female, Male
    Units:
        Female
    		 76 77 40 193
        Male
    		 25 24 11 60
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 13 19 8 40
        Not Hispanic or Latino
    		 88 82 43 213
        Unknown or Not Reported
    		 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 4 3 2 9
        Asian
    		 2 0 1 3
        Black
    		 3 7 5 15
        White
    		 92 86 42 220
        Other, Not Specified
    		 0 5 1 6

    End points

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    End points reporting groups
    Reporting group title
    Open Label Run-In: Etanercept plus Methotrexate
    Reporting group description
    		 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.
    Reporting group title
    Double-Blind Treatment: Methotrexate Monotherapy
    Reporting group description
    		 Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept Monotherapy
    Reporting group description
    		 Etanercept 50 mg weekly by subcutaneous injection plus placebo for methotrexate for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg). Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept plus Methotrexate
    Reporting group description
    		 Etanercept 50 mg weekly by subcutaneous injection plus oral methotrexate 10 to 25 mg weekly for 48 weeks. After randomization, a participant experiencing protocol-defined disease worsening continued on the assigned treatments (as rescue treatment). Participants also receive folic acid as standard of care.

    Primary: Percentage of Participants with Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy

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    End point title
    		 Percentage of Participants with Simplified Disease Activity Index (SDAI) Remission (≤ 3.3) at Week 48: Etanercept Monotherapy vs. Methotrexate Monotherapy [1]
    End point description
    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. Primary Analysis Set: all randomized participants. Nonresponder imputation.
    End point type
    Primary
    End point timeframe
    Week 48
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint was to compare only these 2 arms: Etanercept Monotherapy vs. Methotrexate Monotherapy.
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects analysed
    101
    101
    Units: percentage of participants
        number (not applicable)
    28.7
    49.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [2]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    20.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.6
         upper limit
    		 33.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.7
    Notes
    [2] - The risk difference and its p-value were estimated from the chi-squared test with continuity correction.

    Secondary: Percentage of Participants with SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy

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    End point title
    		 Percentage of Participants with SDAI Remission (≤ 3.3) at Week 48: Etanercept and Methotrexate vs. Methotrexate Monotherapy [3]
    End point description
    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. Primary Analysis Set: all randomized participants. Nonresponder imputation.
    End point type
    Secondary
    End point timeframe
    Week 48
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint was to compare only these 2 arms: Etanercept Monotherapy vs. Methotrexate Monotherapy.
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101
    51
    Units: percentage of participants
        number (not applicable)
    28.7
    52.9
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [4]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    24.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.9
         upper limit
    		 40.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.3
    Notes
    [4] - The risk difference and its p-value were estimated from the chi-squared test with continuity correction.

    Secondary: SDAI Score at All Measured Timepoints

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    End point title
    		 SDAI Score at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [5]
    101 [6]
    51 [7]
    Units: score on a scale
    arithmetic mean (standard error)
        Baseline; n=100, 101, 51
    1.29 ± 0.10
    1.2 ± 0.14
    1.18 ± 0.17
        Week 12; n=100, 100, 51
    7.01 ± 1.01
    4.37 ± 0.75
    4.39 ± 1.22
        Week 24; n=92, 96, 49
    5.61 ± 0.98
    4.98 ± 0.92
    3.28 ± 0.77
        Week 36; n=89, 93, 48
    4.03 ± 0.62
    2.25 ± 0.36
    2.41 ± 0.40
        Week 48; n=84, 90, 47
    3.41 ± 0.40
    2.33 ± 0.23
    2.86 ± 0.92
    Notes
    [5] - n=observed cases at given timepoints
    [6] - n=observed cases at given timepoints
    [7] - n=observed cases at given timepoints
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Etanercept Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.89
         upper limit
    		 0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.66
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.27
         upper limit
    		 2.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.34
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.71
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.55
         upper limit
    		 1.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45

    Secondary: Change From Baseline in SDAI Score at All Measured Timepoints

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    End point title
    		 Change From Baseline in SDAI Score at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [8]
    101 [9]
    51 [10]
    Units: score on a scale
    arithmetic mean (standard error)
        Change at Week 12; n=99, 100, 51
    5.67 ± 1.00
    3.14 ± 0.75
    3.21 ± 1.19
        Change at Week 24; n=91, 96, 49
    4.42 ± 0.98
    3.78 ± 0.91
    2.14 ± 0.78
        Change at Week 36; n=88, 93, 48
    2.90 ± 0.63
    1.06 ± 0.38
    1.30 ± 0.43
        Change at Week 48; n=83, 90, 47
    2.27 ± 0.39
    1.16 ± 0.24
    1.77 ± 0.94
    Notes
    [8] - n=observed cases at given timepoint
    [9] - n=observed cases at given timepoint
    [10] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.68
         upper limit
    		 0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.63
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.99
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.25
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.071
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.75
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.45
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.34
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.11
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.91
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 -0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.73
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 -0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.45

    Secondary: Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints

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    End point title
    		 Disease Activity Score (28 Joint) Calculated Using the Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [11]
    101 [12]
    51 [13]
    Units: score on a scale
    arithmetic mean (standard error)
        Baseline; n=100, 100, 51
    1.80 ± 0.06
    1.88 ± 0.07
    1.84 ± 0.09
        Week 12; n=99, 100, 51
    2.78 ± 0.14
    2.37 ± 0.12
    2.32 ± 0.16
        Week 24; n=92, 95, 49
    2.41 ± 0.13
    2.54 ± 0.14
    2.17 ± 0.12
        Week 36; n=87, 93, 48
    2.32 ± 0.11
    2.17 ± 0.08
    2.16 ± 0.12
        Week 48; n=85, 90, 47
    2.22 ± 0.10
    2.21 ± 0.08
    2.11 ± 0.13
    Notes
    [11] - n=observed cases at given timepoint
    [12] - n=observed cases at given timepoint
    [13] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Change From Baseline in DAS28-ESR at All Measured Timepoints

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    End point title
    		 Change From Baseline in DAS28-ESR at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [14]
    101 [15]
    51 [16]
    Units: score on a scale
    arithmetic mean (standard error)
        Change at Week 12; n=98, 100, 51
    0.96 ± 0.13
    0.50 ± 0.10
    0.48 ± 0.18
        Change at Week 24; n=91, 95, 49
    0.65 ± 0.12
    0.69 ± 0.13
    0.34 ± 0.11
        Change at Week 36; n=86, 92, 48
    0.53 ± 0.10
    0.31 ± 0.08
    0.35 ± 0.12
        Change at Week 48; n=84, 89, 47
    0.43 ± 0.09
    0.34 ± 0.07
    0.32 ± 0.14
    Notes
    [14] - n=observed cases at given time point
    [15] - n=observed cases at given time point
    [16] - n=observed cases at given time point
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.18
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11

    Secondary: Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints

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    End point title
    		 Disease Activity Score (28 Joint) Using the C-Reactive Protein Formula (DAS28-CRP) at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [17]
    101 [18]
    51 [19]
    Units: score on a scale
    arithmetic mean (standard error)
        Baseline; n=101, 100, 51
    1.50 ± 0.03
    1.50 ± 0.04
    1.54 ± 0.05
        Week 12; n=100, 100, 51
    2.36 ± 0.13
    1.91 ± 0.09
    1.94 ± 0.15
        Week 24; n=92, 96, 49
    2.15 ± 0.11
    2.00 ± 0.11
    1.77 ± 0.09
        Week 36; n=89, 93, 48
    1.96 ± 0.09
    1.67 ± 0.06
    1.72 ± 0.08
        Week 48; n=84, 90, 47
    1.87 ± 0.07
    1.67 ± 0.05
    1.72 ± 0.11
    Notes
    [17] - n=observed cases at given time point
    [18] - n=observed cases at given time point
    [19] - n=observed cases at given time point
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.05
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.046
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08

    Secondary: Change From Baseline in DAS28-CRP at All Measured Timepoints

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    End point title
    		 Change From Baseline in DAS28-CRP at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [20]
    101 [21]
    51 [22]
    Units: score on a scale
    arithmetic mean (standard error)
        Change at Week 12; n=99,100, 51
    0.84 ± 0.12
    0.42 ± 0.09
    0.41 ± 0.15
        Change at Week 24; n=91, 96, 49
    0.67 ± 0.11
    0.52 ± 0.11
    0.25 ± 0.08
        Change at Week 36; n=88, 93, 48
    0.49 ± 0.09
    0.18 ± 0.06
    0.20 ± 0.08
        Change at Week 48; n=83, 90, 47
    0.40 ± 0.07
    0.19 ± 0.04
    0.21 ± 0.11
    Notes
    [20] - n=observed cases at given timepoint
    [21] - n=observed cases at given timepoint
    [22] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 -0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08

    Secondary: Clinical Disease Activity Index (CDAI) at All Measured Timepoints

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    End point title
    		 Clinical Disease Activity Index (CDAI) at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [23]
    101 [24]
    51 [25]
    Units: score on a scale
    arithmetic mean (standard error)
        Baseline; n=101, 101, 51
    1.01 ± 0.10
    0.92 ± 0.13
    0.71 ± 0.12
        Week 12; n=100, 101, 51
    6.42 ± 0.98
    4.08 ± 0.74
    3.95 ± 1.20
        Week 24; n=92, 96, 49
    5.07 ± 0.95
    4.63 ± 0.91
    2.35 ± 0.60
        Week 36; n=89, 93, 48
    3.60 ± 0.63
    1.93 ± 0.36
    2.04 ± 0.41
        Week 48; n=85, 92, 47
    3.06 ± 0.38
    2.00 ± 0.23
    2.61 ± 0.91
    Notes
    [23] - n=observed cases at given timepoint
    [24] - n=observed cases at given timepoint
    [25] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.067
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.66
         upper limit
    		 0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.62
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.76
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.23
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.95
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.38
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.04
         upper limit
    		 2.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.32
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.03
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.72
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.43
         upper limit
    		 1.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44

    Secondary: Change From Baseline in CDAI at All Measured Timepoints

    		 Close Top of page
    End point title
    		 Change From Baseline in CDAI at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [26]
    101 [27]
    51 [28]
    Units: score on a scale
    arithmetic mean (standard error)
        Change at Week 12; n=100, 101, 51
    5.39 ± 0.97
    3.15 ± 0.73
    3.24 ± 1.17
        Change at Week 24; n=92, 96, 49
    4.09 ± 0.95
    3.75 ± 0.90
    1.70 ± 0.61
        Change at Week 36; n=89, 93, 48
    2.69 ± 0.63
    1.07 ± 0.37
    1.41 ± 0.40
        Change at Week 48; n=85, 92, 47
    2.17 ± 0.37
    1.15 ± 0.23
    2.00 ± 0.92
    Notes
    [26] - n=observed cases at given timepoint
    [27] - n=observed cases at given timepoint
    [28] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.29
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.59
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Change at Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.067
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.63
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.21
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.62
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.37
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Change at Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.91
         upper limit
    		 2.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.3
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.75
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.91
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Change at Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.72
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.15
         upper limit
    		 1.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Change at Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 two sample t-test
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.88
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43

    Secondary: Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints

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    End point title
    		 Percentage of Participants With SDAI Remission (≤ 3.3) at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [29]
    101 [30]
    51 [31]
    Units: percentage of participants
    number (not applicable)
        Baseline; n=100, 101, 51
    96.0
    92.1
    96.1
        Week 12; n=100, 100, 51
    50.0
    64.0
    74.5
        Week 24; n=98, 99, 50
    38.8
    56.6
    62.0
        Week 36; n=97, 99, 49
    36.1
    55.6
    55.1
        Week 48; n=95, 96, 48
    30.5
    52.1
    56.3
    Notes
    [29] - n=observed cases at given time point
    [30] - n=observed cases at given time point
    [31] - n=observed cases at given time point
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [32]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 6.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [32] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [33]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 2.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.3
    Notes
    [33] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    24.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9
         upper limit
    		 40
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.9
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.063 [34]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 27.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.9
    Notes
    [34] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    23.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.7
         upper limit
    		 39.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.4
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018 [35]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    17.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 31.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    7
    Notes
    [35] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 35.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.6
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    19.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.8
         upper limit
    		 33.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [36]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    25.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.9
         upper limit
    		 42.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.6
    Notes
    [36] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [37]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    21.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.9
         upper limit
    		 35.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    7
    Notes
    [37] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.

    Secondary: Percentage of Participants With Boolean Remission at All Measured Timepoints

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    End point title
    		 Percentage of Participants With Boolean Remission at All Measured Timepoints
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [38]
    101 [39]
    51 [40]
    Units: percentage of participants
    number (not applicable)
        Baseline; n=100, 101, 51
    34.0
    34.7
    45.1
        Week 12; n=100, 100, 51
    18.0
    23.0
    19.6
        Week 24; n=92, 96, 49
    15.2
    16.7
    26.5
        Week 36; n=89, 93, 48
    14.6
    20.4
    27.1
        Week 48; n=84, 90, 47
    20.2
    13.3
    25.5
    Notes
    [38] - n=observed cases at given timepoint
    [39] - n=observed cases at given timepoint
    [40] - n=observed cases at given timepoint
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [41]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 27.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.4
    Notes
    [41] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Baseline
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [42]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.5
         upper limit
    		 13.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.7
    Notes
    [42] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98 [43]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 14.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.8
    Notes
    [43] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 12
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48 [44]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 16.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.7
    Notes
    [44] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16 [45]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 25.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.3
    Notes
    [45] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Week 24
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [46]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 11.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.3
    Notes
    [46] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12 [47]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 27
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.4
    Notes
    [47] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Week 36
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4 [48]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 16.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.6
    Notes
    [48] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.63 [49]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.8
         upper limit
    		 20.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.7
    Notes
    [49] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Week 48
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31 [50]
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 4.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.7
    Notes
    [50] - The risk difference and its p-value were estimated from the Chi-squared test with continuity correction.

    Secondary: Percentage of Participants With Disease Worsening

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    End point title
    		 Percentage of Participants With Disease Worsening
    End point description
    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. Primary Analysis Set: all randomized participants. Observed cases at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36 and Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    101 [51]
    101 [52]
    51 [53]
    Units: percentage of participants
    number (not applicable)
        Baseline; n=100, 101, 51
    0.0
    0.0
    0.0
        Week 12; n=100, 100, 51
    42.0
    23.0
    17.6
        Week 24; n=92, 96, 49
    8.7
    14.6
    6.1
        Week 36; n=89, 93, 48
    10.1
    3.2
    8.3
        Week 48; n=84, 90, 47
    4.8
    0.0
    4.3
    Notes
    [51] - n=observed cases at given timepoint
    [52] - n=observed cases at given timepoint
    [53] - n=observed cases at given timepoint
    No statistical analyses for this end point

    Secondary: Time to Disease Worsening

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    End point title
    		 Time to Disease Worsening
    End point description
    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. Primary Analysis Set: all randomized participants. Participants with disease worsening.
    End point type
    Secondary
    End point timeframe
    up to Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    63
    40
    18
    Units: weeks
        arithmetic mean (standard error)
    17.22 ± 1.70
    17.14 ± 1.45
    23.16 ± 3.22
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [54]
    Method
    		 Logrank
    Confidence interval
    Notes
    [54] - P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [55]
    Method
    		 Logrank
    Confidence interval
    Notes
    [55] - P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.

    Secondary: Time to Recapture SDAI Remission After Starting Rescue Treatment

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    End point title
    		 Time to Recapture SDAI Remission After Starting Rescue Treatment
    End point description
    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. 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.
    End point type
    Secondary
    End point timeframe
    Between rescue and remission or Week 48, whichever comes first.
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    37
    27
    12
    Units: weeks
        arithmetic mean (standard error)
    13.42 ± 1.55
    15.70 ± 1.37
    13.38 ± 2.19
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31 [56]
    Method
    		 Logrank
    Confidence interval
    Notes
    [56] - P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept Monotherapy
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51 [57]
    Method
    		 Logrank
    Confidence interval
    Notes
    [57] - P-value was based on the Log-rank test for overall difference on disease-worsening event between two groups.

    Secondary: Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48

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    End point title
    		 Percentage of Participants Receiving Rescue Treatment Who Experienced SDAI Remission at Week 48
    End point description
    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. 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.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects analysed
    48
    34
    15
    Units: percentage of participants
        number (not applicable)
    54.2
    55.9
    66.7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Double-Blind Treatment: Methotrexate Monotherapy v Double-Blind Treatment: Etanercept plus Methotrexate
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Chi-squared corrected
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 40.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Open-Label Run-In period: from enrollment up to 24 weeks. Double-Blind Treatment period: from randomization up to 48 weeks plus 30 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Open Label Run-In: Etanercept plus Methotrexate
    Reporting group description
    		 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.

    Reporting group title
    Double-Blind Treatment: Methotrexate Monotherapy
    Reporting group description
    		 Oral methotrexate 10 to 25 mg weekly plus placebo for etanercept for 48 weeks. Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept Monotherapy
    Reporting group description
    		 Etanercept 50 mg weekly by subcutaneous injection plus placebo to methotrexate for 48 weeks. Participants also receive folic acid as standard of care.

    Reporting group title
    Double-Blind Treatment: Etanercept plus Methotrexate
    Reporting group description
    		 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.

    Reporting group title
    Open Label Rescue: Etanercept plus Methotrexate
    Reporting group description
    		 After randomization, a participant experiencing protocol-defined disease worsening initiated rescue treatment with etanercept 50 mg QW plus methotrexate (10 to 25 mg).

    Serious adverse events
    		 Open Label Run-In: Etanercept plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate Open Label Rescue: Etanercept plus Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 368 (3.80%)
    3 / 100 (3.00%)
    3 / 99 (3.03%)
    2 / 53 (3.77%)
    4 / 103 (3.88%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pituitary tumour benign
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage III
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 53 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic pseudoaneurysm
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 53 (1.89%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess of salivary gland
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 368 (0.00%)
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 53 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open Label Run-In: Etanercept plus Methotrexate Double-Blind Treatment: Methotrexate Monotherapy Double-Blind Treatment: Etanercept Monotherapy Double-Blind Treatment: Etanercept plus Methotrexate Open Label Rescue: Etanercept plus Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 368 (7.88%)
    21 / 100 (21.00%)
    12 / 99 (12.12%)
    8 / 53 (15.09%)
    9 / 103 (8.74%)
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    3 / 368 (0.82%)
    18 / 100 (18.00%)
    7 / 99 (7.07%)
    3 / 53 (5.66%)
    2 / 103 (1.94%)
         occurrences all number
    3
    19
    7
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 368 (1.63%)
    0 / 100 (0.00%)
    3 / 99 (3.03%)
    4 / 53 (7.55%)
    0 / 103 (0.00%)
         occurrences all number
    6
    0
    3
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 368 (5.43%)
    3 / 100 (3.00%)
    3 / 99 (3.03%)
    1 / 53 (1.89%)
    7 / 103 (6.80%)
         occurrences all number
    20
    4
    5
    1
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 May 2015
    - Provided clarification for reporting hepatotoxicity as a serious adverse event - Clarified indications regarding use of etanercept in the United States and Canada, and added medical information phone number as a reference for countries other than United States and Canada - Provided clarification for inclusion criteria for etanercept use, specifying the dose - Provided clarification for inclusion criteria for methotrexate use, accommodating conversion from SC to oral route and provided clarification regarding formulation of methotrexate - Provided clarifications regarding joint assessments, to strengthen wording related to continuity of assessors in the study, and allowing for assessments by principal investigators - Provided updates throughout to reflect the number of global participating sites - Added the EudraCT number - Added medical information phone number as a reference for countries other than United States and Canada
    08 Jul 2015
    - Provided updated pregnancy and contraception language.
    30 Oct 2015
    - Updated to be consistent with international regulations and requirements.
    03 Nov 2016
    - Updated clinical hypothesis to align with the primary objective of the study. - Updated CTCAE grading version to 4.0 to reflect the most recent version. - Updated inclusion and exclusion criteria to decrease the stringency of subject eligibility. - Reduced study sample size due to adjustments in estimated effect sizes for treatment groups. - Removed prior use of a biologic agent as a covariate influencing primary and secondary endpoints. - Removed sequential testing to align with the updated clinical hypothesis.
    20 Dec 2016
    - Reduced strictness of subject re-screening criteria.
    17 Oct 2017
    - Reduced study sample size due to adjustments in estimated effect sizes for treatment groups.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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