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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy

    Summary
    EudraCT number
    2012-002322-73
    Trial protocol
    HU   GR   BE   LV   GB   DE   PT   CZ   NL   LT   SK   ES   SI  
    Global end of trial date
    29 Sep 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    04 Aug 2017
    First version publication date
    26 Mar 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Revision required

    Trial information

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    Trial identification
    Sponsor protocol code
    13978
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01710358
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 13978, Trial Alias: I4V-MC-JADV
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine whether baricitinib is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to methotrexate (MTX) treatment.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Oct 2012
    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
    Argentina: 255
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 54
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 37
    Country: Number of subjects enrolled
    Japan: 249
    Country: Number of subjects enrolled
    Korea, Republic of: 57
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Lithuania: 26
    Country: Number of subjects enrolled
    Mexico: 125
    Country: Number of subjects enrolled
    Poland: 80
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 78
    Country: Number of subjects enrolled
    Slovakia: 20
    Country: Number of subjects enrolled
    Slovenia: 5
    Country: Number of subjects enrolled
    South Africa: 56
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 94
    Worldwide total number of subjects
    1305
    EEA total number of subjects
    308
    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)
    1064
    From 65 to 84 years
    240
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    All started participants received at least one dose of study drug.

    Pre-assignment
    Screening details
    Participants who did not respond (nonresponders) to study drug were eligible for rescue treatment beginning at Week 16. Participants not rescued at Week 16 may be rescued at the discretion of the investigator anytime thereafter. Nonresponders were defined as lack of improvement of at least 20% in both tender joint count and swollen joint count.

    Period 1
    Period 1 title
    Treatment Period Part A (Weeks 0 to 24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo administered orally (PO) once daily (QD) through Week 24. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.
    Arm type
    Placebo

    Investigational medicinal product name
    Baricitinib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally once daily through Week 24.

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab placebo administered by SC injection every 2 weeks through Week 50.

    Arm title
    Baricitinib
    Arm description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo by subcutaneous (SC) injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.
    Arm type
    Experimental

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    Other name
    LY3009104
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib will continue to receive baricitinib 4 mg administered orally once daily through Week 52.

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab placebo administered by SC injection every 2 weeks through Week 50.

    Arm title
    Adalimumab
    Arm description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 52. Participants will continue to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 52.

    Investigational medicinal product name
    Baricitinib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baricitinib placebo administered orally once daily through Week 52.

    Number of subjects in period 1
    Placebo Baricitinib Adalimumab
    Started
    488
    487
    330
    Rescued
    128 [1]
    35 [2]
    40 [3]
    Completed
    424
    449
    302
    Not completed
    64
    38
    28
         Physician decision
    1
    -
    -
         Lack of efficacy
    18
    4
    3
         Adverse event, serious fatal
    1
    2
    -
         Entry Criteria Not Met
    -
    1
    1
         Adverse event, non-fatal
    23
    22
    9
         Consent withdrawn by subject
    17
    8
    15
         Sponsor Decision
    4
    -
    -
         Lost to follow-up
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who were nonresponders based on tender/swollen joint count were entered into the rescue milestone calculation.
    Period 2
    Period 2 title
    Treatment Period Part B (Weeks 24 to 52)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo administered by SC injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study. Placebo arm also receives baricitinib during this period.
    Arm type
    Placebo

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab placebo administered by SC injection every 2 weeks through Week 50.

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    Other name
    LY3009104
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50.

    Arm title
    Baricitinib
    Arm description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.
    Arm type
    Experimental

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    Other name
    LY3009104, INCB 028050
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52.

    Investigational medicinal product name
    Adalimumab Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab placebo administered by SC injection every 2 weeks through Week 50.

    Arm title
    Adalimumab
    Arm description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.
    Arm type
    Active comparator

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who are nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Investigational medicinal product name
    Baricitinib Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baricitinib placebo administered orally once daily through Week 52.

    Number of subjects in period 2 [4]
    Placebo Baricitinib Adalimumab
    Started
    310
    424
    267
    Received at Least 1 Dose of Study Drug
    306
    424
    267
    Rescued
    5 [5]
    8 [6]
    11 [7]
    Completed
    293
    402
    251
    Not completed
    17
    22
    16
         Physician decision
    -
    1
    -
         Lack of efficacy
    1
    -
    1
         Adverse event, serious fatal
    1
    -
    1
         Adverse event, non-fatal
    10
    16
    6
         Consent withdrawn by subject
    4
    3
    7
         Sponsor Decision
    1
    2
    -
         Lost to follow-up
    -
    -
    1
    Notes
    [4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Excludes participants rescued during Part A.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Nonresponders could be rescued at the discretion of the investigator.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Nonresponders could be rescued at the discretion of the investigator.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Nonresponders could be rescued at the discretion of the investigator.
    Period 3
    Period 3 title
    Follow-up Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo - Follow-up
    Arm description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Baricitinib - Follow-up
    Arm description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes patients who were rescued or switched to Baricitinib 4 mg.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Adalimumab Follow-up
    Arm description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [8]
    Placebo - Follow-up Baricitinib - Follow-up Adalimumab Follow-up
    Started
    33
    76
    20
    Completed
    33
    76
    20
    Notes
    [8] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Includes participants who entered the post-treatment follow-up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered orally (PO) once daily (QD) through Week 24. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.

    Reporting group title
    Baricitinib
    Reporting group description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo by subcutaneous (SC) injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.

    Reporting group title
    Adalimumab
    Reporting group description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 52. Participants will continue to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.

    Reporting group values
    Placebo Baricitinib Adalimumab Total
    Number of subjects
    488 487 330 1305
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    53.4 ± 11.8 53.5 ± 12.2 52.9 ± 12.3 -
    Gender, Male/Female
    Units: participants
        Female
    382 375 251 1008
        Male
    106 112 79 297
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    26 19 18 63
        Asian
    148 143 101 392
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    4 2 4 10
        White
    302 312 204 818
        More than one race
    7 11 3 21
        Unknown or Not Reported
    1 0 0 1
    Region of Enrollment
    Units: Subjects
        Argentina
    91 107 57 255
        Belgium
    2 3 3 8
        Canada
    5 4 2 11
        China
    21 22 11 54
        Croatia
    1 0 0 1
        Czech Republic
    16 10 10 36
        France
    8 8 7 23
        Germany
    0 0 2 2
        Greece
    1 0 2 3
        Hungary
    18 11 8 37
        Japan
    93 93 63 249
        Korea, Republic of
    21 21 15 57
        Latvia
    2 2 5 9
        Lithuania
    4 12 10 26
        Mexico
    50 36 39 125
        Poland
    26 35 19 80
        Portugal
    1 1 1 3
        Romania
    8 6 2 16
        Russian Federation
    27 28 23 78
        Slovakia
    8 8 4 20
        Slovenia
    4 1 0 5
        South Africa
    24 21 11 56
        Spain
    15 11 5 31
        Taiwan
    6 5 7 18
        United Kingdom
    2 6 0 8
        United States
    34 36 24 94
    Duration of Rheumatoid Arthritis
    Units: years
        arithmetic mean (standard deviation)
    10.4 ± 8.7 10.3 ± 8.8 9.6 ± 8.5 -
    Tender Joint Count of 68 Evaluable Joints
    Units: Number of Joints
        arithmetic mean (standard deviation)
    23.3 ± 13.5 23.4 ± 13 23.4 ± 13.7 -
    Swollen Joint Count of 66 Evaluable Joints
    Units: Number of Joints
        arithmetic mean (standard deviation)
    15.5 ± 9.4 15 ± 8.2 15.4 ± 9.1 -
    High Sensitivity C-Reactive Protein (hsCRP)
    Units: milligrams per liter (mg/L)
        arithmetic mean (standard deviation)
    19.66 ± 20.97 22.2 ± 22.85 21.78 ± 20.83 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered orally (PO) once daily (QD) through Week 24. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.

    Reporting group title
    Baricitinib
    Reporting group description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo by subcutaneous (SC) injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.

    Reporting group title
    Adalimumab
    Reporting group description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who are nonresponders will be rescued with baricitinib 4 mg orally once daily through Week 52. Participants will continue to take background MTX therapy throughout study. All started participants received at least one dose of study drug. "Not completed" participants include participants who were rescued during Part A and discontinued study during Part B.
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered by SC injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study. Placebo arm also receives baricitinib during this period.

    Reporting group title
    Baricitinib
    Reporting group description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Adalimumab
    Reporting group description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.
    Reporting group title
    Placebo - Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

    Reporting group title
    Baricitinib - Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes patients who were rescued or switched to Baricitinib 4 mg.

    Reporting group title
    Adalimumab Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

    Subject analysis set title
    Baricitinib
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All randomized participants who received at least 1 dose of study drug with evaluable PK data.

    Primary: Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)

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    End point title
    Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)
    End point description
    ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). "ACR20 Responder" is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain due to arthritis, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinued study or drug or were rescued before analysis time point were deemed non-responders. Analysis Population Description: Modified Intent-to-Treat (mITT) population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using nonresponder imputation (NRI).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488
    487
    330
    Units: percentage of participants
        number (not applicable)
    40.2
    69.6
    61.2
    Statistical analysis title
    Statistical Analysis for ACR20
    Comparison groups
    Baricitinib v Placebo
    Number of subjects included in analysis
    975
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Regression, Logistic
    Confidence interval

    Secondary: Change from Baseline in the Modified Total Sharp Score (mTSS)

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    End point title
    Change from Baseline in the Modified Total Sharp Score (mTSS)
    End point description
    X-rays of the hands/wrists and feet were scored for structural progression as measured using the mTSS. This methodology quantified the extent of bone erosions and joint space narrowing for 44 and 42 joints, with higher scores representing greater damage. The mTSS at a time point is the sum of the erosion (range from 0 to 280) and JSN (range from 0 to 168) scores, for a maximum score of 448. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessments. Missing values due to discontinuation of study, rescue, or missing data were imputed using linear extrapolation (LE).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    452
    470
    312
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.84 ± 2.32
    0.35 ± 1.59
    0.29 ± 1.47
    No statistical analyses for this end point

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

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    End point title
    Change from Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score
    End point description
    The HAQ-DI questionnaire assesses the participant's self-perception on the degree of difficulty (0 [without any difficulty], 1 [with some difficulty], 2 [with much difficulty], and 3 [unable to do]) when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area were averaged to calculate the HAQ-DI score, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition. Analysis Population Description: mITT population includes all randomized participants who received at least 1 dose of the study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using modified baseline observation carried forward (mBOCF).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488
    487
    330
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.33 ± 0.51
    -0.65 ± 0.59
    -0.56 ± 0.54
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and high-sensitivity C-reactive Protein (DAS28-hsCRP)

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    End point title
    Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and high-sensitivity C-reactive Protein (DAS28-hsCRP)
    End point description
    Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity using visual analog scale (VAS) (participant global VAS). DAS28 was calculated using following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis Population Description: mITT population includes all randomized participants who received at least 1 dose of the study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mBOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488
    487
    330
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.01 ± 1.12
    -2.27 ± 1.22
    -1.98 ± 1.28
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) and 70% (ACR70) Response

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    End point title
    Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) and 70% (ACR70) Response
    End point description
    ACR50 and ACR70 Responder Index is a composite of clinical, laboratory, and functional measures in RA. ACR50 and ACR70 Responder is a participant who has at least 50% or 70% improvement, respectively, in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, HAQ-DI, pain due to arthritis, and hsCRP. Participants with missing responses and participants who discontinued study or drug or were rescued before analysis time point were deemed non-responders. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.
    End point type
    Secondary
    End point timeframe
    Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488 [1]
    487
    330
    Units: percentage of participants
    number (not applicable)
        ACR50 Week 12
    16.8
    45
    34.8
        ACR50 Week 24
    19.3
    50.5
    45.5
        ACR50 Week 52
    99999999
    55.9
    47
        ACR70 Week 12
    4.7
    18.9
    12.7
        ACR70 Week 24
    8
    29.8
    21.8
        ACR70 Week 52
    9999999
    37.2
    30.6
    Notes
    [1] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI) Score

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    End point title
    Change from Baseline in Clinical Disease Activity Index (CDAI) Score
    End point description
    The CDAI is a tool for measurement of disease activity in RA that does not require a laboratory component and was scored by the investigative site. It integrates TJC28, SJC28, Patient's Global Assessment of Disease Activity using visual analog scale (cm), and Physician's Global Assessment of Disease Activity using visual analog scale (cm). The CDAI is calculated by summing the values of the 4 components. Lower scores indicated less disease activity. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using modified last observation carried forward (mLOCF).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    481 [2]
    478
    324
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 12
    -13.53 ± 13.88
    -23 ± 12.66
    -20.42 ± 13.47
        Week 24
    -14.21 ± 15.13
    -25.04 ± 13.61
    -22.92 ± 14.63
        Week 52
    99999999 ± 99999999
    -26.44 ± 14.42
    -23.48 ± 15.28
    Notes
    [2] - 9999999= No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) Score ≤3.3

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    End point title
    Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) Score ≤3.3
    End point description
    SDAI is a tool for measurement of disease activity in RA that integrates TJC28, SJC28, acute phase response using C-reactive protein (milligrams per liter), Patient's Global Assessment of Disease Activity using VAS centimeters (cm), and Physician's Global Assessment of Disease Activity using VAS (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. An index-based definition of remission occurs with an SDAI score ≤3.3. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.
    End point type
    Secondary
    End point timeframe
    Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488 [3]
    478
    324
    Units: percentage of participants
    number (not applicable)
        Week 12
    1.8
    8.4
    7.3
        Week 24
    3.1
    16
    13.6
        Week 52
    9999999
    22.6
    17.9
    Notes
    [3] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) remission

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    End point title
    Percentage of participants achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) remission
    End point description
    The ACR/EULAR definitions of RA remission includes a Boolean-based definition. The Boolean-based definition of remission occurs when all 4 of the following criteria are met at the same visit: TJC28 ≤1, SJC28 ≤1, acute phase response using C-reactive protein (milligrams per deciliter) ≤1, Patient's Global Assessment of Disease Activity using VAS (cm) ≤1. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using NRI.
    End point type
    Secondary
    End point timeframe
    Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    488 [4]
    487
    330
    Units: percentage of participants
    number (not applicable)
        Week 12
    1
    7.2
    5.2
        Week 24
    2.7
    12.1
    10
        Week 52
    9999999
    15.6
    13
    Notes
    [4] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Median of Individual Participant Mean Duration of Morning Joint Stiffness in the Prior 7 Days as Collected in Electronic Diaries

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    End point title
    Median of Individual Participant Mean Duration of Morning Joint Stiffness in the Prior 7 Days as Collected in Electronic Diaries
    End point description
    Participants recorded the duration of their morning joint stiffness (MJS) in hours and minutes into electronic diaries daily. If morning joint stiffness duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. The average value across the 7 days preceding each visit was calculated. A decrease in duration of morning joint stiffness indicated an improvement in the participant's condition. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    479
    479
    323
    Units: Minutes
        median (confidence interval 95%)
    60 (60 to 75)
    27.1 (20 to 30)
    36.6 (30 to 45.7)
    No statistical analyses for this end point

    Secondary: Mean severity of morning joint stiffness Numeric Rating Scale (NRS) in the prior 7 days as collected in electronic diaries

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    End point title
    Mean severity of morning joint stiffness Numeric Rating Scale (NRS) in the prior 7 days as collected in electronic diaries
    End point description
    Participants rated the severity of their morning joint stiffness by selecting a number from 0 to 10 that best described their overall level of morning joint stiffness from the time they woke up, where 0 represents "no joint stiffness" and 10 represents "joint stiffness as bad as you can imagine". Participants reported their severity daily in electronic diaries. The average value across the 7 days preceding each visit was calculated. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    479
    479
    323
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.1 ± 2.3
    3 ± 2.2
    3.4 ± 2.3
    No statistical analyses for this end point

    Secondary: Mean Worst Tiredness numeric rating scale (NRS) in the prior 7 days as collected in electronic diaries

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    End point title
    Mean Worst Tiredness numeric rating scale (NRS) in the prior 7 days as collected in electronic diaries
    End point description
    Participants rated their tiredness by selecting a number from 0 to 10 that best described their worst tiredness during the last 24 hours, where 0 represents "no tiredness" and 10 represents "as bad as you can imagine". Participants reported their worst tiredness in electronic diaries. The average value across the 7 days preceding each visit is calculated. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    479
    479
    323
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.4 ± 2.3
    3.6 ± 2.2
    3.9 ± 2.3
    No statistical analyses for this end point

    Secondary: Mean Worst Joint Pain NRS in the prior 7 days as collected in electronic diaries

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    End point title
    Mean Worst Joint Pain NRS in the prior 7 days as collected in electronic diaries
    End point description
    Participants rated their joint pain by selecting a number from 0 to 10 that best described their worst joint pain during the last 24 hours, where 0 represents "no pain" and 10 represents "pain as bad as you can imagine". Participants reported their worst joint pain in daily electronic diaries. The average value across the 7 days preceding each visit was calculated. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of the study drug and had at least 4 entries within any post-baseline 7-day window are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    479
    479
    323
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.6 ± 2.2
    3.4 ± 2.2
    4 ± 2.3
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale scores

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    End point title
    Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale scores
    End point description
    The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale is a brief 13-item, symptom-specific questionnaire that specifically assesses the participant's self-reported severity of fatigue and its impact upon daily activities and functioning. The FACIT-F uses a numeric rating scale of 0 ("Not at all") to 4 ("Very much") for each item to assess fatigue and its impact in the past 7 days. Total scores range from 0 to 52, with higher scores indicating less fatigue. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    475 [5]
    479
    320
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 12
    6.8 ± 9.9
    9.6 ± 10.4
    9.5 ± 10.1
        Week 24
    6.6 ± 10.4
    10.4 ± 10.8
    9.9 ± 11.2
        Week 52
    9999999 ± 9999999
    10.8 ± 10.9
    9.8 ± 10.8
    Notes
    [5] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Change from baseline in Mental Component Score (MCS), Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)

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    End point title
    Change from baseline in Mental Component Score (MCS), Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute)
    End point description
    The SF-36 is a health-related survey that assesses participant's quality of life and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (mental [MCS] and physical [PCS]). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale with higher scores indicating better health status or functioning. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    475 [6]
    479
    320
    Units: units on a scale
    arithmetic mean (standard deviation)
        MCS Week 12
    3.2 ± 10.3
    3.3 ± 10.5
    3.8 ± 10.8
        MCS Week 24
    2.2 ± 11.4
    3.8 ± 10.9
    3.9 ± 11.6
        MCS Week 52
    9999999 ± 9999999
    4 ± 10.8
    3.7 ± 11.2
        PCS Week 12
    4.3 ± 7.1
    8.9 ± 8.1
    7.6 ± 8.2
        PCS Week 24
    4.6 ± 7.8
    9.9 ± 8.2
    8.3 ± 9.1
        PCS Week 52
    9999999 ± 9999999
    10.4 ± 9
    9 ± 9.2
    Notes
    [6] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) scores

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    End point title
    Change from Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) scores
    End point description
    EQ-5D-5L is a standardized measure of health status of the participant. One component consists of a descriptive system of the respondent's health comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1. A higher score indicates better health state. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    475 [7]
    479
    320
    Units: units on a scale
    arithmetic mean (standard deviation)
        Index Score (US Algorithm) Week 12
    0.073 ± 0.151
    0.132 ± 0.156
    0.13 ± 0.159
        Index Score (US Algorithm) Week 24
    0.065 ± 0.168
    0.143 ± 0.168
    0.137 ± 0.167
        Index Score (US Algorithm) Week 52
    9999999 ± 9999999
    0.152 ± 0.163
    0.141 ± 0.189
        Index Score (UK Algorithm) Week 12
    0.107 ± 0.221
    0.188 ± 0.228
    0.186 ± 0.232
        Index Score (UK Algorithm) Week 24
    0.094 ± 0.247
    0.203 ± 0.244
    0.195 ± 0.245
        Index Score (UK Algorithm) Week 52
    9999999 ± 9999999
    0.215 ± 0.235
    0.198 ± 0.273
    Notes
    [7] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) scores

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    End point title
    Change from Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) scores
    End point description
    The Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) questionnaire was developed to measure the effect of general health and symptom severity on work productivity and regular activities in the 7 days prior to the visit. It contains 6 items covering overall work productivity (health), overall work productivity (symptom), impairment of regular activities (health), and impairment of regular activities (symptom). Scores are calculated as impairment percentages. The WPAI-RA yields four types of scores: Absenteeism (work time missed), Presenteeism (impairment at work), Work productivity loss (overall work impairment), and Activity impairment. Analysis Population Description: mITT population includes all randomized participants who received at least 1 dose of the study drug, with a baseline value and an observed value at the time point being summarized.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    458 [8]
    474
    315
    Units: units on a scale
    arithmetic mean (standard deviation)
        Absenteeism Week 12 (n=160,168,118)
    0.5 ± 27.7
    -4.9 ± 20.6
    -0.5 ± 25.7
        Absenteeism Week 24 (n=118,139,102)
    -1.6 ± 24.5
    -1.8 ± 25.2
    -3.2 ± 23.8
        Absenteeism Week 52 (n=NA,124,92)
    9999999 ± 9999999
    -3.8 ± 25.1
    -3.7 ± 24.3
        Presenteeism Week 12 (n=147,160,113)
    -11 ± 23
    -21 ± 26
    -16 ± 24
        Presenteeism Week 24 (n=110,134,99)
    -11 ± 22
    -23 ± 27
    -22 ± 26
        Presenteeism Week 52 (n=NA,119,88)
    9999999 ± 9999999
    -25 ± 27
    -25 ± 27
        Work Productivity Loss Week 12 (n=147,160,113)
    -10.4 ± 24.3
    -21.6 ± 28
    -14 ± 25.6
        Work Productivity Loss Week 24 (n=110,134,99)
    -9 ± 24.9
    -22.1 ± 30.2
    -21.4 ± 27.2
        Work Productivity Loss Week 24 (n=NA,119,88)
    9999999 ± 9999999
    -24.4 ± 30.1
    -24.6 ± 29.8
        Activity Impairment Week 12 (n=458,474,315)
    -11 ± 25
    -25 ± 26
    -20 ± 25
        Activity Impairment Week 24 (n=333,430,272)
    -16 ± 26
    -28 ± 27
    -26 ± 26
        Activity Impairment Week 52 (n=NA,396,240)
    99999999 ± 9999999
    -30 ± 27
    -28 ± 27
    Notes
    [8] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Secondary: Change From Baseline in joint space narrowing (JSN) and bone erosion scores

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    End point title
    Change From Baseline in joint space narrowing (JSN) and bone erosion scores
    End point description
    X-rays of the hands/wrists and feet were assessed for JSN and bone erosions. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, is scored from 0 to 4, with 0 indicating no (normal) JSN and 4 indicating complete loss of joint space, bony ankylosis or luxation. JSN scores ranged from 0-168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints of the feet. Each joint is scored according to the surface area involved from 0 to 5 for hand joints and 0 to 10 for the foot joints, with 0 indicating no erosion and the highest score indicating extensive loss of bone from more than one half of the articulating bone. Erosion scores ranged from 0 (no erosion) to 280 (high erosion). mITT population: Missing values due to discontinuation of study, rescue, or missing data were imputed using LE.
    End point type
    Secondary
    End point timeframe
    Baseline, up to Week52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    452
    473
    312
    Units: units on a scale
    arithmetic mean (standard deviation)
        Joint Space Narrowing Week 24 (n= 452, 470, 312)
    0.27 ± 1.15
    0.1 ± 0.74
    0.09 ± 0.52
        Joint Space Narrowing Week 52 (n= 452, 473, 312)
    0.56 ± 2.33
    0.18 ± 1.02
    0.17 ± 1
        Bone Erosion Score Week 24 (n=452, 470, 312)
    0.57 ± 1.58
    0.25 ± 1.12
    0.2 ± 1.08
        Bone Erosion Score Week 52 (n= 452, 473, 312)
    1.15 ± 3.21
    0.42 ± 1.91
    0.34 ± 2
    No statistical analyses for this end point

    Secondary: Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib

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    End point title
    Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib
    End point description
    Analysis Population Description: All randomized participants who received at least 1 dose of study drug with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 12; Week 24; Week 32: Pre-dose
    End point values
    Baricitinib
    Number of subjects analysed
    635
    Units: nanomole/Liter (nmol/L)
        geometric mean (geometric coefficient of variation)
    143 ± 19.7
    No statistical analyses for this end point

    Secondary: Population PK: Area Under the Concentration Versus Time Curve at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib

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    End point title
    Population PK: Area Under the Concentration Versus Time Curve at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib
    End point description
    Analysis Population Description: All randomized participants who received at least 1 dose of study drug with evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 12; Week 24; Week 32: Pre-dose
    End point values
    Baricitinib
    Number of subjects analysed
    635
    Units: nanomole*hr/Liter (nmol*hr/L)
        geometric mean (geometric coefficient of variation)
    1120 ± 45.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)

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    End point title
    Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)
    End point description
    A second component of the EQ-5D-5L is a self-perceived health score which is assessed using a VAS that ranges from 0 to 100 millimeter (mm), where 0 indicates the worst health you can imagine and 100 indicates the best health you can imagine. Analysis Population Description: mITT population: all randomized participants who received at least 1 dose of study drug, with a baseline value and at least 1 post-baseline value. Missing values due to discontinuation of study or drug, rescue, or missing data were imputed using mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 52
    End point values
    Placebo Baricitinib Adalimumab
    Number of subjects analysed
    475 [9]
    479
    320
    Units: millimeter
    arithmetic mean (standard deviation)
        Self-Perceived Health Week 12
    7.9 ± 26.2
    14.9 ± 25.8
    10.7 ± 26.9
        Self-Perceived Health Week 24
    5.6 ± 27.1
    17.5 ± 28.3
    12.6 ± 28.9
        Self-Perceived Health Week 52
    99999999 ± 99999999
    19.9 ± 28
    13.3 ± 29.7
    Notes
    [9] - 9999999: No data available. There is no Placebo Arm at week 52.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Follow-up
    Adverse event reporting additional description
    I4V-MC-JADV
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo Treatment A
    Reporting group description
    Placebo administered orally (PO) once daily (QD) through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout

    Reporting group title
    Baricitinib Treatment A
    Reporting group description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Adalimumab Treatment A
    Reporting group description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Placebo Treatment B
    Reporting group description
    Placebo administered PO QD through Week 24 and placebo administered by SC injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 mg orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Baricitinib Treatment B
    Reporting group description
    Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Adalimumab Treatment B
    Reporting group description
    Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Rescue
    Reporting group description
    Baricitinib 4 mg administered PO QD through Week 52. Participants continued to take background MTX therapy throughout study.

    Reporting group title
    Placebo - Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

    Reporting group title
    Baricitinib - Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug. Includes participants who were rescued or switched to Baricitinib 4 mg.

    Reporting group title
    Adalimumab Follow-up
    Reporting group description
    No study drug received. Participants return for safety follow-up visit 28 days after the last dose of study drug.

    Serious adverse events
    Placebo Treatment A Baricitinib Treatment A Adalimumab Treatment A Placebo Treatment B Baricitinib Treatment B Adalimumab Treatment B Rescue Placebo - Follow-up Baricitinib - Follow-up Adalimumab Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 488 (5.33%)
    26 / 487 (5.34%)
    7 / 330 (2.12%)
    12 / 306 (3.92%)
    16 / 424 (3.77%)
    9 / 267 (3.37%)
    17 / 227 (7.49%)
    2 / 33 (6.06%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    circulatory collapse
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    thrombophlebitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    bladder repair
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fracture treatment
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hysterectomy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed [1]
    1 / 382 (0.26%)
    0 / 375 (0.00%)
    0 / 251 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    knee arthroplasty
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    breast cancer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    clear cell renal cell carcinoma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lung squamous cell carcinoma stage iii
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lymphoproliferative disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ovarian cancer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed [2]
    1 / 382 (0.26%)
    0 / 375 (0.00%)
    0 / 251 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    squamous cell carcinoma of lung
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    uterine leiomyoma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed [3]
    1 / 382 (0.26%)
    0 / 375 (0.00%)
    0 / 251 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    non-cardiac chest pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    generalised anxiety disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    insomnia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    metrorrhagia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed [4]
    0 / 382 (0.00%)
    1 / 375 (0.27%)
    0 / 251 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    2 / 306 (0.65%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    humerus fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    joint injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    laceration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    post concussion syndrome
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    radius fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    road traffic accident
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    spinal fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ulna fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    cardiac failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    sinus bradycardia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    supraventricular tachycardia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    nasal septum perforation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pleurisy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia aspiration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    2 / 487 (0.41%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    2 / 227 (0.88%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lymphocytosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    cataract
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    glaucoma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    macular fibrosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    retinal detachment
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    duodenal ulcer haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    enterocolitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    2 / 227 (0.88%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastric ulcer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    jejunal ulcer
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    large intestine polyp
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pancreatitis acute
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    calculus urinary
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    nephrolithiasis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    nephrosclerosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    renal impairment
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct stone
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 488 (0.41%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholangitis sclerosing
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholelithiasis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    drug-induced liver injury
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    dermatitis allergic
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    back pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bursitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    chondrocalcinosis pyrophosphate
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myositis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    osteoarthritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    osteoporosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    rheumatoid arthritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 488 (0.82%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    dehydration
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    diabetes mellitus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    diabetes mellitus inadequate control
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hypoproteinaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    arthritis bacterial
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    arthritis infective
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    atypical pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bacteraemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    2 / 487 (0.41%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholecystitis infective
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cystitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    disseminated tuberculosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    1 / 330 (0.30%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    epiglottitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    escherichia sepsis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 488 (0.41%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    2 / 487 (0.41%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    kidney infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    muscle abscess
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    necrotising fasciitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    1 / 424 (0.24%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    1 / 487 (0.21%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    pneumonia pseudomonal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    1 / 267 (0.37%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pyelonephritis acute
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pyelonephritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    soft tissue infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tuberculosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 488 (0.20%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    2 / 424 (0.47%)
    0 / 267 (0.00%)
    1 / 227 (0.44%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    viral infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    1 / 306 (0.33%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Placebo Treatment A Baricitinib Treatment A Adalimumab Treatment A Placebo Treatment B Baricitinib Treatment B Adalimumab Treatment B Rescue Placebo - Follow-up Baricitinib - Follow-up Adalimumab Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 488 (36.27%)
    196 / 487 (40.25%)
    132 / 330 (40.00%)
    58 / 306 (18.95%)
    70 / 424 (16.51%)
    38 / 267 (14.23%)
    46 / 227 (20.26%)
    3 / 33 (9.09%)
    0 / 76 (0.00%)
    3 / 20 (15.00%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    13 / 488 (2.66%)
    9 / 487 (1.85%)
    11 / 330 (3.33%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    13
    9
    11
    0
    0
    0
    0
    0
    0
    0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 488 (1.02%)
    8 / 487 (1.64%)
    9 / 330 (2.73%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    5
    9
    9
    0
    0
    0
    0
    0
    0
    0
    blood creatine phosphokinase increased
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 488 (0.61%)
    13 / 487 (2.67%)
    2 / 330 (0.61%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    5 / 227 (2.20%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    15
    2
    0
    0
    0
    5
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    8 / 488 (1.64%)
    7 / 487 (1.44%)
    7 / 330 (2.12%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    9
    7
    7
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    15 / 488 (3.07%)
    16 / 487 (3.29%)
    4 / 330 (1.21%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    8 / 227 (3.52%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    16
    16
    4
    0
    0
    0
    9
    0
    0
    0
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    12 / 488 (2.46%)
    14 / 487 (2.87%)
    13 / 330 (3.94%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    12
    17
    16
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    blepharitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    constipation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    5 / 227 (2.20%)
    1 / 33 (3.03%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    1
    0
    0
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    14 / 488 (2.87%)
    11 / 487 (2.26%)
    8 / 330 (2.42%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    16
    12
    10
    0
    0
    0
    0
    0
    0
    0
    dyspepsia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    7 / 488 (1.43%)
    9 / 487 (1.85%)
    8 / 330 (2.42%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    7
    9
    8
    0
    0
    0
    0
    0
    0
    0
    nausea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 488 (1.23%)
    14 / 487 (2.87%)
    9 / 330 (2.73%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    0 / 227 (0.00%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    7
    15
    9
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    benign prostatic hyperplasia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed [5]
    0 / 488 (0.00%)
    0 / 487 (0.00%)
    0 / 330 (0.00%)
    0 / 306 (0.00%)
    0 / 424 (0.00%)
    0 / 267 (0.00%)
    1 / 47 (2.13%)
    0 / 33 (0.00%)
    0 / 76 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0</