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    Clinical Trial Results:
    A Phase IV Registry of Etanercept in Children With Juvenile Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2012-001171-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    31 Jan 2008

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20021626
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00078793
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    Amgen Medical Information, Amgen, 001 8007726436, medinfo@amgen.com
    Scientific contact
    Amgen Medical Information, Amgen, 001 8007726436, medinfo@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000029-PIP01-08
    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
    31 Jan 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the long-term safety of etanercept administered with or without other disease-modifying anti-rheumatic drugs (DMARDS) in pediatric subjects with polyarticular course or systemic juvenile rheumatoid arthritis (JRA) compared to a control cohort of subjects with polyarticular course or systemic JRA receiving methotrexate (with or without other DMARDS).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH), and Good Clinical Practice (GCP) regulations/guidelines. All subjects, or their legally acceptable guardian/representative, provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and the sponsor received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2000
    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
    United States: 563
    Country: Number of subjects enrolled
    Canada: 31
    Worldwide total number of subjects
    594
    EEA total number of subjects
    0
    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)
    3
    Children (2-11 years)
    353
    Adolescents (12-17 years)
    227
    Adults (18-64 years)
    11
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was a multicenter registry utilizing study sites from the Pediatric Rheumatology Collaborative Study Group (PRCSG) in the United States and Canada.

    Pre-assignment
    Screening details
    		 Boys or girls age 2 to 18 years (inclusive) with a diagnosis of systemic, polyarticular, or pauciarticular JRA defined by the American College of Rheumatology (ACR) criteria. This was a non-randomized study. Subjects who satisfied all eligibility criteria were enrolled into 1 of 3 cohorts in the study based on their baseline treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Methotrexate Only
    Arm description
    		 Subjects received methotrexate at a minimum dose of 10 mg/m²/week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Parenteral use
    Dosage and administration details
    Subjects received methotrexate at a minimum dose of 10 mg/m²/week (~ 0.3 mg/kg/week, maximum dose of 1 mg/kg/week).

    Arm title
    		 Etanercept Only
    Arm description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg (maximum dose of 50 mg/week).

    Arm title
    		 Etanercept + Methotrexate
    Arm description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg and methotrexate at a minimum dose of 10 mg/m²/week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Parenteral use
    Dosage and administration details
    Subjects received methotrexate at a minimum dose of 10 mg/m²/week (~ 0.3 mg/kg/week, maximum dose of 1 mg/kg/week).

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Enbrel
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg (maximum dose of 50 mg/week).

    Number of subjects in period 1
    		Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Started
    197
    103
    294
    Completed
    66
    47
    132
    Not completed
    131
    56
    162
         Physician decision
    4
    3
    4
         Insufficient therapeutic effect
    36
    8
    59
         Other
    30
    16
    48
         Adverse event
    3
    2
    1
         Refusal - subject
    8
    4
    13
         Remission
    24
    8
    12
         Refusal - parent/guardian
    9
    5
    11
         Protocol deviation
    17
    10
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Methotrexate Only
    Reporting group description
    		 Subjects received methotrexate at a minimum dose of 10 mg/m²/week.

    Reporting group title
    Etanercept Only
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg.

    Reporting group title
    Etanercept + Methotrexate
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg and methotrexate at a minimum dose of 10 mg/m²/week.

    Reporting group values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate Total
    Number of subjects
    		 197 103 294 594
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.02 ± 4.4 10.78 ± 4.1 10.09 ± 4.69 -
    Gender categorical
    Units: Subjects
        Female
    		 145 83 214 442
        Male
    		 52 20 80 152
    Race
    Units: Subjects
        Asian
    		 1 4 6 11
        African American
    		 12 5 29 46
        Caucasian
    		 151 78 214 443
        Hispanic
    		 24 7 29 60
        Native American
    		 0 1 1 2
        Other
    		 9 8 15 32
    JRA Disease Duration
    Units: months
        arithmetic mean (standard deviation)
    		 20.15 ± 30.69 58.11 ± 44.53 40.66 ± 41.68 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 133.02 ± 25.29 141.19 ± 22.79 137.2 ± 26.23 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 37.18 ± 20.82 42.68 ± 22.82 40.14 ± 21.84 -

    End points

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    End points reporting groups
    Reporting group title
    Methotrexate Only
    Reporting group description
    		 Subjects received methotrexate at a minimum dose of 10 mg/m²/week.

    Reporting group title
    Etanercept Only
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg.

    Reporting group title
    Etanercept + Methotrexate
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg and methotrexate at a minimum dose of 10 mg/m²/week.

    Subject analysis set title
    Methotrexate: Age ≤ 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects ≤ 4 years of age who received methotrexate only.

    Subject analysis set title
    Etanercept: Age ≤ 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects ≤ 4 years of age who received etanercept only.

    Subject analysis set title
    Etanercept+MTX: Age ≤ 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects ≤ 4 years old who received etanercept and methotrexate.

    Subject analysis set title
    Methotrexate: Age 5-7
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 5-7 years old who received methotrexate only.

    Subject analysis set title
    Etanercept: Age 5-7
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 5-7 years old who received etanercept only.

    Subject analysis set title
    Etanercept+MTX: Age 5-7
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 5-7 years old who received etanercept and methotrexate.

    Subject analysis set title
    Methotrexate: Age 8-12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 8-12 years old who received methotrexate only.

    Subject analysis set title
    Etanercept: Age 8-12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 8-12 years old who received etanercept only.

    Subject analysis set title
    Etanercept+MTX: Age 8-12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 8-12 years old who received etanercept and methotrexate

    Subject analysis set title
    Methotrexate: Age 13-18
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 13-18 years old who received methotrexate only.

    Subject analysis set title
    Etanercept: Age 13-18
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 13-18 years old who received etanercept only.

    Subject analysis set title
    Etanercept+MTX: Age 13-18
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 13-18 years old who received etanercept and methotrexate.

    Primary: Number of subjects with adverse events

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    End point title
    		 Number of subjects with adverse events
    End point description
    The severity grading scale used in this study was common toxicity criteria (CTC) version 2.0.
    End point type
    Primary
    End point timeframe
    36 months
    End point values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Number of subjects analysed
    197
    103
    294
    Units: subjects
        Any adverse event
    43
    26
    78
        Infectious episodes
    4
    4
    11
        AEs leading to withdrawal from drug
    5
    1
    9
        Serious adverse events
    14
    9
    28
        Medically important infections
    4
    4
    11
        Death
    0
    0
    0
        Autoimmune diseases
    15
    8
    13
        Grade 3 or 4 adverse events
    13
    11
    29
        Cancers
    0
    0
    0
    Statistical analysis title
    		 Any Adverse Events
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2242
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Infectious Episodes
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3004
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 AEs Leading to Withdrawal from Drug
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5794
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Serious Adverse Events
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4384
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Medically Important Infections
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3004
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Autoimmune Diseases
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.675
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Grade 3 and 4 Adverse Events
    Statistical analysis description
    Comparison of event rates of methotrexate only versus etanercept only or etanercept and methotrexate using logistic regression adjusted for age, sex, baseline disease characteristics and treatment crossover.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1827
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Change From Baseline in Height Percentile

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    End point title
    		 Change From Baseline in Height Percentile
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1, Year 2, Year 3 and Last Visit
    End point values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Number of subjects analysed
    197 [1]
    103 [2]
    294 [3]
    Units: percentile
    arithmetic mean (standard deviation)
        Year 1 (n=121, 69, 215)
    -0.21 ± 10.58
    1.21 ± 11.86
    2.36 ± 9.3
        Year 2 (n=91, 48, 151)
    -0.95 ± 13.78
    2.8 ± 15.11
    3.29 ± 12.61
        Year 3 (n=62, 44, 120)
    -2.38 ± 16.75
    4.8 ± 17.24
    5.58 ± 15.76
        Last Visit (n=186, 95, 269)
    -1.56 ± 14.98
    2.64 ± 13.77
    2.36 ± 14.31
    Notes
    [1] - Enrolled subjects who completed at least 1 evaluation while on drug
    [2] - Enrolled subjects who completed at least 1 evaluation while on drug
    [3] - Enrolled subjects who completed at least 1 evaluation while on drug
    Statistical analysis title
    		 Year 1
    Statistical analysis description
    Comparison of mean percentile change in height in methotrexate alone versus etanercept alone or etanercpt plus methotrexate
    Comparison groups
    Etanercept Only v Etanercept + Methotrexate v Methotrexate Only
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0497
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Year 2
    Statistical analysis description
    Comparison of mean percentile change in height in methotrexate alone versus etanercept alone or etanercpt plus methotrexate
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Year 3
    Statistical analysis description
    Comparison of mean percentile change in height in methotrexate alone versus etanercept alone or etanercpt plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Last Visit
    Statistical analysis description
    Comparison of mean percentile change in height in methotrexate alone versus etanercept alone or etanercpt plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0049
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change From Baseline in Weight Percentile

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    End point title
    		 Change From Baseline in Weight Percentile
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1, Year 2, Year 3 and Last Visit
    End point values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Number of subjects analysed
    197 [4]
    103 [5]
    294 [6]
    Units: percentile
    arithmetic mean (standard deviation)
        Year 1 (n=122, 71, 218)
    1.59 ± 14.02
    7.44 ± 12.85
    2.91 ± 13.52
        Year 2 (n=92, 48, 152)
    1.55 ± 11.25
    9.97 ± 16.96
    6.93 ± 14.99
        Year 3 (n=64, 44, 122)
    -1.4 ± 15.2
    13.01 ± 20.88
    8.38 ± 16.42
        Last Visit (n=189, 98, 272)
    0.98 ± 14.27
    5.9 ± 18.83
    4.05 ± 16.12
    Notes
    [4] - Enrolled subjects completing at least 1 evaluation while on drug
    [5] - Enrolled subjects completing at least 1 evaluation while on drug
    [6] - Enrolled subjects completing at least 1 evaluation while on drug
    Statistical analysis title
    		 Year 1
    Statistical analysis description
    Comparison of mean percentile change in weight in methotrexate only versus etanercept only or etanercept plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2975
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Year 2
    Statistical analysis description
    Comparison of mean percentile change in weight in methotrexate only versus etanercept only or etanercept plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0051
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Year 3
    Statistical analysis description
    Comparison of mean percentile change in weight in methotrexate only versus etanercept only or etanercept plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Last Visit
    Statistical analysis description
    Comparison of mean percentile change in weight in methotrexate only versus etanercept only or etanercept plus methotrexate.
    Comparison groups
    Methotrexate Only v Etanercept Only v Etanercept + Methotrexate
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0041
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Tanner Stage Assessment by Age Group Over Time

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    End point title
    		 Tanner Stage Assessment by Age Group Over Time
    End point description
    Tanner assessment scores document the stage of development of secondary sexual characteristics. Female pubertal development staged by breast size; male pubertal development staged by size of the external genitalia. Rated in 5 stages: stage 1 (prepubertal) to 5 (adult-like development). "n" indicates the number of subjects with available data in each age and treatment group at each time point. Please note that for the Etanercept: Age ≤ 4 group, standard deviation could not be calculated for Month 6 and Month 24 due to a sample size of 1.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 6, 12, 18, 24, 30 and 36
    End point values
    		 Methotrexate: Age ≤ 4 Etanercept: Age ≤ 4 Etanercept+MTX: Age ≤ 4 Methotrexate: Age 5-7 Etanercept: Age 5-7 Etanercept+MTX: Age 5-7 Methotrexate: Age 8-12 Etanercept: Age 8-12 Etanercept+MTX: Age 8-12 Methotrexate: Age 13-18 Etanercept: Age 13-18 Etanercept+MTX: Age 13-18
    Number of subjects analysed
    38
    9
    47
    41
    15
    56
    66
    41
    85
    52
    38
    106
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=20,3,19,20,6,24,33,14,29,19,10,31)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.6 ± 0.8
    1.6 ± 1.2
    1.7 ± 1.1
    4.2 ± 1.1
    4.2 ± 0.8
    4.4 ± 0.8
        Month 6 (n=14,1,15,19,4,18,22,13,25,13,7,30)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    2.2 ± 1.4
    1.6 ± 1
    1.9 ± 1.2
    4.4 ± 1
    4.6 ± 0.5
    4.3 ± 0.9
        Month 12 (n=11,3,13,19,5,14,20,12,24,9,7,25)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.2 ± 0.4
    1 ± 0
    2.5 ± 1.5
    1.6 ± 1
    2.6 ± 1.3
    4.3 ± 1.1
    4.7 ± 0.5
    4.4 ± 0.6
        Month 18 (n=7,3,10,16,5,14,17,9,20,8,4,21)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    2.4 ± 1.4
    1.8 ± 1.1
    2.8 ± 1.5
    4.8 ± 0.5
    4.8 ± 0.5
    4.5 ± 0.7
        Month 24 (=8,1,11,14,3,15,16,8,19,7,5,15)
    1 ± 0
    1 ± 0
    1 ± 0
    1.1 ± 0.4
    1 ± 0
    1.1 ± 0.4
    2.8 ± 1.6
    2 ± 1.1
    3.1 ± 1.4
    4.7 ± 0.5
    4.8 ± 0.4
    4.6 ± 0.6
        Month 30 (n=5,2,8,10,2,12,11,8,16,5,5,13)
    1 ± 0
    1 ± 0
    1 ± 0
    1.2 ± 0.4
    1.5 ± 0.7
    1.1 ± 0.3
    2.9 ± 1.6
    2.6 ± 1.3
    3.3 ± 1.4
    4.6 ± 0.5
    4.8 ± 0.4
    4.8 ± 0.4
        Month 36 (=4,2,8,6,3,11,9,6,13,5,4,15)
    1 ± 0
    1 ± 0
    1 ± 0
    1.3 ± 0.5
    1.3 ± 0.6
    1.5 ± 0.5
    3.3 ± 1.7
    2.5 ± 1.4
    3.4 ± 1.2
    4.6 ± 0.5
    5 ± 0
    4.8 ± 0.6
    No statistical analyses for this end point

    Secondary: Tanner Pubic Stage Assessment by Age Over Time

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    End point title
    		 Tanner Pubic Stage Assessment by Age Over Time
    End point description
    The Tanner pubic hair scale ranges from stage 1 (no pubic hair at all; prepubertal state) to stage 5 (hair extends to medial surface of the thighs. "n" indicates the number of subjects with available data in each age and treatment group at each time point. Note that the standard deviation could not be calculated for the Etanercept: Age ≤ 4 group at Month 6 and Month 24 as the sample size was 1.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 6, 12, 18, 24, 30 and 36
    End point values
    		 Methotrexate: Age ≤ 4 Etanercept: Age ≤ 4 Etanercept+MTX: Age ≤ 4 Methotrexate: Age 5-7 Etanercept: Age 5-7 Etanercept+MTX: Age 5-7 Methotrexate: Age 8-12 Etanercept: Age 8-12 Etanercept+MTX: Age 8-12 Methotrexate: Age 13-18 Etanercept: Age 13-18 Etanercept+MTX: Age 13-18
    Number of subjects analysed
    38
    9
    47
    41
    15
    56
    66
    41
    85
    52
    38
    106
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=20,3,19,20,6,24,33,14,28,19,10,31)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.6 ± 0.8
    1.6 ± 1.2
    1.6 ± 1
    4.4 ± 1
    4.1 ± 1.1
    4.4 ± 0.8
        Month 6 (n=14,1,15,19,4,18,23,14,25,13,7,30)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    2.1 ± 0.4
    1.6 ± 1.1
    2 ± 1.2
    4.4 ± 1.2
    4.6 ± 0.5
    4.3 ± 0.9
        Month 12 (n=11,3,13,19,5,14,20,12,23,9,7,26)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.2 ± 0.4
    1 ± 0
    2.4 ± 1.5
    1.7 ± 1.1
    2.4 ± 1.4
    4.3 ± 1.1
    4.6 ± 0.5
    4.5 ± 0.6
        Month 18 (n=7,3,10,16,5,14,17,9,20,8,4,21)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.1 ± 0.3
    2.5 ± 1.4
    1.7 ± 1.1
    2.7 ± 1.5
    4.8 ± 0.5
    4.8 ± 0.5
    4.4 ± 0.9
        Month 24 (n=8,1,11,14,3,15,15,8,19,7,5,15)
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1 ± 0
    1.1 ± 0.3
    2.9 ± 1.5
    1.8 ± 1
    3.1 ± 1.4
    4.7 ± 0.5
    4.8 ± 0.4
    4.5 ± 0.6
        Month 30 (n=5,2,8,10,2,12,12,8,17,5,5,13)
    1 ± 0
    1 ± 0
    1 ± 0
    1.1 ± 0.3
    1 ± 0
    1.2 ± 0.4
    3 ± 1.4
    2.5 ± 1.3
    3.2 ± 1.4
    4.8 ± 0.4
    4.8 ± 0.4
    4.7 ± 0.5
        Month 36 (n=4,2,8,6,3,11,9,6,13,5,4,15)
    1 ± 0
    1 ± 0
    1 ± 0
    1.3 ± 0.5
    1 ± 0
    1.1 ± 0.3
    3.3 ± 1.7
    2.7 ± 1.6
    3.3 ± 1.3
    4.8 ± 0.4
    5 ± 0
    4.7 ± 0.6
    No statistical analyses for this end point

    Secondary: Child Behavior Checklist (Ages 4 to 18) Total Problem Score Over Time

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    End point title
    		 Child Behavior Checklist (Ages 4 to 18) Total Problem Score Over Time
    End point description
    The Child Behavior Checklist (CBCL) is a checklist parents complete to detect emotional and behavioural problems in children and adolescents. For subjects 4 to 18 years old the checklist consists of 110 single-item questions and one 8-item question including the following behaviors: withdrawn, somatic problems, anxious/depressed, social problems, thought problems, attention problems, delinquent behavior, aggressive behavior, sex problems, and other problems. Each question is scored on a three-point Likert scale (0=absent, 1= occurs sometimes, 2=occurs often). The total score is obtained by adding responses to all questions (excluding question on asthma and allergy); the range of the total score is 0 to 236 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline, and Months 3, 6, 9, 12, 18, 24, 30, and 36
    End point values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Number of subjects analysed
    162
    91
    248
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=162, 91, 248)
    21.85 ± 16.44
    17.56 ± 16.97
    20.5 ± 17.89
        Month 3 (n=145, 81, 232)
    16.04 ± 13.3
    15.94 ± 17
    16.38 ± 14.41
        Month 6 (n=123, 76, 212)
    15.74 ± 14.96
    16.88 ± 19.57
    15.61 ± 16.3
        Month 9 (n=109, 68, 196)
    14.21 ± 14.54
    12.85 ± 14.66
    14.78 ± 15.28
        Month 12 (n=108, 65, 198)
    14.25 ± 13.77
    13.43 ± 18.13
    14.43 ± 14.24
        Month 18 (n=98, 56, 166)
    13.02 ± 14.43
    14.21 ± 17.3
    14.45 ± 14.57
        Month 24 (n=88, 46, 139)
    11.89 ± 13.49
    14.87 ± 13.99
    15.71 ± 17.72
        Month 30 (n=68, 43, 133)
    12.79 ± 13.92
    15.84 ± 16.41
    14.38 ± 15.12
        Month 36/Early Discontinuation (n=141, 75, 210)
    13.47 ± 14.04
    13.35 ± 14.85
    14.92 ± 15.93
    No statistical analyses for this end point

    Secondary: Child Behavior Checklist (Ages 2 to 3) Total Problem Score Over Time

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    End point title
    		 Child Behavior Checklist (Ages 2 to 3) Total Problem Score Over Time
    End point description
    The Child Behavior Checklist (CBCL) is a checklist parents complete to detect emotional and behavioural problems in children and adolescents. For subjects 2 to 3 years old the checklist consists of 100 single-item questions including the following behaviors: anxious/depressed, withdrawn, sleep problems, somatic problems, aggressive behavior, destructive behavior, and other problems. Each question is scored on a three-point Likert scale (0=absent, 1= occurs sometimes, 2=occurs often). The total score is obtained by adding responses to all questions; the range of the total score is 0 to 200 (worst). "0" indicates values that could not be calculated due to a sample size of 0 or 1.
    End point type
    Secondary
    End point timeframe
    Baseline and Months 3, 6, 9, 12, 18, 24, and 36
    End point values
    		 Methotrexate Only Etanercept Only Etanercept + Methotrexate
    Number of subjects analysed
    25
    6
    28
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=25, 6, 28)
    36.32 ± 21.36
    38.33 ± 16.98
    32.25 ± 20.58
        Month 3 (n=16, 6, 18)
    34.69 ± 24.24
    30.5 ± 17.69
    30.61 ± 23.63
        Month 6 (n=10, 4, 15)
    29.9 ± 11.99
    23.75 ± 17.08
    31.27 ± 24.85
        Month 9 (n=12, 1, 7)
    27.58 ± 20.97
    52 ± 0
    25.43 ± 15.75
        Month 12 (n=8, 0, 8)
    17.88 ± 14.13
    0 ± 0
    26 ± 15
        Month 18 (n=5, 0, 4)
    7.8 ± 7.85
    0 ± 0
    33.25 ± 25.05
        Month 24 (n=0, 0, 3)
    0 ± 0
    0 ± 0
    25.67 ± 18.9
        Month 36/Early Discontinuation (n=5, 2, 3)
    39.8 ± 33.51
    29 ± 2.83
    61.67 ± 16.56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    36 months
    Adverse event reporting additional description
    Enbrel Protocol 20021626
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Methotrexate Only
    Reporting group description
    		 Subjects received methotrexate at a minimum dose of 10 mg/m²/week.

    Reporting group title
    Etanercept + Methotrexate
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg and methotrexate at a minimum dose of 10 mg/m²/week.

    Reporting group title
    Etanercept Only
    Reporting group description
    		 Subjects received weekly subcutaneous injections of etanercept at a dose of 0.8 mg/kg.

    Serious adverse events
    		 Methotrexate Only Etanercept + Methotrexate Etanercept Only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 197 (7.11%)
    28 / 294 (9.52%)
    9 / 103 (8.74%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vesicoureteral reflux surgery
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Histiocytosis haematophagic
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 294 (1.02%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perianal abscess
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 197 (0.51%)
    5 / 294 (1.70%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 294 (0.34%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aseptic meningitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteremia
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycoplasma infection
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 197 (0.00%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus insulin-dependent
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Methotrexate Only Etanercept + Methotrexate Etanercept Only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 197 (10.66%)
    30 / 294 (10.20%)
    10 / 103 (9.71%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 197 (3.05%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences all number
    8
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 197 (2.03%)
    1 / 294 (0.34%)
    0 / 103 (0.00%)
         occurrences all number
    5
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    4 / 197 (2.03%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    5
    0
    0
    Injury, poisoning and procedural complications
    Treatment noncompliance
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 294 (1.02%)
    0 / 103 (0.00%)
         occurrences all number
    0
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 294 (1.02%)
    1 / 103 (0.97%)
         occurrences all number
    0
    3
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 197 (0.51%)
    4 / 294 (1.36%)
    1 / 103 (0.97%)
         occurrences all number
    1
    5
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    2 / 197 (1.02%)
    3 / 294 (1.02%)
    2 / 103 (1.94%)
         occurrences all number
    3
    3
    2
    Agitation
         subjects affected / exposed
    3 / 197 (1.52%)
    0 / 294 (0.00%)
    1 / 103 (0.97%)
         occurrences all number
    4
    0
    1
    Anger
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 294 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    3
    0
    0
    Anxiety
         subjects affected / exposed
    2 / 197 (1.02%)
    3 / 294 (1.02%)
    3 / 103 (2.91%)
         occurrences all number
    3
    3
    5
    Depression
         subjects affected / exposed
    3 / 197 (1.52%)
    11 / 294 (3.74%)
    3 / 103 (2.91%)
         occurrences all number
    3
    12
    3
    Insomnia
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 294 (1.02%)
    2 / 103 (1.94%)
         occurrences all number
    0
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 197 (1.02%)
    6 / 294 (2.04%)
    0 / 103 (0.00%)
         occurrences all number
    2
    6
    0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 294 (1.02%)
    0 / 103 (0.00%)
         occurrences all number
    0
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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