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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study to Investigate the Safety and Efficacy of ABT-494 with Background Methotrexate (MTX) in Subjects with Active Rheumatoid Arthritis (RA) Who Have Had an Inadequate Response to MTX Alone.

    Summary
    EudraCT number
    		 2013-003984-72
    Trial protocol
    		 LV   HU   CZ   SK   ES  
    Global end of trial date
    02 Jul 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Oct 2019
    First version publication date
    15 Jul 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction needed

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M13-537
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02066389
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Abbvie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Aileen L. Pangan, AbbVie , aileen.pangan@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the safety and efficacy of multiple doses of ABT-494 versus placebo in subjects with moderately to severely active rheumatoid arthritis on stable background MTX therapy who have not shown an adequate response to MTX alone.
    Protection of trial subjects
    All subjects entering the study had to sign an informed consent that was explained to them and questions encouraged.
    Background therapy
    		 Subjects were to have received oral or parenteral MTX therapy for at least 3 months, and been on a stable prescription (titration completed) of 7.5 to 25 mg/week MTX for at least 4 weeks prior to initiating study drug. Subjects were to continue on their stable dose of MTX throughout the study. In addition, all subjects were to take a dietary supplement of oral folic acid (or equivalent) from 4 weeks prior to Day 1 (Baseline) throughout the study. Folic acid dosing and timing of the regimen was to be followed according to PI instructions.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Bulgaria: 59
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Chile: 31
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Puerto Rico: 3
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 11
    Country: Number of subjects enrolled
    United States: 30
    Worldwide total number of subjects
    300
    EEA total number of subjects
    185
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    232
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 300 subjects were enrolled at 59 study sites located in 16 countries.

    Pre-assignment
    Screening details
    		 This study recruited adult females and males who were at least 18 years of age with a diagnosis of RA, as defined by either the 1987-revised ACR classification criteria or the ACR/European League Against Rheumatism (EULAR) 2010 Criteria, for ≥ 3 months and who had an inadequate response or intolerance to MTX therapy alone.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo capsules twice daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice daily

    Arm title
    		 ABT-494 3 mg BID
    Arm description
    		 Participants received 3 mg ABT-494 twice daily (BID) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-494
    Investigational medicinal product code
    ABT-494
    Other name
    Upadacitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice daily

    Arm title
    		 ABT-494 6 mg BID
    Arm description
    		 Participants received 6 mg ABT-494 twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-494
    Investigational medicinal product code
    ABT-494
    Other name
    Upadacitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice daily

    Arm title
    		 ABT-494 12 mg BID
    Arm description
    		 Participants received 12 mg ABT-494 twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-494
    Investigational medicinal product code
    ABT-494
    Other name
    Upadacitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice daily

    Arm title
    		 ABT-494 18 mg BID
    Arm description
    		 Participants received 18 mg ABT-494 twice daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-494
    Investigational medicinal product code
    ABT-494
    Other name
    Upadacitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice daily

    Arm title
    		 ABT-494 24 mg QD
    Arm description
    		 Participants received 24 mg ABT-494 once daily (QD) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-494
    Investigational medicinal product code
    ABT-494
    Other name
    Upadacitinib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Number of subjects in period 1
    		Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Started
    50
    50
    50
    50
    50
    50
    Received Treatment
    50
    50
    50
    50
    50
    49
    Completed
    45
    49
    44
    47
    43
    45
    Not completed
    5
    1
    6
    3
    7
    5
         Randomized in error
    -
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    4
    -
    5
    1
    1
    2
         Adverse event
    1
    1
    1
    1
    5
    1
         Lost to follow-up
    -
    -
    -
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo capsules twice daily for 12 weeks.

    Reporting group title
    ABT-494 3 mg BID
    Reporting group description
    		 Participants received 3 mg ABT-494 twice daily (BID) for 12 weeks.

    Reporting group title
    ABT-494 6 mg BID
    Reporting group description
    		 Participants received 6 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 12 mg BID
    Reporting group description
    		 Participants received 12 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 18 mg BID
    Reporting group description
    		 Participants received 18 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 24 mg QD
    Reporting group description
    		 Participants received 24 mg ABT-494 once daily (QD) for 12 weeks.

    Reporting group values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD Total
    Number of subjects
    		 50 50 50 50 50 50 300
    Age categorical
    Units: Subjects
        18 to < 45 years
    		 9 11 9 7 13 7 56
        45 to < 65 years
    		 32 30 30 32 25 27 176
        ≥ 65 years
    		 9 9 11 11 12 16 68
    Gender categorical
    Units: Subjects
        Female
    		 38 40 34 41 42 43 238
        Male
    		 12 10 16 9 8 7 62

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo capsules twice daily for 12 weeks.

    Reporting group title
    ABT-494 3 mg BID
    Reporting group description
    		 Participants received 3 mg ABT-494 twice daily (BID) for 12 weeks.

    Reporting group title
    ABT-494 6 mg BID
    Reporting group description
    		 Participants received 6 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 12 mg BID
    Reporting group description
    		 Participants received 12 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 18 mg BID
    Reporting group description
    		 Participants received 18 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 24 mg QD
    Reporting group description
    		 Participants received 24 mg ABT-494 once daily (QD) for 12 weeks.

    Primary: Percentage of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 12

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    End point title
    		 Percentage of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 12
    End point description
    A participant was a responder if the following 3 criteria for improvement from baseline were met: • ≥ 20% improvement in tender joint count; • ≥ 20% improvement in swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦ Physician global assessment of disease activity ◦ Patient global assessment of disease activity ◦ Patient assessment of pain ◦ Health Assessment Questionnaire – Disability Index (HAQ-DI) ◦ High sensitivity C-reactive protein (hsCRP). The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    46
    48
    49
    49
    47
    49
    Units: percentage of participants
        number (not applicable)
    50
    64.6
    73.5
    81.6
    76.6
    81.6
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    Placebo v ABT-494 3 mg BID
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.153
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.018
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.008
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [5] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants with an ACR50 Response at Week 12

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    End point title
    		 Percentage of Participants with an ACR50 Response at Week 12
    End point description
    A participant was a responder if the following 3 criteria for improvement from baseline were met: • ≥ 50% improvement in tender joint count; • ≥ 50% improvement in swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: ◦ Physician global assessment of disease activity ◦ Patient global assessment of disease activity ◦ Patient assessment of pain ◦ Health Assessment Questionnaire – Disability Index (HAQ-DI) ◦ High sensitivity C-reactive protein (hsCRP). The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    46
    48
    49
    50
    47
    48
    Units: percentage of participants
        number (not applicable)
    19.6
    39.6
    49
    50
    44.7
    43.8
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.034
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [7] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [8] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.01
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [9] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.012
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [10] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants with an ACR70 Response at Week 12

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    End point title
    		 Percentage of Participants with an ACR70 Response at Week 12
    End point description
    A participant was a responder if the following 3 criteria for improvement from baseline were met: • ≥ 70% improvement in tender joint count; • ≥ 70% improvement in swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Physician global assessment of disease activity ◦ Patient global assessment of disease activity ◦ Patient assessment of pain ◦ Health Assessment Questionnaire – Disability Index (HAQ-DI) ◦ High sensitivity C-reactive protein (hsCRP). The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    46
    47
    49
    50
    47
    48
    Units: percentage of participants
        number (not applicable)
    6.5
    23.4
    30.6
    16
    27.7
    25
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.023
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [11] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [12] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.145
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [13] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.007
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.014
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [15] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12

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    End point title
    		 Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12
    End point description
    The disease activity score-28-CRP (DAS28 [CRP]) assesses RA disease activity based on a continuous scale of combined measures of 28 tender joint counts (TJC28), 28 swollen joint counts (SJC28), C-reactive protein (CRP), and the patient global assessment of disease activity (measured on a visual analogue scale from 0 to 100 mm). DAS28(CRP) scores range from 0 to 10 where higher scores indicate more disease activity. LDA is defined as a DAS28(CRP) score < 3.2. The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    47
    49
    49
    50
    49
    49
    Units: percentage of participants
        number (not applicable)
    21.3
    49
    57.1
    46
    51
    42.9
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.005
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [16] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [17] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.01
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [18] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.002
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [19] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.024
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [20] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12

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    End point title
    		 Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12
    End point description
    The disease activity score-28-CRP (DAS28 [CRP]) assesses RA disease activity based on a continuous scale of combined measures of 28 tender joint counts (TJC28), 28 swollen joint counts (SJC28), C-reactive protein (CRP), and the patient global assessment of disease activity (measured on a visual analogue scale from 0 to 100 mm). DAS28(CRP) scores range from 0 to 10 where higher scores indicate more disease activity. CR is defined as a DAS28(CRP) score < 2.6. The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    47
    49
    49
    50
    49
    49
    Units: percentage of participants
        number (not applicable)
    14.9
    36.7
    38.8
    34
    42.9
    22.4
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.015
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [21] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.008
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [22] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.029
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [23] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [24] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.343
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [25] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants Achieving Low Disease Activity (LDA) Based on CDAI at Week 12

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    End point title
    		 Percentage of Participants Achieving Low Disease Activity (LDA) Based on CDAI at Week 12
    End point description
    The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of TJC28 and SJC28, patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. LDA is defined as a CDAI score ≤ 10. The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    47
    49
    49
    50
    49
    49
    Units: percentage of participants
        number (not applicable)
    21.3
    40.8
    40.8
    40
    49
    36.7
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.039
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [26] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.039
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [27] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.046
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [28] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.005
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [29] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.096
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [30] - Statistical tests were 1-sided at a significance level of 0.05.

    Secondary: Percentage of Participants Achieving Clinical Remission Based on CDAI at Week 12

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    End point title
    		 Percentage of Participants Achieving Clinical Remission Based on CDAI at Week 12
    End point description
    The clinical disease activity index (CDAI) is a composite index for assessing disease activity based on the summation of the counts of TJC28 and SJC28, patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. LDA or CR is defined as a CDAI score ≤ 2.8. The analysis was performed in all randomized and treated participants; last observation carried forward (LOCF) imputation was used for participants who discontinued prior to Week 12.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Number of subjects analysed
    47
    49
    49
    50
    49
    49
    Units: percentage of participants
        number (not applicable)
    4.3
    12.2
    14.3
    6
    14.3
    6.1
    Statistical analysis title
    		 ABT-494 3 mg BID vs Placebo
    Comparison groups
    ABT-494 3 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.269
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [31] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 6 mg BID vs Placebo
    Comparison groups
    ABT-494 6 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.16
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [32] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 12 mg BID vs Placebo
    Comparison groups
    ABT-494 12 mg BID v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [33] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 18 mg BID vs Placebo
    Comparison groups
    ABT-494 18 mg BID v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.16
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [34] - Statistical tests were 1-sided at a significance level of 0.05.
    Statistical analysis title
    		 ABT-494 24 mg QD vs Placebo
    Comparison groups
    ABT-494 24 mg QD v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [35] - Statistical tests were 1-sided at a significance level of 0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug until 30 days after last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo capsules twice daily for 12 weeks.

    Reporting group title
    ABT-494 3 mg BID
    Reporting group description
    		 Participants received 3 mg ABT-494 twice daily (BID) for 12 weeks.

    Reporting group title
    ABT-494 6 mg BID
    Reporting group description
    		 Participants received 6 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 12 mg BID
    Reporting group description
    		 Participants received 12 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 18 mg BID
    Reporting group description
    		 Participants received 18 mg ABT-494 twice daily for 12 weeks.

    Reporting group title
    ABT-494 24 mg QD
    Reporting group description
    		 Participants received 24 mg ABT-494 once daily (QD) for 12 weeks.

    Serious adverse events
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    2 / 49 (4.08%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    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
    Head Injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ABT-494 3 mg BID ABT-494 6 mg BID ABT-494 12 mg BID ABT-494 18 mg BID ABT-494 24 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 50 (10.00%)
    7 / 50 (14.00%)
    17 / 50 (34.00%)
    6 / 50 (12.00%)
    6 / 49 (12.24%)
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    2 / 50 (4.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    0
    3
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    1
    2
    1
    4
    0
    2
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    0
    1
    3
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    1
    3
    1
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    3
    1
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    4 / 50 (8.00%)
    2 / 50 (4.00%)
    3 / 49 (6.12%)
         occurrences all number
    1
    1
    2
    4
    2
    3
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2014
    ● Updated throughout to reflect that subjects may have had the opportunity to enter the OLE Study M13-538. ● Clarified rescreening and lab retesting requirements. ● Updated the timeframe for PK trough blood draws and requirement for taking morning dose of study drug at the site on visit days. ● Clarified that folic acid and MTX were allowed to be taken on the same day. ● Updated prohibited and acceptable concomitant medications. ● Updated Inclusion Criterion #7 to clarify that tramadol, codeine, hydrocodone, and propoxyphene taken PRN were allowed, but could not be taken 24 hours prior to any study visit. ● Updated Inclusion Criterion #8 to exclude meperidine 4 weeks prior to Baseline as a high potency opiate. ● Updated Exclusion Criterion #6 to clarify that subjects with intra-articular, intramuscular, IV, intra-bursa, or intra-tendon sheath administration of corticosteroids in the preceding 8 weeks prior to the Baseline visit would not be eligible for the study. ● Updated Exclusion Criterion #19 for history of uncontrolled diabetes mellitus (as evidenced by HbA1c ≥ 7.5%) to history of uncontrolled diabetes with the last 6 months prior to screening. ● Updated Exclusion Criterion #21 to add grapefruit juice as a known strong CYP3A inhibitor. ● Removed local requirements for the TB skin test in Czech Republic (due to local requirements not applicable to the study). ● Added clarification that cardiovascular system-related and central nervous system-related events were to be recorded on supplemental eCRF pages.

    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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