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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo- and Active-controlled, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Filgotinib Administered for 52 weeks in Combination with Methotrexate to Subjects with Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate

    Summary
    EudraCT number
    		 2016-000568-41
    Trial protocol
    		 SK   GB   BE   HU   CZ   DE   ES   BG   PL   NL   IT  
    Global end of trial date
    20 Jun 2019

    Results information
    Results version number
    		 v1
    This version publication date
    05 Jul 2020
    First version publication date
    05 Jul 2020
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-417-0301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02889796
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    20 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effects of filgotinib versus placebo for the treatment of signs and symptoms of rheumatoid arthritis (RA) as measured by the percentage of participants achieving an American College of Rheumatology 20% improvement response (ACR20) at week 12.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 Methotrexate (MTX) was used across all the arms as background therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Aug 2016
    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
    Slovakia: 8
    Country: Number of subjects enrolled
    South Africa: 34
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Taiwan: 44
    Country: Number of subjects enrolled
    Thailand: 23
    Country: Number of subjects enrolled
    Ukraine: 235
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 200
    Country: Number of subjects enrolled
    Argentina: 57
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 34
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Czech Republic: 34
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    India: 137
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 147
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 33
    Country: Number of subjects enrolled
    Mexico: 125
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    New Zealand: 18
    Country: Number of subjects enrolled
    Poland: 299
    Country: Number of subjects enrolled
    Romania: 31
    Country: Number of subjects enrolled
    Russian Federation: 118
    Country: Number of subjects enrolled
    Serbia: 21
    Worldwide total number of subjects
    1759
    EEA total number of subjects
    536
    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)
    1425
    From 65 to 84 years
    333
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Asia, South Africa, Australia, Europe, North America, South America and New Zealand. The first participant was screened on 30 August 2016. The last study visit occurred on 20 June 2019.

    Pre-assignment
    Screening details
    		 2582 participants were screened. Completed in the Placebo never received filgotinib arm includes participants who completed 24 weeks of placebo treatment and were not rerandomized to Filgotinib 200 mg or 100 mg groups.

    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
    		 Filgotinib 200 mg
    Arm description
    		 Participants were administered a filgotinib 200 mg tablet orally, once daily + placebo (PBO) to match [PTM] filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg subcutaneous (SC) injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034, GLPG0634
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 100 mg administered once daily

    Investigational medicinal product name
    PTM Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PTM adalimumab 40 mg administered once every 2 weeks

    Arm title
    		 Filgotinib 100 mg
    Arm description
    		 Participants were administered a filgotinib 100 mg tablet orally, once daily + PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034, GLPG0634
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 200 mg administered once daily

    Investigational medicinal product name
    PTM Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PTM adalimumab 40 mg administered once every 2 weeks

    Arm title
    		 Adalimumab
    Arm description
    		 Participants were administered PTM filgotinib 200 mg tablet orally, once daily + PTM filgotinib 100 mg tablet orally, once daily + adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PTM Filgotinib 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 200 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 100 mg administered once daily

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg administered once every 2 weeks

    Arm title
    		 Placebo to Filgotinib 200 mg
    Arm description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 200 mg and were administered a filgotinib 200 mg tablet orally, once daily + PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PTM Filgotinib 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 200 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 100 mg administered once daily

    Investigational medicinal product name
    PTM Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PTM adalimumab 40 mg administered once every 2 weeks

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034, GLPG0634
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg administered once daily

    Arm title
    		 Placebo to Filgotinib 100 mg
    Arm description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 100 mg and were administered a filgotinib 100 mg tablet orally, once daily + PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PTM Filgotinib 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 200 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 100 mg administered once daily

    Investigational medicinal product name
    PTM Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PTM adalimumab 40 mg administered once every 2 weeks

    Investigational medicinal product name
    Filgotinib
    Investigational medicinal product code
    Other name
    GS-6034, GLPG0634
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Arm title
    		 Placebo never received Filgotinib
    Arm description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    PTM Filgotinib 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 200 mg administered once daily

    Investigational medicinal product name
    PTM Filgotinib 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTM filgotinib 100 mg administered once daily

    Investigational medicinal product name
    PTM Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PTM adalimumab 40 mg administered once every 2 weeks

    Number of subjects in period 1 [1]
    		Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo to Filgotinib 200 mg Placebo to Filgotinib 100 mg Placebo never received Filgotinib
    Started
    475
    480
    325
    190
    191
    94
    Completed
    424
    422
    281
    181
    185
    24
    Not completed
    51
    58
    44
    9
    6
    70
         Protocol violation
    -
    1
    3
    -
    -
    4
         Death
    1
    1
    -
    1
    -
    1
         Pregnancy
    -
    1
    1
    -
    -
    -
         Adverse event
    17
    8
    8
    4
    1
    7
         Non-compliance with study drug
    -
    2
    -
    -
    1
    2
         Investigator`s discretion
    10
    9
    10
    3
    -
    15
         Withdrew consent
    18
    29
    20
    1
    2
    35
         Lost to follow-up
    5
    7
    2
    -
    2
    6
    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: Four participants who were randomized but did not receive the study drug are not included in the subject disposition table.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 1755 1755
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.0 ( 12.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1435 1435
        Male
    		 320 320
    Race
    For participants in Not Permitted category: local regulators did not allow collection of race information.
    Units: Subjects
        American Indian or Alaska Native
    		 103 103
        Asian: Japanese
    		 147 147
        Asian: Chinese/Taiwanese/Hong Kong Chinese
    		 51 51
        Asian: Korean
    		 34 34
        Asian: Other
    		 179 179
        Black or African American
    		 35 35
        Native Hawaiian or Pacific Islander
    		 3 3
        White
    		 1184 1184
        Other
    		 17 17
        Not Permitted
    		 2 2
    Ethnicity
    For participants in Not Permitted category: local regulators did not allow collection of ethnicity information.
    Units: Subjects
        Hispanic or Latino
    		 262 262
        Not Hispanic or Latino
    		 1471 1471
        Not Permitted
    		 22 22
    Subject analysis sets

    Subject analysis set title
    Filgotinib 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a filgotinib 200 mg tablet orally, once daily + a placebo to match (PTM) filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg subcutaneous (SC) injection, once every 2 weeks in addition to a weekly stable dose of methotrexate (MTX), orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Filgotinib 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a filgotinib 100 mg tablet orally, once daily + a PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Adalimumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a PTM filgotinib 200 mg tablet orally, once daily + a PTM filgotinib 100 mg tablet orally, once daily + adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Placebo arm included all participants who received placebo in the study. Participants were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Participants could be rerandomized to filgotinib 200 mg or 100 mg groups.

    Subject analysis sets values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects
    475
    480
    325
    475
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52.0 ( 12.8 )
    53.0 ( 12.6 )
    53.0 ( 12.9 )
    53.0 ( 12.8 )
    Gender categorical
    Units: Subjects
        Female
    379
    399
    266
    391
        Male
    96
    81
    59
    84
    Race
    For participants in Not Permitted category: local regulators did not allow collection of race information.
    Units: Subjects
        American Indian or Alaska Native
    27
    27
    20
    29
        Asian: Japanese
    40
    41
    28
    38
        Asian: Chinese/Taiwanese/Hong Kong Chinese
    13
    12
    8
    18
        Asian: Korean
    13
    10
    4
    7
        Asian: Other
    56
    52
    25
    46
        Black or African American
    6
    7
    10
    12
        Native Hawaiian or Pacific Islander
    1
    0
    0
    2
        White
    312
    324
    229
    319
        Other
    7
    6
    1
    3
        Not Permitted
    0
    1
    0
    1
    Ethnicity
    For participants in Not Permitted category: local regulators did not allow collection of ethnicity information.
    Units: Subjects
        Hispanic or Latino
    67
    71
    54
    70
        Not Hispanic or Latino
    404
    399
    268
    400
        Not Permitted
    4
    10
    3
    5

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Filgotinib 200 mg
    Reporting group description
    		 Participants were administered a filgotinib 200 mg tablet orally, once daily + placebo (PBO) to match [PTM] filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg subcutaneous (SC) injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Filgotinib 100 mg
    Reporting group description
    		 Participants were administered a filgotinib 100 mg tablet orally, once daily + PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Adalimumab
    Reporting group description
    		 Participants were administered PTM filgotinib 200 mg tablet orally, once daily + PTM filgotinib 100 mg tablet orally, once daily + adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Placebo to Filgotinib 200 mg
    Reporting group description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 200 mg and were administered a filgotinib 200 mg tablet orally, once daily + PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.

    Reporting group title
    Placebo to Filgotinib 100 mg
    Reporting group description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 100 mg and were administered a filgotinib 100 mg tablet orally, once daily + PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.

    Reporting group title
    Placebo never received Filgotinib
    Reporting group description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks.

    Subject analysis set title
    Filgotinib 200 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a filgotinib 200 mg tablet orally, once daily + a placebo to match (PTM) filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg subcutaneous (SC) injection, once every 2 weeks in addition to a weekly stable dose of methotrexate (MTX), orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Filgotinib 100 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a filgotinib 100 mg tablet orally, once daily + a PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Adalimumab
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered a PTM filgotinib 200 mg tablet orally, once daily + a PTM filgotinib 100 mg tablet orally, once daily + adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Placebo arm included all participants who received placebo in the study. Participants were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Participants could be rerandomized to filgotinib 200 mg or 100 mg groups.

    Primary: Percentage of Participants who Achieved an American College of Rheumatology (ACR) 20% Improvement (ACR20) Response at Week 12

    		 Close Top of page
    End point title
    		 Percentage of Participants who Achieved an American College of Rheumatology (ACR) 20% Improvement (ACR20) Response at Week 12 [1]
    End point description
    ACR20 response is achieved when the participant has: ≥20% improvement (reduction) from baseline in tender joint count based on 68 joints (TJC68), swollen joint count based on 66 joints (SJC66) and in at least 3 of the following 5 items: physician’s global assessment of disease activity (PGA), subject’s global assessment of disease activity (SGA) using visual analog scale (VAS) on a scale of 0 (no disease activity) to 100 (maximum disease activity),participant`s pain assessment using VAS on a scale of 0 (no pain) to 100 (unbearable pain),health assessment questionnaire disability index (HAQ-DI) score contains 20 questions,8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities scored on a scale of 0 (without difficulty) to 3 (unable to do);high-sensitivity C-reactive protein (hsCRP). Full Analysis Set included participants who were randomized and received at least 1 dose of study drug. Participants with missing outcomes were set as non-responders.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Baseline period arms for Placebo [Placebo to Filgotinib 200 mg, Placebo to Filgotinib 100 mg, and Placebo never received Filgotinib] were combined to present data for the total number of participants who received Placebo.
    End point values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects analysed
    475
    480
    325
    475
    Units: percentage of participants
        number (confidence interval 95%)
    76.6 (72.7 to 80.5)
    69.8 (65.6 to 74.0)
    70.5 (65.3 to 75.6)
    49.9 (45.3 to 54.5)
    Statistical analysis title
    		 Filgotinib 200 mg vs Placebo
    Comparison groups
    Filgotinib 200 mg v Placebo
    Number of subjects included in analysis
    950
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    26.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.6
         upper limit
    		 32.8
    Notes
    [2] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.
    Statistical analysis title
    		 Filgotinib 100 mg vs Placebo
    Comparison groups
    Filgotinib 100 mg v Placebo
    Number of subjects included in analysis
    955
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    19.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.6
         upper limit
    		 26.2
    Notes
    [3] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.

    Secondary: Percentage of Participants who Achieved Disease Activity Score for 28 Joint Count Using C-Reactive Protein [DAS28 (CRP)] ≤ 3.2 at Week 12

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    End point title
    		 Percentage of Participants who Achieved Disease Activity Score for 28 Joint Count Using C-Reactive Protein [DAS28 (CRP)] ≤ 3.2 at Week 12 [4]
    End point description
    The DAS28 score is a measure of the participant’s disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient’s Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and hsCRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. Participants in the Full Analysis Set were analyzed. Participants with missing outcomes were set as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    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: The Baseline period arms for Placebo [Placebo to Filgotinib 200 mg, Placebo to Filgotinib 100 mg, and Placebo never received Filgotinib] were combined to present data for the total number of participants who received Placebo.
    End point values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects analysed
    475
    480
    325
    475
    Units: percentage of participants
        number (confidence interval 95%)
    49.7 (45.1 to 54.3)
    38.8 (34.3 to 43.2)
    43.4 (37.8 to 48.9)
    23.4 (19.5 to 27.3)
    Statistical analysis title
    		 Filgotinib 200 mg vs Placebo
    Comparison groups
    Filgotinib 200 mg v Placebo
    Number of subjects included in analysis
    950
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    26.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.2
         upper limit
    		 32.4
    Notes
    [5] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.
    Statistical analysis title
    		 Filgotinib 100 mg vs Placebo
    Comparison groups
    Filgotinib 100 mg v Placebo
    Number of subjects included in analysis
    955
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.4
         upper limit
    		 21.4
    Notes
    [6] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.
    Statistical analysis title
    		 Filgotinib 200 mg vs Adalimumab
    Comparison groups
    Filgotinib 200 mg v Adalimumab
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001 [7]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [7] - P-value of non-inferiority test was calculated from approach proposed by [Liu 2014].
    Statistical analysis title
    		 Filgotinib 100 mg vs Adalimumab
    Comparison groups
    Filgotinib 100 mg v Adalimumab
    Number of subjects included in analysis
    805
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.054 [8]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [8] - P-value of non-inferiority test was calculated from approach proposed by [Liu 2014].
    Statistical analysis title
    		 Filgotinib 200 mg vs Adalimumab
    Comparison groups
    Filgotinib 200 mg v Adalimumab
    Number of subjects included in analysis
    800
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 13.6
    Notes
    [9] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.
    Statistical analysis title
    		 Filgotinib 100 mg vs Adalimumab
    Comparison groups
    Filgotinib 100 mg v Adalimumab
    Number of subjects included in analysis
    805
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -4.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 2.6
    Notes
    [10] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.

    Secondary: Change from Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 12

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    End point title
    		 Change from Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 12 [11]
    End point description
    The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually completed by the participant. Responses in each functional category are collected as 0 (without any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. The eight category scores are averaged into an overall HAQ-DI score on a scale from 0 (no disability) to 3 (completely disabled). When 6 or more categories are non-missing, total possible score is 3. If more than 2 categories are missing, the HAQ-DI score is set to missing. Negative change from baseline indicates improvement (less disability). Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 12
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Baseline period arms for Placebo [Placebo to Filgotinib 200 mg, Placebo to Filgotinib 100 mg, and Placebo never received Filgotinib] were combined to present data for the total number of participants who received Placebo.
    End point values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects analysed
    475
    480
    325
    475
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.59 ( 0.611 )
    1.55 ( 0.625 )
    1.59 ( 0.600 )
    1.63 ( 0.613 )
        Change at Week 12 (n=457, 459, 311, 435)
    -0.69 ( 0.613 )
    -0.56 ( 0.564 )
    -0.61 ( 0.560 )
    -0.42 ( 0.544 )
    Statistical analysis title
    		 Filgotinib 200 mg vs Placebo
    Comparison groups
    Filgotinib 200 mg v Placebo
    Number of subjects included in analysis
    950
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001 [13]
    Method
    		 Mixed effects model for repeated measure
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 -0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [12] - LS-Mean, 95% CI, and P-value were provided from mixed effects model for repeated measure (MMRM). Missing change scores were not imputed using the MMRM approach assuming an unstructured variance-covariance matrix for the repeated measures.
    [13] - MMRM model included treatment, visit, treatment by visit, stratification factors, and baseline value as fixed effects, and subjects being the random effect.
    Statistical analysis title
    		 Filgotinib 100 mg vs Placebo
    Comparison groups
    Filgotinib 100 mg v Placebo
    Number of subjects included in analysis
    955
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.001 [15]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034
    Notes
    [14] - LS-Mean, 95% CI, and P-value were provided from MMRM. Missing change scores were not imputed using the MMRM approach assuming an unstructured variance-covariance matrix for the repeated measures.
    [15] - MMRM model included treatment, visit, treatment by visit, stratification factors, and baseline value as fixed effects, and subjects being the random effect.

    Secondary: Percentage of Participants who Achieved DAS28 (CRP) < 2.6 at Week 24

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    End point title
    		 Percentage of Participants who Achieved DAS28 (CRP) < 2.6 at Week 24 [16]
    End point description
    The DAS28 score is a measure of the participant’s disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), Patient’s Global Assessment of Disease Activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity), and hsCRP for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. Participants in the Full Analysis Set were analyzed. Participants with missing outcomes were set as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Baseline period arms for Placebo [Placebo to Filgotinib 200 mg, Placebo to Filgotinib 100 mg, and Placebo never received Filgotinib] were combined to present data for the total number of participants who received Placebo.
    End point values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects analysed
    475
    480
    325
    475
    Units: percentage of participants
        number (confidence interval 95%)
    48.4 (43.8 to 53.0)
    35.2 (30.8 to 39.6)
    35.7 (30.3 to 41.1)
    16.2 (12.8 to 19.6)
    Statistical analysis title
    		 Filgotinib 200 mg vs Placebo
    Comparison groups
    Filgotinib 200 mg v Placebo
    Number of subjects included in analysis
    950
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    32.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 26.4
         upper limit
    		 38
    Notes
    [17] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.
    Statistical analysis title
    		 Filgotinib 100 mg vs Placebo
    Comparison groups
    Filgotinib 100 mg v Placebo
    Number of subjects included in analysis
    955
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Difference in Response Rates
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.4
         upper limit
    		 24.6
    Notes
    [18] - P-value was calculated from the logistic regression with treatment groups and stratification factors in the model.

    Secondary: Change from Baseline in Modified Total Sharp Score (mTSS) at Week 24

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    End point title
    		 Change from Baseline in Modified Total Sharp Score (mTSS) at Week 24 [19]
    End point description
    Participant`s radiographs of bilateral hands, wrists and feet are taken and evaluated through central review using the mTSS method. The mTSS (range [0-448]) is defined as the erosion score (range [0-280]) plus the joint space narrowing (JSN) score (range [0-168]). An erosion score of 0 to 5 is given to each joint in the hands and wrists, and a score of 0 to 10 is given to each joint in the feet where 0 indicates no erosion while 5 or 10 indicates extensive loss of bone (maximum erosion). JSN is scored from 0 to 4, with 0 indicating normal or no narrowing and 4 indicating complete loss of joint space. The maximal TSS is 448. Negative change in value indicates improvement (less erosion of bone, normal joint spaces). Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Baseline period arms for Placebo [Placebo to Filgotinib 200 mg, Placebo to Filgotinib 100 mg, and Placebo never received Filgotinib] were combined to present data for the total number of participants who received Placebo.
    End point values
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo
    Number of subjects analysed
    467
    471
    319
    466
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    32.47 ( 47.939 )
    36.70 ( 53.065 )
    34.82 ( 55.013 )
    31.60 ( 53.217 )
        Change at Week 24 (n=405, 404, 271, 351)
    0.13 ( 0.937 )
    0.17 ( 0.905 )
    0.16 ( 0.948 )
    0.37 ( 1.417 )
    Statistical analysis title
    		 Filgotinib 200 mg vs Placebo
    Comparison groups
    Filgotinib 200 mg v Placebo
    Number of subjects included in analysis
    933
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.001 [21]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.078
    Notes
    [20] - LS-Mean, 95% CI, and P-value were provided from MMRM. Missing change scores were not imputed using the MMRM approach assuming an unstructured variance-covariance matrix for the repeated measures.
    [21] - MMRM model included treatment, visit, treatment by visit, stratification factors, and baseline value as fixed effects, and subjects being the random effect.
    Statistical analysis title
    		 Filgotinib 100 mg vs Placebo
    Comparison groups
    Filgotinib 100 mg v Placebo
    Number of subjects included in analysis
    937
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.001 [23]
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.078
    Notes
    [22] - LS-Mean, 95% CI, and P-value were provided from MMRM. Missing change scores were not imputed using the MMRM approach assuming an unstructured variance-covariance matrix for the repeated measures.
    [23] - MMRM model included treatment, visit, treatment by visit, stratification factors, and baseline value as fixed effects, and subjects being the random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose date up to last dose date (Maximum: 54 weeks) plus 30 days
    Adverse event reporting additional description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug. Treatment relatedness refers to study drug filgotinib, adalimumab and placebo to match, not other background treatment (MTX).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Filgotinib 200 mg
    Reporting group description
    		 Participants were administered a filgotinib 200 mg tablet orally, once daily + a placebo to match (PTM) filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg subcutaneous (SC) injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Filgotinib 100 mg
    Reporting group description
    		 Participants were administered a filgotinib 100 mg tablet orally, once daily + a PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Adalimumab
    Reporting group description
    		 Participants were administered a PTM filgotinib 200 mg tablet orally, once daily + a PTM filgotinib 100 mg tablet orally, once daily + adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 52.1 weeks.

    Reporting group title
    Placebo to Filgotinib 200 mg
    Reporting group description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 200 mg and were administered a filgotinib 200 mg tablet orally, once daily + PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.

    Reporting group title
    Placebo to Filgotinib 100 mg
    Reporting group description
    		 Participants in the placebo arm were administered a PTM filgotinib 200 mg tablet orally, once daily+ a PTM filgotinib 100 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks. Then the participants in the placebo arm were rerandomized to filgotinib 100 mg and were administered a filgotinib 100 mg tablet orally, once daily + PTM filgotinib 200 mg tablet orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 28.1 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 The Placebo arm included all participants who received placebo in the study. Participants were administered PTM filgotinib 200 mg tablets orally, once daily+ PTM filgotinib 100 mg tablets orally, once daily + PTM adalimumab 40 mg SC injection, once every 2 weeks in addition to a weekly stable dose of MTX, orally for median exposure of 24 weeks.

    Serious adverse events
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo to Filgotinib 200 mg Placebo to Filgotinib 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 475 (7.37%)
    40 / 480 (8.33%)
    22 / 325 (6.77%)
    7 / 190 (3.68%)
    8 / 191 (4.19%)
    21 / 475 (4.42%)
         number of deaths (all causes)
    3
    1
    1
    1
    1
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (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
    Breast cancer stage I
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Cervix carcinoma stage III
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyosarcoma metastatic
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant glioma
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Metastases to liver
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid lung
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Lipase increased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Hip fracture
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Ankle fracture
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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 / 1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale chronic
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Ischaemic stroke
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    1 / 191 (0.52%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 480 (0.42%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (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
    Hemiplegia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Anaemia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (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
    Vertigo
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vitreous opacities
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 480 (0.42%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    Pancreatitis acute
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Abdominal pain
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Peptic ulcer
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Cholecystitis acute
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pustular psoriasis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell dysplasia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Arthralgia
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb asymmetry
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Muscular weakness
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (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
    4 / 475 (0.84%)
    4 / 480 (0.83%)
    3 / 325 (0.92%)
    1 / 190 (0.53%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 4
    2 / 3
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 480 (0.21%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Septic shock
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    1 / 191 (0.52%)
    0 / 475 (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
    Candida infection
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (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
    Infected skin ulcer
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Infective tenosynovitis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    1 / 475 (0.21%)
         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
    Pneumonia viral
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 475 (0.00%)
    0 / 480 (0.00%)
    1 / 325 (0.31%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypervitaminosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 480 (0.21%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 480 (0.00%)
    0 / 325 (0.00%)
    0 / 190 (0.00%)
    0 / 191 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Filgotinib 200 mg Filgotinib 100 mg Adalimumab Placebo to Filgotinib 200 mg Placebo to Filgotinib 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    128 / 475 (26.95%)
    142 / 480 (29.58%)
    82 / 325 (25.23%)
    36 / 190 (18.95%)
    23 / 191 (12.04%)
    61 / 475 (12.84%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 475 (3.58%)
    25 / 480 (5.21%)
    21 / 325 (6.46%)
    7 / 190 (3.68%)
    3 / 191 (1.57%)
    11 / 475 (2.32%)
         occurrences all number
    24
    31
    24
    7
    3
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 475 (2.53%)
    20 / 480 (4.17%)
    17 / 325 (5.23%)
    8 / 190 (4.21%)
    3 / 191 (1.57%)
    9 / 475 (1.89%)
         occurrences all number
    16
    29
    19
    9
    3
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    26 / 475 (5.47%)
    16 / 480 (3.33%)
    6 / 325 (1.85%)
    4 / 190 (2.11%)
    1 / 191 (0.52%)
    7 / 475 (1.47%)
         occurrences all number
    30
    19
    6
    4
    1
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    43 / 475 (9.05%)
    48 / 480 (10.00%)
    24 / 325 (7.38%)
    7 / 190 (3.68%)
    6 / 191 (3.14%)
    25 / 475 (5.26%)
         occurrences all number
    53
    58
    27
    9
    8
    31
    Upper respiratory tract infection
         subjects affected / exposed
    41 / 475 (8.63%)
    49 / 480 (10.21%)
    21 / 325 (6.46%)
    8 / 190 (4.21%)
    6 / 191 (3.14%)
    14 / 475 (2.95%)
         occurrences all number
    49
    65
    27
    10
    6
    16
    Urinary tract infection
         subjects affected / exposed
    18 / 475 (3.79%)
    19 / 480 (3.96%)
    17 / 325 (5.23%)
    10 / 190 (5.26%)
    8 / 191 (4.19%)
    6 / 475 (1.26%)
         occurrences all number
    21
    21
    20
    10
    8
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2016
    • Terminology for the Open Label Extension study was changed to long-term extension (LTE) study • Updated study procedures to collect body weight at all study visits • Added urine biomarker samples as an exploratory endpoint • Updated study procedures to include Treatment Satisfaction Questionnaire for Medication (TSQM) collection at Day 1 and Week 12, 24, 36, and 52 visits. • Clarified eligibility criteria as needed • Updated Study Procedures, to reflect global protocol changes in study procedures and time points • Updated the Prior and Concomitant Medications section to clarify documentation of prior medications and restriction window on injectable corticosteroids • Updated to stipulate that viably frozen peripheral blood mononuclear cells and leukocyte subset samples would be drawn in the US and Canada only; removed peripheral blood mononuclear cell substudy • Clarified that the magnetic resonance imaging (MRI) substudy would be performed postrandomization within 7 days of first dose and at Week 12 within ± 7 days • Clarified that radiographs performed after randomization could be done ± 7 days of the scheduled visit • Added carotid artery ultrasound substudy at selected sites, when available • Updated Criteria for Interruption or Discontinuation of Study Treatment, to align across protocols

    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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