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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of the Human Anti-TNF Monoclonal Antibody Adalimumab in Children With Polyarticular Juvenile Rheumatoid Arthritis

    Summary
    EudraCT number
    2011-001661-40
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    02 Jun 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    DE038
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00048542
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    1 North Waukegan Road, North Chicago, IL, United States, 60064
    Public contact
    Global Medical Information, AbbVie, 001 800-633-9110,
    Scientific contact
    Aileen L. Pangan MD , AbbVie, aileen.pangan@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000036-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
    02 Jun 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a multicenter, Phase 3 randomized, placebo-controlled study designed to evaluate adalimumab in children 4 to 17 years old with polyarticular juvenile idiopathic arthritis (JIA) who are either methotrexate (MTX) treated or non-MTX treated.
    Protection of trial subjects
    The subject and/or parent or legal guardian read and understood information provided about the study and signed an informed consent form. Additionally, a written informed assent was obtained from all children in accordance with individual IRB recommendations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Sep 2002
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 88
    Worldwide total number of subjects
    171
    EEA total number of subjects
    83
    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)
    88
    Adolescents (12-17 years)
    82
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects enrolled at 31 sites in Belgium, Czech Republic, France, Germany, Italy,Slovakia, Spain, and the United States. Subjects were methotrexate (MTX)-naive or had been withdrawn from MTX at least 2 weeks prior to study drug administration (non-MTX stratum), or were inadequate responders to MTX and continued MTX treatment (MTX stratum).

    Pre-assignment
    Screening details
    A total of 171 subjects entered the Open-Label Lead-In (OL-LI) phase and received adalimumab; 160 subjects completed the OL-LI phase; and 133 entered the 32-week Double-Blind Phase (75 in the MTX stratum; 58 in the non-MTX stratum) and were randomized to adalimumab or placebo. For all groups, started indicates when subjects entered the DB Phase.

    Period 1
    Period 1 title
    Double-blind Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Double-Blind Adalimumab + MTX
    Arm description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.
    Arm type
    Experimental

    Investigational medicinal product name
    Double-Blind Adalimumab/Placebo + MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) concomitantly with MTX treatment for 32 weeks during the Double-Blind phase. Total body dose of adalimumab was not to exceed 40 mg.

    Arm title
    Double-Blind Placebo + MTX
    Arm description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.
    Arm type
    Placebo

    Investigational medicinal product name
    Double-Blind Adalimumab/Placebo + MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) concomitantly with MTX treatment for 32 weeks during the Double-Blind phase. Total body dose of adalimumab was not to exceed 40 mg.

    Arm title
    Double-Blind Adalimumab
    Arm description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Double-Blind Adalimumab/Placebo
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) without MTX treatment for 32 weeks during the Double-Blind Phase. Total body dose of adalimumab was not to exceed 40 mg.

    Arm title
    Double-Blind Placebo
    Arm description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose, administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.
    Arm type
    Placebo

    Investigational medicinal product name
    Double-Blind Adalimumab/Placebo
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of 24 mg adalimumab or placebo per square meter of body surface area (BSA) every other week (eow) without MTX treatment for 32 weeks during the Double-Blind Phase. Total body dose of adalimumab was not to exceed 40 mg.

    Number of subjects in period 1 [1]
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX Double-Blind Adalimumab Double-Blind Placebo
    Started
    38
    37
    30
    28
    Completed
    35
    36
    29
    28
    Not completed
    3
    1
    1
    0
         Protocol deviation
             -
             -
             1
             -
         Consent withdrawn by subject
             -
             1
             -
             -
         Randomized in error
             1
             -
             -
             -
         Sponsor request or decision
             2
             -
             -
             -
    Notes
    [1] - 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: For all groups, started indicates when the subjects entered the DB Phase.
    Period 2
    Period 2 title
    Open-label Extension BSA Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Open-label Extension BSA Adalimumab + MTX
    Arm description
    Subjects in the methotrexate (MTX) stratum received subcutaneous injections of 24 mg adalimumab per square meter of body surface area (BSA) up to a maximum of 40 mg total body dose every other week (eow) concomitantly with MTX treatment during the Open-Label Extension BSA Phase of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    OLE BSA Adalimumab/Placebo +/- MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Comparison of subcutaneous injection of 24 mg adalimumab per square meter of body surface area (BSA) every other week (eow) either with or without concomitant MTX treatment for a minimum of 44 weeks (up to a maximum of 136 weeks) during the Open-Label Extension BSA Phase.

    Arm title
    Open-label Extension BSA Adalimumab
    Arm description
    Subjects in the non-methotrexate (MTX) stratum received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose SC eow) without concomitant MTX treatment during the Open-Label Extension BSA Phase.
    Arm type
    Experimental

    Investigational medicinal product name
    OLE BSA Adalimumab/Placebo +/- MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Comparison of subcutaneous injection of 24 mg adalimumab per square meter of body surface area (BSA) every other week (eow) either with or without concomitant MTX treatment for a minimum of 44 weeks (up to a maximum of 136 weeks) during the Open-Label Extension BSA Phase.

    Number of subjects in period 2
    Open-label Extension BSA Adalimumab + MTX Open-label Extension BSA Adalimumab
    Started
    71
    57
    Completed
    59
    47
    Not completed
    12
    10
         Protocol deviation
             -
             1
         Adverse event
             1
             1
         Lack of efficacy
             3
             1
         Consent withdrawn by subject
             3
             6
         Sponsor request or decision
             5
             1
    Period 3
    Period 3 title
    Open-label Extension Fixed Dose Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Open-label Extension FD Adalimumab + MTX
    Arm description
    Subjects in the methotrexate (MTX) stratum received adalimumab concomitantly with MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study in which only body weight (not BSA) determined dosing. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.
    Arm type
    Experimental

    Investigational medicinal product name
    OLE FD Adalimumab/Placebo +/- MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Comparison of adalimumab administered subcutaneously every other week (eow) either with or without concomitant MTX treatment for up to 224 weeks during the Open-Label Extension Fixed Dose (FD) Phase.

    Arm title
    Open-label Extension FD Adalimumab
    Arm description
    Subjects in the non-methotrexate (MTX) stratum received adalimumab without concomitant MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study in which body weight (not BSA) determined dosing. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.
    Arm type
    Experimental

    Investigational medicinal product name
    OLE FD Adalimumab/Placebo +/- MTX
    Investigational medicinal product code
    Other name
    ABT-D2E7, Humira
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Comparison of adalimumab administered subcutaneously every other week (eow) either with or without concomitant MTX treatment for up to 224 weeks during the Open-Label Extension Fixed Dose (FD) Phase.

    Number of subjects in period 3
    Open-label Extension FD Adalimumab + MTX Open-label Extension FD Adalimumab
    Started
    59
    47
    Completed
    37
    25
    Not completed
    22
    22
         Protocol deviation
             1
             1
         Adverse event
             2
             2
         Lack of efficacy
             2
             1
         Consent withdrawn by subject
             6
             3
         Sponsor request or decision
             6
             7
         Lost to follow-up
             5
             8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Placebo + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Reporting group title
    Double-Blind Placebo
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose, administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Reporting group values
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX Double-Blind Adalimumab Double-Blind Placebo Total
    Number of subjects
    38 37 30 28 133
    Age categorical
    Units: Subjects
    Age continuous
    Age for subjects in the Double-blind Phase only.
    Units: years
        arithmetic mean (standard deviation)
    11.7 ± 3.29 10.8 ± 3.36 11.1 ± 4.13 11.3 ± 3.77 -
    Gender categorical
    Numbers represent subjects in the Double-blind Phase only.
    Units: Subjects
        Female
    30 30 23 20 103
        Male
    8 7 7 8 30

    End points

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    End points reporting groups
    Reporting group title
    Double-Blind Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Placebo + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Reporting group title
    Double-Blind Placebo
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose, administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.
    Reporting group title
    Open-label Extension BSA Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum received subcutaneous injections of 24 mg adalimumab per square meter of body surface area (BSA) up to a maximum of 40 mg total body dose every other week (eow) concomitantly with MTX treatment during the Open-Label Extension BSA Phase of the study.

    Reporting group title
    Open-label Extension BSA Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose SC eow) without concomitant MTX treatment during the Open-Label Extension BSA Phase.
    Reporting group title
    Open-label Extension FD Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum received adalimumab concomitantly with MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study in which only body weight (not BSA) determined dosing. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.

    Reporting group title
    Open-label Extension FD Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum received adalimumab without concomitant MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study in which body weight (not BSA) determined dosing. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.

    Subject analysis set title
    Open-label Adalimumab + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received methotrexate (MTX) plus open-label adalimumab (24 mg/square meter up to a maximum of 40 mg total body dose by body surface area [BSA] administered subcutaneously [SC] every other week [eow]) during the Open-Label Lead-In (OL-LI) Phase of the study. The intent-to-treat (ITT) population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Open-label Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received open-label adalimumab (24 mg/square meter up to a maximum of 40 mg total body dose by body surface area [BSA] administered subcutaneously [SC] every other week [eow]), but no methotrexate (MTX), during the Open-Label Lead-In (OL-LI) Phase of the study. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab during the open-label lead-in phase and during the double-blind phase. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab during the open-label lead-in phase and placebo during the double-blind phase. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Adalimumab + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab plus MTX during the open-label lead-in phase and adalimumab plus MTX during the double-blind phase. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Placebo + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab plus MTX during the open-label lead-in phase and placebo plus MTX during the double-blind phase. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    OLE BSA Adalimumab + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab and concomitant MTX during the Open-Label Extension body surface area (BSA) phase. Subjects received OL adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose subcutaneously (SC) every other week (eow). The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    OLE BSA Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab, but not concomitant MTX, during the Open-Label Extension body surface area (BSA) phase. Subjects received OL adalimumab (24 mg/m2 BSA up to a maximum of 40 mg total body dose subcutaneously (SC) every other week (eow). The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    OLE FD Adalimumab + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab and concomitant MTX during the Open-Label Extension fixed dose phase. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab subcutaneously (SC) every other week (eow). Subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    OLE FD Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received adalimumab, but not concomitant MTX, during the Open-Label Extension Fixed Dose phase. Subjects weighing less than 30 kg were dosed with 20 mg of adalimumab subcutaneously (SC) every other week (eow). Subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Double-Blind Adalimumab + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Double-Blind Placebo + MTX
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Double-Blind Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study. The ITT population was defined as all subjects who were randomized and who received at least a single administration of study drug.

    Subject analysis set title
    Double-Blind Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose, administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Primary: Number of Subjects in the Non-MTX Stratum With Disease Flare During the Double-Blind Phase

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    End point title
    Number of Subjects in the Non-MTX Stratum With Disease Flare During the Double-Blind Phase
    End point description
    The primary efficacy endpoint was the number of adalimumab-treated subjects in the non-MTX stratum with disease flare during the Double-Blind Phase compared with the number of placebo-treated subjects in the non-MTX stratum with disease flare during the double-blind phase. Subjects met the criteria for disease flare if they had 1) >= 30% worsening in at least 3 of the 6 Juvenile Rheumatoid Arthritis (JRA) core set criteria and a minimum of 2 active joints, and 2) >= 30% improvement in not more than 1 of the 6 JRA core set criteria. Missing values were treated as disease flare.
    End point type
    Primary
    End point timeframe
    Week 16 to Week 48 (32 weeks)
    End point values
    Double-Blind Adalimumab Double-Blind Placebo
    Number of subjects analysed
    30 [1]
    28 [2]
    Units: subjects
    13
    20
    Notes
    [1] - All subjects in the ITT population in the non-MTX stratum.
    [2] - All subjects in the ITT population in the non-MTX stratum.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The study was sized to detect a difference in the proportion of subjects (40%) between placebo and the active adalimumab dose group who would experience disease flare assuming a placebo rate of 70% vs. a rate of 30% in the active group. Assuming a binomial distribution, an alpha of 0.05, 80% power, two-sided test, and an initial monotherapy responder rate of 70%, a minimum of 29 subjects were needed per treatment group within the appropriate strata.
    Comparison groups
    Double-Blind Adalimumab v Double-Blind Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.031
    Method
    Chi-squared
    Confidence interval

    Secondary: Number of Subjects Meeting Pediatric American College of Rheumatology 30% (PedACR30) Response Criteria at the End of the Open-Label Lead-In Phase

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    End point title
    Number of Subjects Meeting Pediatric American College of Rheumatology 30% (PedACR30) Response Criteria at the End of the Open-Label Lead-In Phase
    End point description
    Responders met the following criteria: >= 30% improvement in >= 3 of 6 JRA core set criteria, and >= 30% worsening in not more than 1 JRA criterion, compared with the open-label baseline. JRA core set criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with limitation of motion [LOM] and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. Missing values were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Open-label Adalimumab + MTX Open-label Adalimumab
    Number of subjects analysed
    85 [3]
    86 [4]
    Units: subjects
    80
    64
    Notes
    [3] - All subjects in the ITT population.
    [4] - All subjects in the ITT population.
    No statistical analyses for this end point

    Secondary: Number of Subjects in the MTX Stratum With Disease Flare During the Double-Blind Phase

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    End point title
    Number of Subjects in the MTX Stratum With Disease Flare During the Double-Blind Phase
    End point description
    Subjects met criteria for disease flare if they had >= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and >= 30% improvement in not more than 1 JRA criterion. JRA core set criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. Missing values were treated as disease flares.
    End point type
    Secondary
    End point timeframe
    Week 16 to Week 48 (32 Weeks)
    End point values
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX
    Number of subjects analysed
    38 [5]
    37 [6]
    Units: subjects
    14
    24
    Notes
    [5] - All subjects in the ITT population in the MTX stratum.
    [6] - All subjects in the ITT population in the MTX stratum.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-Blind Adalimumab + MTX v Double-Blind Placebo + MTX
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.015
    Method
    Chi-squared
    Confidence interval

    Secondary: Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the Non-MTX Stratum

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    End point title
    Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the Non-MTX Stratum
    End point description
    A log rank test was performed and the Kaplan-Meier curve for time to disease flare from double-blind baseline (Week 16) to Week 48 was generated. Disease flare was defined as a >= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and >= 30% improvement in not more than 1 JRA criterion. The percentage of subjects without disease flare at each time point is presented.
    End point type
    Secondary
    End point timeframe
    Week 16 to Week 48 (32 weeks)
    End point values
    Double-Blind Adalimumab Double-Blind Placebo
    Number of subjects analysed
    30 [7]
    28 [8]
    Units: percent subjects w/o disease flare
    number (not applicable)
        Week 20
    90
    78.6
        Week 24
    83.3
    64.3
        Week 28
    80
    60.7
        Week 32
    70
    46.4
        Week 36
    66.7
    46.4
        Week 40
    60
    39.3
        Week 44
    60
    32.1
        Week 48
    56.7
    28.6
    Notes
    [7] - All subjects in the ITT population in the non-MTX stratum.
    [8] - All subjects in the ITT population in the non-MTX stratum.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-Blind Adalimumab v Double-Blind Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.029
    Method
    Logrank
    Confidence interval

    Secondary: Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the MTX Stratum

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    End point title
    Time to Onset of Disease Flare During the Double-Blind Phase in Subjects in the MTX Stratum
    End point description
    A log rank test was performed and the Kaplan-Meier curve for time to disease flare from double-blind baseline (Week 16) to Week 48 was generated. Disease flare was defined as a >= 30% worsening in at least 3 of 6 JRA core set criteria and a minimum of 2 active joints, and >= 30% improvement in not more than 1 JRA criterion. The percentage of subjects without disease flare at each time point is presented.
    End point type
    Secondary
    End point timeframe
    Week 16 to Week 48 (32 weeks)
    End point values
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX
    Number of subjects analysed
    38
    37
    Units: percent subjects w/o disease flare
    number (not applicable)
        Week 20
    86.8
    83.8
        Week 24
    78.9
    70.3
        Week 28
    68.4
    59.5
        Week 32
    68.4
    56.8
        Week 36
    63.2
    48.6
        Week 40
    63.2
    45.9
        Week 44
    63.2
    43.2
        Week 48
    63.2
    35.1
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-Blind Adalimumab + MTX v Double-Blind Placebo + MTX
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.031
    Method
    Logrank
    Confidence interval

    Secondary: Number of Subjects Meeting PedACR30 Response Criteria at the End of the Double-Blind Phase

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    End point title
    Number of Subjects Meeting PedACR30 Response Criteria at the End of the Double-Blind Phase
    End point description
    Responders met the following criteria: >= 30% improvement in >= 3 of 6 JIA core set criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core criteria are included in PedACR criteria. Missing values were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    30 [9]
    28 [10]
    38 [11]
    37 [12]
    Units: subjects
    17
    9
    24
    14
    Notes
    [9] - All subjects in the ITT population.
    [10] - All subjects in the ITT population.
    [11] - All subjects in the ITT population.
    [12] - All subjects in the ITT population.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Adalimumab v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.061
    Method
    Pearson's Chi-square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Adalimumab + MTX v Placebo + MTX
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.028
    Method
    Pearson's Chi-square test
    Confidence interval

    Secondary: Number of Subjects Meeting PedACR50 Response Criteria at the End of the Double-Blind Phase

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    End point title
    Number of Subjects Meeting PedACR50 Response Criteria at the End of the Double-Blind Phase
    End point description
    Responders met the following criteria: >= 50% improvement in >= 3 of 6 JIA core set criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core variables are included in PedACR criteria. Missing values were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    30 [13]
    28 [14]
    38 [15]
    37 [16]
    Units: subjects
    16
    9
    24
    14
    Notes
    [13] - All subjects in the ITT population.
    [14] - All subjects in the ITT population.
    [15] - All subjects in the ITT population.
    [16] - All subjects in the ITT population.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Adalimumab
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.103
    Method
    Pearson's Chi-square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Adalimumab + MTX v Placebo + MTX
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.028
    Method
    Pearson's Chi-square test
    Confidence interval

    Secondary: Number of Subjects Meeting PedACR70 Response Criteria at the End of the Double-Blind Phase

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    End point title
    Number of Subjects Meeting PedACR70 Response Criteria at the End of the Double-Blind Phase
    End point description
    Responders met the following criteria: >= 70% improvement in >= 3 of 6 JIA core set criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with the OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; number of active joints (joints with swelling or with LOM and with pain, tenderness or both); number of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core variables are included in PedACR criteria. Missing values were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    30 [17]
    28 [18]
    38 [19]
    37 [20]
    Units: subjects
    14
    8
    24
    10
    Notes
    [17] - All subjects in the ITT population.
    [18] - All subjects in the ITT population.
    [19] - All subjects in the ITT population.
    [20] - All subjects in the ITT population.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Adalimumab v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.156
    Method
    Pearson's Chi-square test
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Adalimumab + MTX v Placebo + MTX
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002
    Method
    Pearson's Chi-square test
    Confidence interval

    Secondary: Mean Change From Baseline in Physician's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase

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    End point title
    Mean Change From Baseline in Physician's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
    End point description
    A 100 mm horizontal visual analog scale (VAS) was used to assess the Physician Global Assessment of Disease Activity. The left end of the VAS scale (0 mm) signified the absence of symptoms and the right end (100 mm) maximum disease activity. The mean change from open-label baseline to Week 48 was determined. Negative mean changes indicated improvement. Observed data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    17 [21]
    9 [22]
    24 [23]
    15 [24]
    Units: units on a scale
        arithmetic mean (standard error)
    -52.06 ± 3.713
    -38.73 ± 6.554
    -48.5 ± 3.89
    -38.73 ± 6.554
    Notes
    [21] - All subjects in the ITT population who remained in the study at Week 48.
    [22] - All subjects in the ITT population who remained in the study at Week 48.
    [23] - All subjects in the ITT population who remained in the study at Week 48.
    [24] - All subjects in the ITT population who remained in the study at Week 48.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Parent's/Patient's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase

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    End point title
    Mean Change From Baseline in Parent's/Patient's Global Assessment of Disease Activity at Week 48 of the Double-Blind Phase
    End point description
    A 100 mm horizontal visual analog scale (VAS) was used to assess the Parent's/Patient's Global Assessment of Disease Activity. The left end of the VAS (0 mm) signified the absence of symptoms and the right end (100 mm) maximum disease activity. The mean change from open-label baseline to Week 48 was determined. Negative mean changes indicated improvement. Observed data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    17 [25]
    9 [26]
    24 [27]
    15 [28]
    Units: units on a scale
        arithmetic mean (standard error)
    -41.53 ± 5.562
    -50.56 ± 6.129
    -36.42 ± 5.177
    -26.87 ± 5.644
    Notes
    [25] - All subjects in the ITT population who completed Week 48.
    [26] - All subjects in the ITT population who completed Week 48.
    [27] - All subjects in the ITT population who completed Week 48.
    [28] - All subjects in the ITT population who completed Week 48.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in C-Reactive Protein Levels at Week 48 of the Double-Blind Phase

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    End point title
    Mean Change From Baseline in C-Reactive Protein Levels at Week 48 of the Double-Blind Phase
    End point description
    Serum levels of C-reactive protein (CRP) were measured at screening (open-label baseline) and at Week 48. Negative mean changes in CRP from open-label baseline to Week 48 indicated improvement. Observed data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    Adalimumab Placebo Adalimumab + MTX Placebo + MTX
    Number of subjects analysed
    17 [29]
    9 [30]
    24 [31]
    15 [32]
    Units: mg/dL
        arithmetic mean (standard error)
    -1.79 ± 0.803
    -3.91 ± 2
    -1.71 ± 0.529
    -0.1 ± 0.333
    Notes
    [29] - All subjects in the ITT population who remained in the study at Week 48.
    [30] - All subjects in the ITT population who remained in the study at Week 48.
    [31] - All subjects in the ITT population who remained in the study at Week 48.
    [32] - All subjects in the ITT population who remained in the study at Week 48.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Body Surface Area Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Body Surface Area Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Open-Label Lead-In Phase Baseline
    End point values
    OLE BSA Adalimumab + MTX OLE BSA Adalimumab
    Number of subjects analysed
    67 [33]
    53 [34]
    Units: subjects
        PedACR30 Baseline
    55
    46
        PedACR50 Baseline
    47
    41
        PedACR70 Baseline
    35
    30
    Notes
    [33] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    [34] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 56 of the Open-Label Extension Body Surface Area Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 56 of the Open-Label Extension Body Surface Area Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    OLE BSA Adalimumab + MTX OLE BSA Adalimumab
    Number of subjects analysed
    55 [35]
    41 [36]
    Units: subjects
        PedACR30 Week 56
    50
    40
        PedACR50 Week 56
    49
    40
        PedACR70 Week 56
    43
    35
    Notes
    [35] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    [36] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 104 of the Open-Label Extension Body Surface Area Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 104 of the Open-Label Extension Body Surface Area Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    OLE BSA Adalimumab + MTX OLE BSA Adalimumab
    Number of subjects analysed
    19 [37]
    17 [38]
    Units: subjects
        PedACR30 Week 104
    18
    16
        PedACR50 Week 104
    16
    16
        PedACR70 Week 104
    14
    14
    Notes
    [37] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    [38] - The ITT population was used for analysis in the Open-Label Extension Body Surface Area phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Fixed Dose Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Baseline of the Open-Label Extension Fixed Dose Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL-LI baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    53 [39]
    45 [40]
    Units: subjects
        PedACR30 OLE FD Baseline
    53
    44
        PedACR50 OLE FD Baseline
    50
    43
        PedACR70 OLE FD Baseline
    46
    40
    Notes
    [39] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    [40] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 48 of the Open-Label Extension Fixed Dose Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 48 of the Open-Label Extension Fixed Dose Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL-LI baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    51 [41]
    40 [42]
    Units: subjects
        PedACR30 Week 48
    47
    40
        PedACR50 Week 48
    47
    39
        PedACR70 Week 48
    44
    38
    Notes
    [41] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    [42] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 112 of the Open-Label Extension Fixed Dose Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at Week 112 of the Open-Label Extension Fixed Dose Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. All core assessments are included in PedACR criteria.
    End point type
    Secondary
    End point timeframe
    Week 112
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    41 [43]
    31 [44]
    Units: subjects
        PedACR30 Week 112
    39
    31
        PedACR50 Week 112
    39
    30
        PedACR70 Week 112
    34
    29
    Notes
    [43] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    [44] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting PedACR30/50/70 Response Criteria at the Final Visit (up to 224 Weeks) of the Open-Label Extension Fixed Dose Phase

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    End point title
    Number of Subjects Meeting PedACR30/50/70 Response Criteria at the Final Visit (up to 224 Weeks) of the Open-Label Extension Fixed Dose Phase
    End point description
    Responders met the following criteria: >= 30%/50%/70% improvement in >= 3 of 6 JIA core criteria, and >= 30% worsening in not more than 1 JIA criterion, compared with OL baseline. JIA core criteria included: physician's global assessment of disease severity; parent's/patient's global assessment of overall well-being; # of active joints (joints with swelling or with LOM and with pain, tenderness or both); # of joints with LOM; physical function of the Disability Index of Childhood Health Assessment Questionnaire; C-reactive protein. Final Visit = last visit per subject (up to 224 weeks).
    End point type
    Secondary
    End point timeframe
    Final Visit (up to 224 weeks of OLE FD phase)
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    55 [45]
    46 [46]
    Units: subjects
        PedACR30 Final Visit
    48
    44
        PedACR50 Final Visit
    45
    43
        PedACR70 Final Visit
    43
    40
    Notes
    [45] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    [46] - The ITT population was used for analysis in the Open-Label Extension Fixed Dose phase.
    No statistical analyses for this end point

    Other pre-specified: Baseline Measure: Gender, Female/Male - OLE BSA Phase

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    End point title
    Baseline Measure: Gender, Female/Male - OLE BSA Phase
    End point description
    Gender (female/male) recorded at Baseline of the Open-Label Extension BSA phase of the study. This measure was excluded from Baseline Characteristics due to difficulty maintaining correct subject numbers and Baseline value totals in that section while including this phase of the study.
    End point type
    Other pre-specified
    End point timeframe
    Baseline OLE BSA Phase
    End point values
    OLE BSA Adalimumab + MTX OLE BSA Adalimumab
    Number of subjects analysed
    71
    57
    Units: subjects
        OLE BSA Phase - Female
    56
    42
        OLE BSA Phase - Male
    15
    15
    No statistical analyses for this end point

    Other pre-specified: Baseline Measure: Age Continuous - OLE BSA Phase

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    End point title
    Baseline Measure: Age Continuous - OLE BSA Phase
    End point description
    Age continuous (mean +/- SD) recorded at Baseline of the Open-Label Extension BSA phase of the study. This measure was excluded from Baseline Characteristics due to difficulty maintaining correct subject numbers and Baseline value totals in that section with this phase included.
    End point type
    Other pre-specified
    End point timeframe
    Baseline OLE BSA Phase
    End point values
    OLE BSA Adalimumab + MTX OLE BSA Adalimumab
    Number of subjects analysed
    71
    57
    Units: years
        arithmetic mean (standard deviation)
    11.3 ± 3.32
    11.2 ± 3.96
    No statistical analyses for this end point

    Other pre-specified: Baseline Measure: Gender, Female/Male - OLE FD Phase

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    End point title
    Baseline Measure: Gender, Female/Male - OLE FD Phase
    End point description
    Gender (female/male) recorded at Baseline of the Open-Label Extension FD phase of the study. This measure was excluded from Baseline Characteristics due to difficulty maintaining correct subject numbers and Baseline value totals in that section while including this phase of the study.
    End point type
    Other pre-specified
    End point timeframe
    Baseline OLE FD Phase
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    59
    47
    Units: subjects
        OLE FD Phase - Female
    45
    33
        OLE FD Phase - Male
    14
    14
    No statistical analyses for this end point

    Other pre-specified: Baseline Measure: Age Continuous - OLE FD Phase

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    End point title
    Baseline Measure: Age Continuous - OLE FD Phase
    End point description
    Age continuous (mean +/- SD) recorded at Baseline of the Open-Label Extension FD phase of the study. This measure was excluded from Baseline Characteristics due to difficulty maintaining correct subject numbers and Baseline value totals in that section with this phase included.
    End point type
    Other pre-specified
    End point timeframe
    Baseline OLE FD Phase
    End point values
    OLE FD Adalimumab + MTX OLE FD Adalimumab
    Number of subjects analysed
    59
    47
    Units: years
        arithmetic mean (standard deviation)
    11.1 ± 3.36
    11 ± 4.12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    DB Phase - Week 16 to 48 (32 Weeks), Open-Label Extension BSA Phase - OLE BSA Baseline to Week 136 (136 weeks), Open-Label Extension FD Phase - OLE FD Baseline to Final Visit (up to 224 weeks)* *Last observation of each subject in FD population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Double-Blind Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Placebo + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum, who had an inadequate response to MTX and were adalimumab responders during the Open-Label Lead-In (OL-LI) phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week) plus concomitant MTX treatment during the Double-Blind Phase of the study. MTX-treated inadequate responders must have had active disease on MTX treatment for at least 3 months prior to screening.

    Reporting group title
    Double-Blind Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Reporting group title
    Double-Blind Placebo
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum who were either naïve to MTX or withdrawn from MTX at least 2 weeks prior to study drug administration, and were adalimumab responders during the OL-LI phase, received placebo (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose, administered subcutaneously every other week), but no concomitant MTX treatment, during the Double-Blind Phase of the study.

    Reporting group title
    Open-Label Extension BSA Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum received subcutaneous injections of 24 mg adalimumab per square meter of body surface area (BSA) up to a maximum of 40 mg total body dose every other week (eow) concomitantly with MTX treatment during the Open-Label Extension BSA Phase of the study.

    Reporting group title
    Open-Label Extension BSA Adalimumab
    Reporting group description
    Subjects in the non-methotrexate (MTX) stratum received adalimumab (24 mg/square meter of body surface area [BSA], up to a maximum of 40 mg total body dose SC eow) without concomitant MTX treatment during the Open-Label Extension BSA Phase.

    Reporting group title
    Open-Label Extension FD Adalimumab + MTX
    Reporting group description
    Subjects in the methotrexate (MTX) stratum received adalimumab concomitantly with MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study, in which subjects were dosed based on body weight (not BSA). Subjects were separated into 2 body weight categories; subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.

    Reporting group title
    Open-Label Extension FD Adalimumab
    Reporting group description
    Subjects in the methotrexate (MTX) stratum received adalimumab without concomitant MTX treatment during the Open-Label Extension (OLE) Fixed Dose (FD) Phase of the study, in which subjects were dosed based on body weight (not BSA). Subjects were separated into 2 body weight categories; subjects weighing less than 30 kg were dosed with 20 mg of adalimumab SC eow, and subjects weighing 30 kg or more were dosed with 40 mg of adalimumab SC eow.

    Serious adverse events
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX Double-Blind Adalimumab Double-Blind Placebo Open-Label Extension BSA Adalimumab + MTX Open-Label Extension BSA Adalimumab Open-Label Extension FD Adalimumab + MTX Open-Label Extension FD Adalimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 37 (5.41%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    13 / 71 (18.31%)
    9 / 57 (15.79%)
    7 / 59 (11.86%)
    10 / 47 (21.28%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast enlargement
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Laboratory test abnormal
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hydrocephalus
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Malabsorption
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Juvenile arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    5 / 71 (7.04%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 9
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Knee deformity
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Double-Blind Adalimumab + MTX Double-Blind Placebo + MTX Double-Blind Adalimumab Double-Blind Placebo Open-Label Extension BSA Adalimumab + MTX Open-Label Extension BSA Adalimumab Open-Label Extension FD Adalimumab + MTX Open-Label Extension FD Adalimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 38 (73.68%)
    22 / 37 (59.46%)
    21 / 30 (70.00%)
    20 / 28 (71.43%)
    63 / 71 (88.73%)
    48 / 57 (84.21%)
    54 / 59 (91.53%)
    38 / 47 (80.85%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
    2 / 71 (2.82%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    3 / 47 (6.38%)
         occurrences all number
    2
    0
    3
    2
    3
    3
    4
    5
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    2 / 57 (3.51%)
    2 / 59 (3.39%)
    3 / 47 (6.38%)
         occurrences all number
    3
    1
    3
    0
    2
    3
    2
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    2 / 71 (2.82%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    1
    1
    2
    2
    3
    0
    Influenza like illness
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 37 (10.81%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    4 / 71 (5.63%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    6
    0
    0
    5
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    1
    10
    0
    0
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    7 / 38 (18.42%)
    7 / 37 (18.92%)
    9 / 30 (30.00%)
    3 / 28 (10.71%)
    14 / 71 (19.72%)
    10 / 57 (17.54%)
    4 / 59 (6.78%)
    4 / 47 (8.51%)
         occurrences all number
    48
    49
    45
    16
    172
    108
    8
    6
    Injection site reaction
         subjects affected / exposed
    7 / 38 (18.42%)
    1 / 37 (2.70%)
    3 / 30 (10.00%)
    1 / 28 (3.57%)
    8 / 71 (11.27%)
    9 / 57 (15.79%)
    2 / 59 (3.39%)
    1 / 47 (2.13%)
         occurrences all number
    19
    1
    11
    1
    35
    30
    2
    2
    Pain
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    3 / 30 (10.00%)
    3 / 28 (10.71%)
    0 / 71 (0.00%)
    3 / 57 (5.26%)
    0 / 59 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    13
    1
    9
    23
    0
    10
    0
    3
    Pyrexia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    4 / 71 (5.63%)
    6 / 57 (10.53%)
    2 / 59 (3.39%)
    5 / 47 (10.64%)
         occurrences all number
    3
    0
    1
    1
    6
    6
    3
    5
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    2 / 71 (2.82%)
    3 / 57 (5.26%)
    3 / 59 (5.08%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    1
    6
    3
    5
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
    4 / 71 (5.63%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    0
    3
    4
    2
    0
    3
    Contusion
         subjects affected / exposed
    7 / 38 (18.42%)
    5 / 37 (13.51%)
    2 / 30 (6.67%)
    2 / 28 (7.14%)
    4 / 71 (5.63%)
    3 / 57 (5.26%)
    1 / 59 (1.69%)
    4 / 47 (8.51%)
         occurrences all number
    12
    7
    2
    5
    4
    5
    1
    6
    Excoriation
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 37 (2.70%)
    3 / 30 (10.00%)
    1 / 28 (3.57%)
    7 / 71 (9.86%)
    4 / 57 (7.02%)
    2 / 59 (3.39%)
    4 / 47 (8.51%)
         occurrences all number
    10
    1
    6
    1
    12
    4
    2
    7
    Injury
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    4 / 28 (14.29%)
    3 / 71 (4.23%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    4 / 47 (8.51%)
         occurrences all number
    2
    1
    0
    4
    4
    1
    1
    6
    Joint sprain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    3 / 28 (10.71%)
    1 / 71 (1.41%)
    4 / 57 (7.02%)
    1 / 59 (1.69%)
    2 / 47 (4.26%)
         occurrences all number
    2
    0
    0
    3
    1
    6
    1
    2
    Muscle strain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
    1 / 71 (1.41%)
    4 / 57 (7.02%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    3
    1
    1
    4
    0
    0
    Skin laceration
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    1
    0
    4
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 37 (8.11%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    1
    3
    0
    1
    1
    0
    0
    0
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    3 / 59 (5.08%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    4
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    2 / 57 (3.51%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    0
    0
    0
    3
    1
    1
    Cough
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    6 / 71 (8.45%)
    5 / 57 (8.77%)
    2 / 59 (3.39%)
    2 / 47 (4.26%)
         occurrences all number
    2
    0
    1
    1
    6
    6
    2
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    6 / 71 (8.45%)
    0 / 57 (0.00%)
    4 / 59 (6.78%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    1
    6
    0
    4
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    5
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 37 (10.81%)
    2 / 30 (6.67%)
    4 / 28 (14.29%)
    9 / 71 (12.68%)
    8 / 57 (14.04%)
    4 / 59 (6.78%)
    11 / 47 (23.40%)
         occurrences all number
    3
    5
    2
    10
    13
    11
    4
    21
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    4 / 57 (7.02%)
    2 / 59 (3.39%)
    2 / 47 (4.26%)
         occurrences all number
    2
    0
    0
    0
    0
    4
    2
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    2 / 57 (3.51%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
    3 / 71 (4.23%)
    1 / 57 (1.75%)
    5 / 59 (8.47%)
    4 / 47 (8.51%)
         occurrences all number
    0
    1
    0
    3
    3
    1
    5
    6
    Abdominal pain upper
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    0 / 71 (0.00%)
    1 / 57 (1.75%)
    1 / 59 (1.69%)
    4 / 47 (8.51%)
         occurrences all number
    1
    1
    0
    1
    0
    1
    1
    4
    Nausea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    9 / 71 (12.68%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    6 / 47 (12.77%)
         occurrences all number
    1
    1
    0
    1
    15
    6
    4
    8
    Vomiting
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 37 (5.41%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    5 / 71 (7.04%)
    3 / 57 (5.26%)
    2 / 59 (3.39%)
    3 / 47 (6.38%)
         occurrences all number
    3
    2
    0
    1
    5
    4
    2
    4
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
    3 / 71 (4.23%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    2 / 47 (4.26%)
         occurrences all number
    1
    0
    2
    1
    3
    2
    4
    2
    Blister
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    5 / 71 (7.04%)
    0 / 57 (0.00%)
    3 / 59 (5.08%)
    4 / 47 (8.51%)
         occurrences all number
    0
    0
    1
    0
    5
    0
    3
    4
    Ecchymosis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 37 (5.41%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
    5 / 71 (7.04%)
    4 / 57 (7.02%)
    2 / 59 (3.39%)
    6 / 47 (12.77%)
         occurrences all number
    1
    0
    2
    0
    5
    4
    2
    7
    Erythema
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    1
    3
    1
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
    5 / 71 (7.04%)
    6 / 57 (10.53%)
    4 / 59 (6.78%)
    7 / 47 (14.89%)
         occurrences all number
    4
    0
    2
    1
    7
    9
    7
    12
    Arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    3 / 71 (4.23%)
    1 / 57 (1.75%)
    4 / 59 (6.78%)
    7 / 47 (14.89%)
         occurrences all number
    0
    0
    0
    1
    3
    1
    5
    10
    Juvenile arthritis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    2 / 71 (2.82%)
    3 / 57 (5.26%)
    4 / 59 (6.78%)
    4 / 47 (8.51%)
         occurrences all number
    2
    1
    1
    1
    3
    3
    5
    5
    Muscle spasms
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    3 / 57 (5.26%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
    4 / 71 (5.63%)
    0 / 57 (0.00%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
         occurrences all number
    0
    0
    0
    2
    4
    0
    1
    1
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    7 / 71 (9.86%)
    7 / 57 (12.28%)
    7 / 59 (11.86%)
    6 / 47 (12.77%)
         occurrences all number
    0
    1
    0
    0
    11
    8
    11
    10
    Synovitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 37 (5.41%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    4 / 71 (5.63%)
    0 / 57 (0.00%)
    6 / 59 (10.17%)
    0 / 47 (0.00%)
         occurrences all number
    1
    3
    0
    0
    6
    0
    10
    0
    Bronchitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    4 / 71 (5.63%)
    2 / 57 (3.51%)
    1 / 59 (1.69%)
    2 / 47 (4.26%)
         occurrences all number
    0
    1
    1
    1
    5
    2
    1
    2
    Ear infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    4 / 71 (5.63%)
    0 / 57 (0.00%)
    7 / 59 (11.86%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    1
    1
    4
    0
    7
    3
    Gastroenteritis viral
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    1 / 71 (1.41%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    1 / 47 (2.13%)
         occurrences all number
    0
    1
    0
    1
    1
    2
    3
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
    1 / 71 (1.41%)
    0 / 57 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    0
    Impetigo
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    5 / 57 (8.77%)
    0 / 59 (0.00%)
    2 / 47 (4.26%)
         occurrences all number
    3
    0
    2
    0
    3
    5
    0
    2
    Influenza
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
    2 / 71 (2.82%)
    4 / 57 (7.02%)
    3 / 59 (5.08%)
    5 / 47 (10.64%)
         occurrences all number
    1
    1
    1
    2
    2
    4
    3
    5
    Nasopharyngitis
         subjects affected / exposed
    4 / 38 (10.53%)
    4 / 37 (10.81%)
    0 / 30 (0.00%)
    3 / 28 (10.71%)
    8 / 71 (11.27%)
    4 / 57 (7.02%)
    7 / 59 (11.86%)
    3 / 47 (6.38%)
         occurrences all number
    4
    6
    0
    4
    9
    6
    7
    3
    Oral herpes
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 37 (5.41%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    0 / 47 (0.00%)
         occurrences all number
    1
    5
    0
    0
    3
    3
    3
    0
    Otitis media
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    2 / 71 (2.82%)
    5 / 57 (8.77%)
    3 / 59 (5.08%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1
    0
    0
    2
    6
    3
    2
    Paronychia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
    3 / 71 (4.23%)
    1 / 57 (1.75%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    1
    0
    2
    1
    3
    1
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 37 (5.41%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    9 / 71 (12.68%)
    4 / 57 (7.02%)
    6 / 59 (10.17%)
    1 / 47 (2.13%)
         occurrences all number
    2
    2
    0
    1
    12
    4
    9
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 37 (2.70%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    3 / 71 (4.23%)
    6 / 57 (10.53%)
    1 / 59 (1.69%)
    3 / 47 (6.38%)
         occurrences all number
    0
    1
    1
    1
    3
    8
    1
    3
    Rhinitis
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 37 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
    4 / 71 (5.63%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    4 / 47 (8.51%)
         occurrences all number
    3
    0
    3
    0
    4
    3
    6
    5
    Sinusitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    7 / 71 (9.86%)
    7 / 57 (12.28%)
    7 / 59 (11.86%)
    3 / 47 (6.38%)
         occurrences all number
    3
    0
    0
    2
    8
    10
    7
    4
    Tonsillitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 37 (2.70%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
    0 / 71 (0.00%)
    2 / 57 (3.51%)
    3 / 59 (5.08%)
    2 / 47 (4.26%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    3
    5
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 37 (10.81%)
    6 / 30 (20.00%)
    5 / 28 (17.86%)
    21 / 71 (29.58%)
    19 / 57 (33.33%)
    15 / 59 (25.42%)
    13 / 47 (27.66%)
         occurrences all number
    7
    5
    6
    6
    34
    40
    23
    27
    Urinary tract infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 37 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
    5 / 71 (7.04%)
    4 / 57 (7.02%)
    5 / 59 (8.47%)
    2 / 47 (4.26%)
         occurrences all number
    2
    0
    0
    1
    6
    4
    10
    2
    Viral infection
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 37 (5.41%)
    6 / 30 (20.00%)
    3 / 28 (10.71%)
    13 / 71 (18.31%)
    9 / 57 (15.79%)
    15 / 59 (25.42%)
    8 / 47 (17.02%)
         occurrences all number
    7
    3
    7
    3
    22
    12
    17
    11
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 37 (0.00%)
    1 / 30 (3.33%)
    1 / 28 (3.57%)
    3 / 71 (4.23%)
    4 / 57 (7.02%)
    2 / 59 (3.39%)
    2 / 47 (4.26%)
         occurrences all number
    0
    0
    1
    1
    3
    6
    2
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2002
    To clarify that subjects who respond to treatment with adalimumab will be randomized at Week 16; all sites will develop their institution-specific informed consent form.
    26 Sep 2002
    To add an additional pharmacokinetic blood sample to be taken between Day 2 and Day 10 after the first dose of adalimumab; to incorporate the open-label extension study (subjects who complete 48 weeks of treatment or are withdrawn from the double-blind phase due to disease flare were eligible).
    03 Jul 2003
    To expand the safety assessments to include a serum pregnancy on all females aged 10 years and older at all visits, and clarify the visit schedule for the OL extension portion.
    05 Feb 2004
    To extend the OL extension portion of study to up to 5 years or 60 days post marketing approval in each country; clarify which study visits require a blinded joint assessor, clarify the requirements for chest X-rays and/or PPD skin tests in Europe; clarify the study visit window schedule.
    26 Aug 2005
    To switch subjects from a dose of study medication based on BSA to a fixed dose of study drug (20 or 40 mg eow based on weight); remove Post Study Visit (Follow-Up); update the schedule for drug administration at the study site; amend study visit schedule to allow for pharmacokinetic sampling and validate safety and efficacy of new fixed dosing regimen; clarify that the DSMB will not participate in the OL portion of the trial; change the evaluation time period for joints injected with intra-articular and/or soft-tissue corticosteroids from non-evaluable for the duration of the study to evaluable after 3 months;
    01 Apr 2009
    To extend the fixed dose portion of the study to 244 weeks to accommodate patients in Europe who are not yet able to receive drug commercially because of their age; and add 4 additional visits to the OL Fixed Dose.
    24 Sep 2009
    To update the protocol to reflect the renaming and reclassification of juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA); clarify study visits and procedures for subjects in the EU who will be continuing in the study past Fixed Dose Week 176; update conditions in which a subject should be withdrawn for safety reasons; update introduction, CTC Grading Severity of Adverse Events version, excluded medications.

    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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