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    Clinical Trial Results:
    Randomized, double-blind, placebo-controlled, multicenter, phase IIb dose finding study of GLPG0634 administered for 24 weeks as monotherapy to subjects with moderately to severely active rheumatoid arthritis who have an inadequate response to methotrexate alone

    Summary
    EudraCT number
    		 2012-003654-86
    Trial protocol
    		 HU   DE   AT   ES   LV   BG  
    Global end of trial date
    29 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2016
    First version publication date
    14 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GLPG0634-CL-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01894516
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Galapagos N.V.
    Sponsor organisation address
    Generaal De Wittelaan L11 A3, 2800, Mechelen, Belgium,
    Public contact
    Clinical Trial Information Desk, Galapagos N.V., +32 (0)15 342 900, rd@glpg.com
    Scientific contact
    Clinical Trial Information Desk, Galapagos N.V., +32 (0)15 342 900, rd@glpg.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
    29 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy in terms of the percentage of subjects achieving an American College of Rheumatology (ACR)20 response, of different doses of GLPG0634 given once daily compared to placebo at Week 12.
    Protection of trial subjects
    Before initiation of the study at each study center, the protocol, the informed consent form (ICF), other written material given to the subjects, and any other relevant study documentation was to be submitted to the appropriate IEC/IRB. Written approval of the study and all relevant study information was to be obtained before the study center could be initiated or the study medication was released to the investigator. Any necessary extensions or renewals of IEC/IRB approval were to be obtained for changes to the study such as modification of the protocol, the ICF or other study documentation. The written approval of the IEC/IRB together with the approved ICF was to be filed in the study files. The investigator was to promptly report to the IEC/IRB any new information that could have adversely affected the safety of the subjects or the conduct of the study. The investigator was to submit written summaries of the study status to the IEC/IRB as required. On completion of the study, the IEC/IRB was to be notified that the study had ended.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 2013
    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
    Mexico: 29
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Guatemala: 9
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Moldova, Republic of: 10
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Latvia: 4
    Worldwide total number of subjects
    287
    EEA total number of subjects
    77
    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)
    245
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Latin America, Europe, United States, and New Zealand. The first participant was screened on 08 October 2013. The last study visit occurred on 29 May 2015.

    Pre-assignment
    Screening details
    		 625 participants were screened.

    Period 1
    Period 1 title
    Period 1: Weeks 1-12
    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
    		 Placebo during Weeks 1-12 and switched to GLPG0634 100 mg QD during Weeks 13-24
    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
    2 placebo capsules in the morning

    Arm title
    		 GLPG0634 50 mg QD
    Arm description
    		 GLPG0634 50 mg once daily during Weeks 1-12; responders (having at least 20% improvement on TJC68 and SJC66) remained on the same treatment while nonresponders switched to 100 mg QD during Weeks 13-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 25 mg capsules once daily in the morning

    Arm title
    		 GLPG0634 100 mg QD
    Arm description
    		 GLPG0634 100 mg once daily during Weeks 1-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 50 mg capsules once daily in the morning

    Arm title
    		 GLPG0634 200 mg QD
    Arm description
    		 GLPG0634 200 mg once daily during Weeks 1-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 100 mg capsules once daily in the morning

    Number of subjects in period 1 [1]
    		Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Started
    72
    72
    70
    69
    Completed
    65
    67
    67
    66
    Not completed
    7
    5
    3
    3
         Non compliance with the study medication
    1
    1
    -
    -
         Withdrawal of the subject's consent
    2
    3
    1
    2
         Treatment failure
    -
    -
    1
    -
         Adverse event, non-fatal
    2
    -
    -
    1
         Other
    -
    1
    1
    -
         Adverse event and treatment failure
    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: 4 subjects who were enrolled but not treated are not included in the subject disposition table.
    Period 2
    Period 2 title
    Period 2: Weeks 13-24
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Switch to GLPG0634 100 mg QD
    Arm description
    		 Placebo during Weeks 1-12 and switched to GLPG0634 100 mg QD during Weeks 13-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 50 mg capsules once daily in the morning

    Arm title
    		 GLPG0634 50 mg QD Responders
    Arm description
    		 GLPG0634 50 mg once daily during Weeks 1-12; responders remained on the same treatment during Weeks 13-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 25 mg capsules once daily in the morning

    Arm title
    		 50 mg QD Switch to GLPG0634 100 mg
    Arm description
    		 Nonresponders from the 50 mg QD group were re-randomized to receive GLPG0634 100 mg during Weeks 13-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 50 mg capsules once daily in the morning

    Arm title
    		 GLPG0634 100 mg QD
    Arm description
    		 GLPG0634 100 mg once daily during Weeks 1-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 50 mg capsules once daily in the morning

    Arm title
    		 GLPG0634 200 mg QD
    Arm description
    		 GLPG0634 200 mg once daily during Weeks 1-24
    Arm type
    		 Experimental

    Investigational medicinal product name
    GLPG0634
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2 GLPG0634 100 mg capsules once daily in the morning

    Number of subjects in period 2
    		Placebo Switch to GLPG0634 100 mg QD GLPG0634 50 mg QD Responders 50 mg QD Switch to GLPG0634 100 mg GLPG0634 100 mg QD GLPG0634 200 mg QD
    Started
    65
    52
    15
    67
    66
    Completed
    63
    50
    15
    64
    65
    Not completed
    2
    2
    0
    3
    1
         Withdrawal of the subject's consent
    1
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    2
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo during Weeks 1-12 and switched to GLPG0634 100 mg QD during Weeks 13-24

    Reporting group title
    GLPG0634 50 mg QD
    Reporting group description
    		 GLPG0634 50 mg once daily during Weeks 1-12; responders (having at least 20% improvement on TJC68 and SJC66) remained on the same treatment while nonresponders switched to 100 mg QD during Weeks 13-24

    Reporting group title
    GLPG0634 100 mg QD
    Reporting group description
    		 GLPG0634 100 mg once daily during Weeks 1-24

    Reporting group title
    GLPG0634 200 mg QD
    Reporting group description
    		 GLPG0634 200 mg once daily during Weeks 1-24

    Reporting group values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD Total
    Number of subjects
    		 72 72 70 69 283
    Age categorical
    Units: Subjects
        < 45
    		 19 20 13 18 70
        ≥ 45 to < 65
    		 43 36 48 44 171
        ≥ 65 to < 75
    		 9 13 6 4 32
        ≥ 75
    		 1 3 3 3 10
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 51.5 (20 to 77) 52.1 (18 to 79) 52.8 (22 to 78) 51.8 (25 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 56 62 53 60 231
        Male
    		 16 10 17 9 52
    Race
    Units: Subjects
        Asian
    		 0 1 0 0 1
        Black or African American
    		 1 1 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        White
    		 53 53 53 54 213
        Other
    		 17 17 16 15 65
    Rheumatoid arthritis (RA) duration
    Units: years
        arithmetic mean (full range (min-max))
    		 9.46 (0.7 to 28.9) 8.63 (0.5 to 23.4) 8.57 (0.5 to 33.7) 8.68 (0.5 to 49.6) -
    C-reactive protein (CRP) at Baseline
    Units: mg/L
        arithmetic mean (full range (min-max))
    		 35.26 (1 to 175) 24.67 (1 to 162.9) 25.55 (1.6 to 244.1) 23.16 (1 to 91.3) -
    Corrected tender joint count based on 68 joints (TJC68) at Baseline
    68 joints were assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68.
    Units: units on a scale
        arithmetic mean (full range (min-max))
    		 25.226 (8 to 63) 25.58 (9 to 64) 27.195 (8 to 65) 26.242 (8 to 65.94) -
    Corrected swollen joint count based on 66 joints (SJC66) at Baseline
    66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66.
    Units: units on a scale
        arithmetic mean (full range (min-max))
    		 15.98 (7 to 38) 16.969 (7 to 48) 18.653 (6 to 56) 15.74 (6 to 46) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo during Weeks 1-12 and switched to GLPG0634 100 mg QD during Weeks 13-24

    Reporting group title
    GLPG0634 50 mg QD
    Reporting group description
    		 GLPG0634 50 mg once daily during Weeks 1-12; responders (having at least 20% improvement on TJC68 and SJC66) remained on the same treatment while nonresponders switched to 100 mg QD during Weeks 13-24

    Reporting group title
    GLPG0634 100 mg QD
    Reporting group description
    		 GLPG0634 100 mg once daily during Weeks 1-24

    Reporting group title
    GLPG0634 200 mg QD
    Reporting group description
    		 GLPG0634 200 mg once daily during Weeks 1-24
    Reporting group title
    Placebo Switch to GLPG0634 100 mg QD
    Reporting group description
    		 Placebo during Weeks 1-12 and switched to GLPG0634 100 mg QD during Weeks 13-24

    Reporting group title
    GLPG0634 50 mg QD Responders
    Reporting group description
    		 GLPG0634 50 mg once daily during Weeks 1-12; responders remained on the same treatment during Weeks 13-24

    Reporting group title
    50 mg QD Switch to GLPG0634 100 mg
    Reporting group description
    		 Nonresponders from the 50 mg QD group were re-randomized to receive GLPG0634 100 mg during Weeks 13-24

    Reporting group title
    GLPG0634 100 mg QD
    Reporting group description
    		 GLPG0634 100 mg once daily during Weeks 1-24

    Reporting group title
    GLPG0634 200 mg QD
    Reporting group description
    		 GLPG0634 200 mg once daily during Weeks 1-24

    Primary: Percentage of subjects achieving an ACR20 response at Week 12

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    End point title
    		 Percentage of subjects achieving an ACR20 response at Week 12
    End point description
    The American College of Rheumatology (ACR) response is a measurement of improvement in multiple disease assessment criteria. The ACR20 response was defined as: 1) ≥ 20% improvement from baseline in swollen joint count based on 66 joints (SJC66), and 2) ≥ 20% improvement from baseline in tender joint count based on 68 joints (TJC68), and 3) ≥ 20% improvement from baseline in at least 3 of the following 5 items: 1. Pain visual analog scale (VAS) (taken from the Health Assessment Questionnaire – Disability Index [HAQ-DI]), 2. Patient’s Global Assessment of Disease Activity VAS, 3. Physician's Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. C-reactive protein (CRP). Intent-to-Treat (ITT) Population: all participants in the Safety Population who had post-randomization data for at least one efficacy parameter. Non-responder imputation was used (ie, to impute a missing response, the subject was assumed to be a non-responder).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72
    72
    70
    69
    Units: percentage of subjects
        number (not applicable)
    29.2
    66.7
    65.7
    72.5
    Statistical analysis title
    		 ACR20 Response at Week 12 - Placebo vs 50 mg QD
    Statistical analysis description
    Pairwise comparisons of each group vs. the placebo group using a logistic regression model with factors treatment group, geographical region, and prior use of biologics.
    Comparison groups
    Placebo v GLPG0634 50 mg QD
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in percentage rates
    Point estimate
    37.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.4
         upper limit
    		 52.6
    Notes
    [1] - P-value has been corrected for multiplicity according to Hommels' closed-testing method.
    Statistical analysis title
    		 ACR20 Response at Week 12 - Placebo vs 100 mg QD
    Statistical analysis description
    Pairwise comparisons of each group vs. the placebo group using a logistic regression model with factors treatment group, geographical region, and prior use of biologics.
    Comparison groups
    Placebo v GLPG0634 100 mg QD
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in percentage rates
    Point estimate
    36.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.3
         upper limit
    		 51.8
    Notes
    [2] - P-value has been corrected for multiplicity according to Hommels' closed-testing method.
    Statistical analysis title
    		 ACR20 Response at Week 12 - Placebo vs 200 mg QD
    Statistical analysis description
    Pairwise comparisons of each group vs. the placebo group using a logistic regression model with factors treatment group, geographical region, and prior use of biologics.
    Comparison groups
    Placebo v GLPG0634 200 mg QD
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in percentage rates
    Point estimate
    43.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.4
         upper limit
    		 58.2
    Notes
    [3] - P-value has been corrected for multiplicity according to Hommels' closed-testing method.

    Secondary: Percentage of subjects achieving an ACR20 response at Week 24

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    End point title
    		 Percentage of subjects achieving an ACR20 response at Week 24 [4]
    End point description
    ACR20 response was defined as: 1) ≥ 20% improvement from baseline in SJC66, and 2) ≥ 20% improvement from baseline in TJC68, and 3) ≥ 20% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI), 2. Patient’s Global Assessment of Disease Activity VAS, 3. Physician’s Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. Non-responder imputation was used.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point values
    		 GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72
    70
    69
    Units: percentage of subjects
        number (not applicable)
    56.9
    78.6
    66.7
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving an ACR50 response at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 Percentage of subjects achieving an ACR50 response at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    ACR50 response was defined as: 1) ≥ 50% improvement from baseline in SJC66, and 2) ≥ 50% improvement from baseline in TJC68, and 3) ≥ 50% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI), 2. Patient’s Global Assessment of Disease Activity VAS, 3. Physician’s Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. Non-responder imputation was used. Denominator for percentage calculations = total number of subjects per group with a response at that time point. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [5]
    72
    70
    69
    Units: percentage of subjects
    number (not applicable)
        Week 1
    1.4
    1.4
    10
    7.2
        Week 2
    4.2
    5.6
    7.1
    21.7
        Week 4
    4.2
    15.3
    18.6
    23.2
        Week 8
    5.6
    16.7
    25.7
    31.9
        Week 12
    11.1
    34.7
    37.1
    43.5
        Week 24
    999
    33.3
    38.6
    44.9
    Notes
    [5] - Except for at Week 24 (N = 0) because all placebo subjects switched to GLPG0634 at Week 12.
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving ACR70 response at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 Percentage of subjects achieving ACR70 response at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    ACR70 response: 1) ≥ 70% improvement from baseline in SJC66, and 2) ≥ 70% improvement from baseline in TJC68, and 3) ≥ 70% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI), 2. Patient’s Global Assessment of Disease Activity VAS, 3. Physician’s Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. Non-responder imputation was used. Denominator for percentage calculations = total number of subjects per group with a response at that time point. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [6]
    72
    70
    69
    Units: percentage of subjects
    number (not applicable)
        Week 1
    0
    0
    1.4
    1.4
        Week 2
    2.8
    1.4
    1.4
    4.3
        Week 4
    1.4
    8.3
    5.7
    11.6
        Week 8
    2.8
    6.9
    11.4
    17.4
        Week 12
    2.8
    8.3
    18.6
    13
        Week 24
    999
    19.4
    25.7
    24.6
    Notes
    [6] - Except for at Week 24 (N = 0) because all placebo subjects switched to GLPG0634 at Week 12.
    No statistical analyses for this end point

    Secondary: ACR N% improvement (ACR-N) response at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 ACR N% improvement (ACR-N) response at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    The ACR-N is the smallest percentage improvement in swollen and tender joints and the median of the remaining 5 core parameters, and is expected to be more sensitive to change than the ACR20, ACR50 or ACR70. It is a number varying between 0 and 100, with higher numbers indicating less severity of symptoms. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. Last observation carried forward (LOCF) algorithm was used (ie, to impute a missing value, the last preceding nonmissing value was used). 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [7]
    72
    70
    69
    Units: units on a scale
    arithmetic mean (standard error)
        Week 1
    6.79 ( 1.34 )
    11.66 ( 1.641 )
    12.84 ( 2.291 )
    16.84 ( 2.346 )
        Week 2
    10.79 ( 1.917 )
    17.11 ( 2.362 )
    16.06 ( 2.261 )
    27.01 ( 2.776 )
        Week 4
    12.03 ( 2.058 )
    25 ( 2.852 )
    24.06 ( 2.898 )
    32.21 ( 3.172 )
        Week 8
    13.35 ( 2.24 )
    30.46 ( 2.986 )
    32.66 ( 3.154 )
    39.24 ( 3.375 )
        Week 12
    16.28 ( 2.723 )
    35.03 ( 3.178 )
    38.35 ( 3.533 )
    41 ( 3.477 )
        Week 24
    999 ( 999 )
    38.75 ( 3.748 )
    46.32 ( 3.295 )
    46.78 ( 3.648 )
    Notes
    [7] - Except for at Week 24 (N = 0) because all placebo subjects switched to GLPG0634 at Week 12.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with Disease Activity Score 28 Joints Corrected for CRP (DAS28 (CRP)) European League Against Rheumatism (EULAR) response at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 Percentage of subjects with Disease Activity Score 28 Joints Corrected for CRP (DAS28 (CRP)) European League Against Rheumatism (EULAR) response at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    DAS28 (CRP) was categorized into EULAR response categories (none, moderate, good) as follows: Good = Actual DAS28 (CRP) ≤ 3.2 AND Improvement in DAS28 (CRP) from baseline > 1.2; None = Actual DAS28 (CRP) ≤ 3.2, > 3.2 to ≤ 5.1, or > 5.1 AND Improvement in DAS28 (CRP) from baseline ≤ 6.0 or > 0.6 to ≤ 1.2; Moderate = Actual DAS28 (CRP) ≤ 3.2 AND Improvement in DAS28 (CRP) from baseline > 0.6 to ≤ 1.2, Actual DAS28 (CRP) > 3.2 to ≤ 5.1 or > 5.1 AND Improvement in DAS28 (CRP) from baseline > 1.2, or Actual DAS28 (CRP) > 3.2 to ≤ 5.1 AND Improvement in DAS28 (CRP) from baseline > 0.6 to ≤ 1.2. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. LOCF algorithm was used. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [8]
    72
    70
    69
    Units: percentage of subjects
    number (not applicable)
        Week 1: None
    72
    57
    63
    49
        Week 1: Moderate
    26
    40
    31
    43
        Week 1: Good
    1
    3
    6
    7
        Week 2: None
    67
    44
    47
    26
        Week 2: Moderate
    31
    49
    46
    64
        Week 2: Good
    3
    7
    7
    10
        Week 4: None
    58
    38
    39
    22
        Week 4: Moderate
    35
    47
    46
    55
        Week 4: Good
    7
    15
    16
    23
        Week 8: None
    54
    36
    24
    12
        Week 8: Moderate
    36
    39
    54
    54
        Week 8: Good
    10
    25
    21
    35
        Week 12: None
    49
    31
    20
    14
        Week 12: Moderate
    38
    46
    53
    41
        Week 12: Good
    14
    24
    27
    45
        Week 24: None
    999
    28
    9
    10
        Week 24: Moderate
    999
    36
    41
    43
        Week 24: Good
    999
    36
    50
    46
    Notes
    [8] - Except for at Week 24 (N = 0) because all placebo subjects switched to GLPG0634 at Week 12.
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving ACR/EULAR remission at Weeks 4, 8, 12, and 24

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    End point title
    		 Percentage of subjects achieving ACR/EULAR remission at Weeks 4, 8, 12, and 24
    End point description
    A subject’s disease activity status can be defined as being in remission when scores on the TJC28, SJC28, CRP (actual value in mg/dL) and Patient Global Assessment of Disease Activity (cm) are all ≤ 1. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. Non-responder imputation was used. Denominator for percentage calculations = total number of subjects per group with a response at that time point. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [9]
    72
    70
    69
    Units: percentage of subjects
    number (not applicable)
        Week 4
    0
    1.4
    0
    1.4
        Week 8
    0
    0
    0
    7.2
        Week 12
    1.4
    1.4
    4.3
    4.3
        Week 24
    999
    8.3
    8.6
    8.7
    Notes
    [9] - Except for at Week 24 (N = 0) because all placebo subjects switched to GLPG0634 at Week 12.
    No statistical analyses for this end point

    Secondary: Simplified Disease Activity Index (SDAI) at baseline and change from baseline at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 Simplified Disease Activity Index (SDAI) at baseline and change from baseline at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, Patient Global Assessment of Disease Activity (in cm), Physician’s Global Assessment of Disease Activity (in cm), and CRP (mg/dL). The SDAI was categorized as follows: • High disease activity: SDAI > 26 • Moderate disease activity: 11 to 26 • Low disease activity: 3.3 to 11 • Remission: ≤ 3.3. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. LOCF algorithm was used. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [10]
    72 [11]
    70
    69 [12]
    Units: units on a scale
    arithmetic mean (standard error)
        Baseline
    45.73 ( 1.4789 )
    43.77 ( 1.5609 )
    46.608 ( 1.6538 )
    44.139 ( 1.5079 )
        Change at Week 1
    -7.45 ( 1.5528 )
    -9.596 ( 1.2567 )
    -10.886 ( 1.6511 )
    -14.349 ( 1.4346 )
        Change at Week 2
    -10.022 ( 1.371 )
    -12.194 ( 1.5982 )
    -13.172 ( 1.6209 )
    -18.27 ( 1.6934 )
        Change at Week 4
    -10.927 ( 1.7771 )
    -17.57 ( 1.7653 )
    -18.862 ( 1.8073 )
    -21.288 ( 1.6619 )
        Change at Week 8
    -12.452 ( 1.7748 )
    -20.144 ( 1.9425 )
    -23.119 ( 1.8041 )
    -25.556 ( 1.6949 )
        Change at Week 12
    -12.574 ( 1.984 )
    -21.413 ( 1.7953 )
    -25.269 ( 1.9856 )
    -26.499 ( 1.7534 )
        Change at Week 24
    999 ( 999 )
    -23.16 ( 1.9364 )
    -30.983 ( 1.7732 )
    -29.564 ( 1.8583 )
    Notes
    [10] - Except at Wk 24 (N=0) because all placebo subjects switched to GLPG0634 at Wk 12; Baseline (N=71)
    [11] - Except for at Baseline (N = 70)
    [12] - Except for at Baseline (N = 68)
    No statistical analyses for this end point

    Secondary: Clinical Disease Activity Index (CDAI) at baseline and change from baseline at Weeks 1, 2, 4, 8, 12, and 24

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    End point title
    		 Clinical Disease Activity Index (CDAI) at baseline and change from baseline at Weeks 1, 2, 4, 8, 12, and 24
    End point description
    The CDAI is the SDAI modified to exclude CRP and is the sum of the 4 outcome parameters: TJC28, SJC28, Patient Global Assessment of Disease Activity (in cm), and Physician’s Global Assessment of Disease Activity (in cm). The CDAI was be categorized as follows: • High disease activity: > 22 • Moderate disease activity: 10 to 22 • Mild disease activity: 2.8 to 10 • Remission: ≤ 2.8. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. LOCF algorithm was used. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 4, 8, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [13]
    72 [14]
    70
    69 [15]
    Units: units on a scale
    arithmetic mean (standard error)
        Baseline
    42.168 ( 1.3272 )
    41.348 ( 1.4777 )
    44.052 ( 1.5383 )
    41.869 ( 1.423 )
        Change at Week 1
    -6.867 ( 1.4538 )
    -9.226 ( 1.1545 )
    -9.853 ( 1.5591 )
    -13.148 ( 1.4085 )
        Change at Week 2
    -9.861 ( 1.1909 )
    -11.803 ( 1.5275 )
    -12.306 ( 1.5618 )
    -16.999 ( 1.702 )
        Change at Week 4
    -10.743 ( 1.7184 )
    -16.701 ( 1.7003 )
    -17.654 ( 1.6987 )
    -20.044 ( 1.6396 )
        Change at Week 8
    -12.071 ( 1.6982 )
    -19.087 ( 1.8583 )
    -21.703 ( 1.7491 )
    -24.228 ( 1.6479 )
        Change at Week 12
    -11.696 ( 1.8752 )
    -21.019 ( 1.7168 )
    -24.044 ( 1.9665 )
    -25.071 ( 1.742 )
        Change at Week 24
    999 ( 999 )
    -22.278 ( 1.8637 )
    -29.502 ( 1.6928 )
    -28.102 ( 1.818 )
    Notes
    [13] - Except at Wk 24 (N=0) because all placebo subjects switched to GLPG0634 at Wk 12; at Baseline (N=71)
    [14] - Except for at Baseline (N = 70)
    [15] - Except for at Baseline (N = 68)
    No statistical analyses for this end point

    Secondary: Quality of Life using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale at baseline and change from baseline at Weeks 4, 12, and 24

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    End point title
    		 Quality of Life using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale at baseline and change from baseline at Weeks 4, 12, and 24
    End point description
    FACIT-Fatigue scale is a 13-item questionnaire, each scored on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the subject's response to the questions (with the exception of 2 negatively stated that are scored reversely), the greater the fatigue. The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score), with a higher score indicating a better quality of life. Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. LOCF algorithm was used. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [16]
    72 [17]
    70
    69
    Units: units on a scale
    arithmetic mean (standard error)
        Baseline
    25.1 ( 1.12 )
    25.1 ( 1.28 )
    24.8 ( 1.13 )
    24.8 ( 1.16 )
        Change at Week 4
    1.4 ( 1.14 )
    7.2 ( 1.3 )
    7.2 ( 1.26 )
    8.5 ( 1.3 )
        Change at Week 12
    3.9 ( 1.23 )
    9.5 ( 1.43 )
    10.2 ( 1.21 )
    11.2 ( 1.44 )
        Change at Week 24
    999 ( 999 )
    10 ( 1.43 )
    11.3 ( 1.2 )
    13.7 ( 1.38 )
    Notes
    [16] - Except at Wk 24 (N=0) because all placebo subjects switched to GLPG0634 at Wk 12; at Baseline (N=71)
    [17] - Except for at Baseline (N = 70)
    No statistical analyses for this end point

    Secondary: Quality of Life using the Short Form-36 (SF-36) scores at baseline and change from baseline at Weeks 4, 12, and 24

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    End point title
    		 Quality of Life using the Short Form-36 (SF-36) scores at baseline and change from baseline at Weeks 4, 12, and 24
    End point description
    The SF-36 is a 36-item questionnaire measuring 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. Two summary scale scores were computed based on weighted combinations of the 8 domain scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Intent-to-Treat (ITT) Population. Subjects who switched treatment at Week 12 were handled as if they discontinued at Week 12. LOCF algorithm was used. 999 = NA; all placebo subjects switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 12, and 24
    End point values
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Number of subjects analysed
    72 [18]
    72 [19]
    70
    69
    Units: units on a scale
    arithmetic mean (standard error)
        PCS at Baseline
    31.1 ( 0.6988 )
    31.05 ( 0.816 )
    30.946 ( 0.7631 )
    31.804 ( 0.8965 )
        PCS Change at Week 4
    2.1 ( 0.72 )
    5.7 ( 1.04 )
    5.1 ( 0.92 )
    6.8 ( 0.92 )
        PCS Change at Week 12
    3 ( 0.89 )
    7.1 ( 1.11 )
    7.8 ( 1.04 )
    8.6 ( 1.09 )
        PCS Change at Week 24
    999 ( 999 )
    6.9 ( 1.16 )
    10 ( 1.17 )
    9.7 ( 1.09 )
        MCS at Baseline
    40.525 ( 1.3053 )
    42.793 ( 1.3247 )
    41.185 ( 1.2347 )
    42.613 ( 1.1674 )
        MCS Change at Week 4
    2.1 ( 1.1 )
    3.6 ( 1.09 )
    5.3 ( 1.04 )
    3.9 ( 1.16 )
        MCS Change at Week 12
    2.7 ( 1.04 )
    4.9 ( 1.18 )
    6.9 ( 1.04 )
    6.8 ( 1.33 )
        MCS Change at Week 24
    999 ( 999 )
    5.1 ( 1.27 )
    7.7 ( 1.16 )
    8.5 ( 1.12 )
    Notes
    [18] - Except at Wk 24 (N=0) because all placebo subjects switched to GLPG0634 at Wk 12; at Baseline (N=71)
    [19] - Except for at Baseline (N = 70)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through end of study drug treatment (average exposure: 161.0 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Adverse events reported in this group includes all subjects randomized to the Placebo group during Weeks 1-12. Subjects who switched treatment at Week 12 were included in the other groups of the same dose for adverse events reported during Weeks 13-24.

    Reporting group title
    GLPG0634 50 mg QD
    Reporting group description
    		 Adverse events reported in this group includes all subjects randomized to the GLPG0634 50 mg QD group during Weeks 1-12 and responders in this group during Weeks 13-24. Subjects who switched treatment at Week 12 were included in the other groups of the same dose for adverse events reported during Weeks 13-24.

    Reporting group title
    GLPG0634 100 mg QD
    Reporting group description
    		 Adverse events reported in this group includes all subjects randomized to the GLPG0634 100 mg QD group during Weeks 1-24 and all nonresponders originally assigned to the GLPG0634 50 mg QD group during Weeks 13-24.

    Reporting group title
    GLPG0634 200 mg QD
    Reporting group description
    		 Adverse events reported in this group includes all subjects randomized to the GLPG0634 200 mg QD group during Weeks 1-24.

    Serious adverse events
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 72 (2.78%)
    3 / 85 (3.53%)
    3 / 69 (4.35%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
    0 / 85 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    1 / 85 (1.18%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    0 / 85 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    0 / 85 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
    0 / 85 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    1 / 85 (1.18%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
    0 / 85 (0.00%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    0 / 85 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 72 (0.00%)
    1 / 85 (1.18%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo GLPG0634 50 mg QD GLPG0634 100 mg QD GLPG0634 200 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 72 (37.50%)
    38 / 72 (52.78%)
    45 / 85 (52.94%)
    33 / 69 (47.83%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 72 (4.17%)
    1 / 85 (1.18%)
    2 / 69 (2.90%)
         occurrences all number
    4
    3
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 72 (5.56%)
    1 / 85 (1.18%)
    3 / 69 (4.35%)
         occurrences all number
    1
    10
    2
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
    0 / 85 (0.00%)
    4 / 69 (5.80%)
         occurrences all number
    0
    1
    0
    4
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 72 (2.78%)
    4 / 85 (4.71%)
    4 / 69 (5.80%)
         occurrences all number
    2
    2
    4
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 72 (4.17%)
    7 / 85 (8.24%)
    4 / 69 (5.80%)
         occurrences all number
    1
    4
    10
    6
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 72 (5.56%)
    5 / 85 (5.88%)
    1 / 69 (1.45%)
         occurrences all number
    3
    5
    5
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 72 (2.78%)
    5 / 85 (5.88%)
    1 / 69 (1.45%)
         occurrences all number
    1
    2
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2013
    • Due to the implementation of a new method for CRP measurements carried out by the central laboratory (Quest Diagnostics), the ULN and its fold change that were used to calculate the numeric value for the inclusion criteria were likely to change. Therefore, instead of a numeric value, CRP as inclusion criterion was expressed as a 1.5 fold change ULN. • As adjustments for the body surface area were not going to be carried out (Cockroft- Gault formula), the estimated creatinine clearance was expressed as ml/min/. • In order to reduce the recording burden for patients, the date and time of the taken capsules was recorded on selected visits only and not at every visit. • Size of the SST tubes that were planned to be used for the additional pharmacodynamics assessment, was changed (instead of two 4-ml SST tubes, only one 8.5-ml SST tube was collected).
    17 Apr 2013
    Introduced stratification according to the previous use of a biological DMARD in a single clinical study setting, in addition to the stratification according to region. This aimed to obtain equal distribution of subjects who had been previously exposed to a biological DMARD during a single clinical study setting between the study groups, to reduce heterogeneity and therefore be beneficial for results interpretation. Consequently the statistical methods section was adapted accordingly: Cochran-Mantel-Haenszel and logrank tests, both controlling for region, were changed to logistic and proportional hazards regression models in order to include more factors.
    02 Aug 2013
    Addressed specific comments received from Competent Authorities and Ethics Committees. In addition, some clarifications were introduced upon request of investigators. Changes introduced included: • The overall benefit/risk assessment was updated in view of recent advances in the product development and the current status of the scientific field for JAK development. • The inclusion/exclusion criteria were refined with further specified and strengthened laboratory test limits, and additional criteria to manage the overall health status at Screening were introduced. • Criteria for individual subject withdrawal were further specified. • An independent DSMB was introduced. • The section on prior and concomitant therapy was updated. Note: Amendment was applicable to all countries apart from the US.
    23 May 2014
    • The inclusion/exclusion criteria were adjusted to better represent the current RA population without compromising the study objective, including a decrease in entry level for CRP to >0.70xULN. • The individual subject withdrawal criteria were adjusted • The general study procedures (calendar days, re-Screening and retesting guidelines) were refined to provide further guidance to investigators. Note: Amendment was applicable to all countries apart from the US.

    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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