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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Inadequate Response to Conventional Disease-Modifying Antirheumatic Drugs with Moderately to Severely Active Rheumatoid Arthritis

    Summary
    EudraCT number
    2012-002339-27
    Trial protocol
    HU   BE   DE   IT   PT   GB   CZ   SK   ES  
    Global end of trial date
    19 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Mar 2017
    First version publication date
    26 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14059
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01721057
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 14059, Trial Alias: I4V-MC-JADX
    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
    19 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2014
    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 4 milligram (mg) once daily (QD) is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had inadequate response to or are intolerant to at least 1 conventional disease-modifying antirheumatic drug (cDMARD)(cDMARD-IR [inadequate response] participants) and who have not received a biologic disease-modifying antirheumatic drug (DMARD).
    Protection of trial subjects
    This study was conducted in accordance with 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
    Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Dec 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: 64
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 58
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Taiwan: 82
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 176
    Worldwide total number of subjects
    684
    EEA total number of subjects
    181
    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)
    587
    From 65 to 84 years
    97
    85 years and over
    0

    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. Nonresponders were defined as lack of improvement of at least 20% in both tender joint count and swollen joint count at both Weeks 14 and 16 compared to baseline.

    Period 1
    Period 1 title
    Treatment Period (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. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.
    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 (PO) once daily (QD) through Week 24. Participants continued to take background cDMARD therapy throughout study.

    Arm title
    Baricitinib 2 mg
    Arm description
    Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.
    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 PO QD through week 24. Participants continued to take background cDMARD therapy throughout study.

    Arm title
    Baricitinib 4 mg
    Arm description
    Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.
    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 PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study.

    Number of subjects in period 1
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Started
    228
    229
    227
    Rescue Week 16-24
    55 [1]
    21 [2]
    15 [3]
    Completed
    199
    209
    203
    Not completed
    29
    20
    24
         Physician decision
    -
    1
    3
         Lack of efficacy
    7
    4
    1
         Adverse event, serious fatal
    2
    -
    -
         Adverse event, non-fatal
    8
    10
    12
         Consent withdrawn by subject
    11
    5
    8
         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
    Follow Up
    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 2 mg- 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 4 mg- 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 participants who were rescued to Baricitinib 4 mg.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [4]
    Placebo-Follow Up Baricitinib 2 mg- Follow Up Baricitinib 4 mg- Follow Up
    Started
    17
    19
    22
    Completed
    17
    19
    22
    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: 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. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.

    Reporting group title
    Baricitinib 2 mg
    Reporting group description
    Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

    Reporting group title
    Baricitinib 4 mg
    Reporting group description
    Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

    Reporting group values
    Placebo Baricitinib 2 mg Baricitinib 4 mg Total
    Number of subjects
    228 229 227 684
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    197 196 194 587
        From 65-84 years
    31 33 33 97
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    51.4 ± 12.5 52.2 ± 12.3 51.8 ± 12.1 -
    Gender, Male/Female
    Units: participants
        Female
    189 184 187 560
        Male
    39 45 40 124
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    12 15 17 44
        Not Hispanic or Latino
    45 43 43 131
        Unknown or Not Reported
    171 171 167 509
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    3 2 9 14
        Asian
    60 61 59 180
        Native Hawaiian or Other Pacific Islander
    1 0 0 1
        Black or African American
    10 9 9 28
        White
    153 156 148 457
        More than one race
    1 1 1 3
        Unknown or Not Reported
    0 0 1 1
    Region of Enrollment
    Units: Subjects
        Argentina
    25 21 18 64
        Australia
    8 1 6 15
        Belgium
    1 4 6 11
        Canada
    10 10 8 28
        Croatia
    0 2 2 4
        Czech Republic
    7 5 3 15
        Germany
    4 2 3 9
        Hungary
    7 8 5 20
        India
    19 19 20 58
        Italy
    3 3 4 10
        Japan
    8 6 7 21
        Korea, Republic of
    6 7 4 17
        Mexico
    3 8 11 22
        Poland
    18 13 20 51
        Portugal
    2 2 1 5
        Romania
    1 3 2 6
        Russian Federation
    4 10 6 20
        Slovakia
    3 5 3 11
        Spain
    14 10 10 34
        Taiwan
    26 28 28 82
        United Kingdom
    1 4 0 5
        United States
    58 58 60 176
    Duration of Rheumatoid Arthritis
    n= 228, 225, 225 and 678
    Units: years
        arithmetic mean (standard deviation)
    7.2 ± 7.5 7.6 ± 7.6 7.7 ± 7.9 -
    Tender Joint Count of 68 Evaluable Joints
    Units: Number of Joints
        arithmetic mean (standard deviation)
    24.3 ± 15 23.5 ± 14.1 24.3 ± 14 -
    Swollen Joint Count of 66 Evaluable Joints
    Units: Number of Joints
        arithmetic mean (standard deviation)
    13.1 ± 7.2 13.6 ± 8.7 13.5 ± 6.9 -
    High Sensitivity C-Reactive Protein (hsCRP)
    Units: milligram per Liter (mg/L)
        arithmetic mean (standard deviation)
    17.7 ± 20.4 18.2 ± 21.5 14.2 ± 14.5 -

    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. Participants continued to take background conventional disease-modifying antirheumatic drug (cDMARD) therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD. All started participants received at least one dose of study drug.

    Reporting group title
    Baricitinib 2 mg
    Reporting group description
    Baricitinib 2 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.

    Reporting group title
    Baricitinib 4 mg
    Reporting group description
    Baricitinib 4 mg PO QD through Week 24. Participants continued to take background cDMARD therapy throughout study. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg PO, QD.
    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 2 mg- 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 4 mg- 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 to Baricitinib 4 mg.

    Subject analysis set title
    PK population 2 mg Baricitinib
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All randomized participants who received at least 1 dose of 2 mg baricitinib with evaluable PK data.

    Subject analysis set title
    PK Population 4 mg Baricitinib
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All randomized participants who received at least 1 dose of 4 mg baricitinib 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), participant's assessment of pain, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinue study or drug or are rescued before analysis timepoint are deemed non-responders. Analysis Population Description: 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 non-responder imputation (NRI).
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of participants
        number (not applicable)
    39.5
    65.9
    61.7
    Statistical analysis title
    Statistical Analysis for ACR20
    Comparison groups
    Baricitinib 4 mg v Placebo
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Regression, Logistic
    Confidence interval

    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: 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.3 ± 0.45
    -0.52 ± 0.59
    -0.52 ± 0.6
    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 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.05 ± 1.23
    -1.83 ± 1.22
    -1.91 ± 1.21
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) ≤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), Participant'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 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
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of participants
        number (not applicable)
    0.9
    9.2
    8.8
    No statistical analyses for this end point

    Secondary: Mean Duration of Morning Joint Stiffness (MJS) in the Prior 7 Days as Collected in Electronic Daily Diaries

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    End point title
    Mean Duration of Morning Joint Stiffness (MJS) in the Prior 7 Days as Collected in Electronic Daily Diaries
    End point description
    Participants reported the duration of their morning joint stiffness (MJS) in hours and minutes into daily electronic diaries. If MJS 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 is calculated. A decrease in duration of MJS indicated an improvement in the participant's condition. Analysis Population Description: 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    221
    223
    222
    Units: minutes
        median (confidence interval 95%)
    60 (50.7 to 76.7)
    44.4 (30 to 60)
    34.6 (23.7 to 51.4)
    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 MJS by selecting a number from 0 to 10 that best described their overall level of MJS 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 is calculated. A decrease in severity rating indicated an improvement in the participant's condition. Analysis Population Description: 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    221
    223
    222
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.2 ± 2.3
    3.5 ± 2.5
    3.4 ± 2.2
    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 level of worst tiredness during the past 24 hours, where 0 represents "no tiredness" and 10 represents "as bad as you can imagine". Participants reported their worst tiredness in daily electronic diaries. The average value across the 7 days preceding each visit is calculated. A decrease in tiredness severity rating indicated an improvement in the participant's condition. Analysis Population Description: 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    221
    223
    222
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.5 ± 2.2
    4 ± 2.5
    4 ± 2.3
    No statistical analyses for this end point

    Secondary: Mean Worst Joint Pain Numeric Rating Scale (NRS) in the Prior 7 days as Collected in Electronic Diaries

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    End point title
    Mean Worst Joint Pain Numeric Rating Scale (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 is calculated. A decrease in joint pain severity rating indicated an improvement in the participant's condition. Analysis Population Description: 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 2 mg Baricitinib 4 mg
    Number of subjects analysed
    221
    223
    222
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.7 ± 2.2
    3.9 ± 2.5
    3.8 ± 2.2
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response
    End point description
    ACR50 Responder Index is composite of clinical, laboratory, and functional measures in RA. “ACR50 Responder” is a participant who has at least 50% 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, HAQ-DI, participant's assessment of pain, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis timepoint are deemed non-responders. Analysis Population Description: 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
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of participants
    number (not applicable)
        Week 12
    12.7
    33.6
    33.5
        Week 24
    21.5
    41.5
    44.1
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response
    End point description
    ACR70 Responder Index is composite of clinical, laboratory, and functional measures in RA. “ACR70 Responder” is a participant who has at least 70% 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, HAQ-DI, participant's assessment of pain, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis timepoint are deemed non-responders. Analysis Population Description: 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
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of participants
    number (not applicable)
        Week 12
    3.1
    17.9
    18.1
        Week 24
    7.9
    25.3
    24.2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Measures of Clinical Disease Activity Index (CDAI) Score

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    End point title
    Change From Baseline in Measures of 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: 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 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    218
    224
    219
    Units: units on a scale
        arithmetic mean (standard deviation)
    -14.29 ± 16.04
    -20.99 ± 14.48
    -23.18 ± 13.47
    No statistical analyses for this end point

    Secondary: Change from Baseline in Measures of Simplified Disease Activity Index (SDAI) Score

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    End point title
    Change from Baseline in Measures of Simplified Disease Activity Index (SDAI) Score
    End point description
    The 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 visual analog scale (cm), and Physician's Global Assessment of Disease Activity using visual analog scale (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. Analysis Population Description: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    218
    224
    219
    Units: units on a scale
        arithmetic mean (standard deviation)
    -14.55 ± 16.37
    -21.87 ± 14.99
    -23.78 ± 13.94
    No statistical analyses for this end point

    Secondary: Change from Baseline in DAS28-Erythrocyte Sedimentation Rate (DAS28-ESR)

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    End point title
    Change from Baseline in DAS28-Erythrocyte Sedimentation Rate (DAS28-ESR)
    End point description
    DAS28 consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), Erythrocyte Sedimentation Rate (ESR) (millimeters per hour), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using following formula: DAS28-ESR=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.70*natural log(ESR)+0.014*Patient's Global VAS. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. Analysis Population Description: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    220
    226
    221
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.16 ± 1.27
    -1.89 ± 1.23
    -1.97 ± 1.16
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) Remission – Boolean Remission

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    End point title
    Percentage of Participants Achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) Remission – Boolean Remission
    End point description
    The ACR/EULAR definition of RA remission include 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: 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
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of participants
        number (not applicable)
    0.4
    7
    6.6
    No statistical analyses for this end point

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

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    End point title
    Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 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: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12; Baseline Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    216
    227
    216
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 12
    7.6 ± 10.3
    8.7 ± 11.1
    8.8 ± 10.6
        Week 24
    7.8 ± 11
    9.2 ± 10.7
    9.7 ± 10.8
    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, as well as 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: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12; Baseline, Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    218
    229
    219
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 12, MCS
    3.3 ± 10.6
    3.6 ± 10.5
    3.3 ± 11
        Week 24, MCS
    2.7 ± 11.5
    3 ± 10.4
    3.3 ± 11.3
        Week 12, PCS
    4.1 ± 7.3
    7.7 ± 8.5
    7 ± 8.3
        Week 24, PCS
    4.9 ± 8
    8.5 ± 9
    8.6 ± 9
    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
    European Quality of Life-5 Dimensions-5 Level (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: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline Week 12; Baseline Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    216
    227
    216
    Units: units on a scale
    arithmetic mean (standard deviation)
        Index Score (US Algorithm) Week 12
    0.054 ± 0.155
    0.117 ± 0.151
    0.109 ± 0.165
        Index Score (US Algorithm) Week 24
    0.051 ± 0.149
    0.113 ± 0.172
    0.129 ± 0.173
        Index Score (UK Algorithm) Week 12
    0.074 ± 0.23
    0.167 ± 0.221
    0.159 ± 0.237
        Index Score (UK Algorithm) Week 24
    0.075 ± 0.218
    0.162 ± 0.254
    0.185 ± 0.25
    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: 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 mLOCF.
    End point type
    Secondary
    End point timeframe
    Baseline Week 12; Baseline Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    216
    227
    216
    Units: mm
    arithmetic mean (standard deviation)
        Self-Perceived Health, Week 12
    5.7 ± 23.8
    13.4 ± 21.8
    11.5 ± 25.2
        Self-Perceived Health, Week 24
    8.4 ± 25.1
    13.1 ± 25.8
    10.4 ± 28.9
    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: All randomized participants who received at least 1 dose of the study drug. Change from baseline includes participants with a baseline value and an observed value at the time point being summarized.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12; Baseline, Week 24
    End point values
    Placebo Baricitinib 2 mg Baricitinib 4 mg
    Number of subjects analysed
    228
    229
    227
    Units: percentage of impairment
    arithmetic mean (standard deviation)
        Absenteeism Week 12 (n= 73,72,69)
    2.6 ± 23.5
    -6.3 ± 26.5
    2.5 ± 24.7
        Absenteeism Week 24 (n= 44,62,56)
    -2.1 ± 13.9
    -3.8 ± 28.2
    4 ± 27.2
        Presenteeism Week 12 (n= 71, 69, 66)
    -8 ± 26
    -17 ± 25
    -15 ± 27
        Presenteeism Week 24 (n= 44,61,53)
    -17 ± 26
    -20 ± 23
    -17 ± 21
        Work Productivity Loss Week 12 (n= 71,69,66)
    -4.2 ± 27.7
    -17.6 ± 30.4
    -9.9 ± 23.7
        Work Productivity Loss Week 24 (n= 44,61,53)
    -15.9 ± 26.1
    -19.6 ± 25
    -14.3 ± 23
        Activity Impairment Week 12(n=206, 222, 213)
    -13 ± 25
    -19 ± 27
    -19 ± 25
        Activity Impairment Week 24 (n= 141,187,187)
    -18 ± 27
    -23 ± 28
    -21 ± 27
    No statistical analyses for this end point

    Secondary: Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104

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    End point title
    Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0: 30 and 90 minutes postdose; Week 8: 1 hour postdose; Week 12, Week 20 and Week 24:predose
    End point values
    PK population 2 mg Baricitinib PK Population 4 mg Baricitinib
    Number of subjects analysed
    246
    245
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    70.2 ± 26.2
    138 ± 25.7
    No statistical analyses for this end point

    Secondary: Population PK: Maximum Concentration at Steady State of Dosing (AUC,ss) of LY3009104

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    End point title
    Population PK: Maximum Concentration at Steady State of Dosing (AUC,ss) of LY3009104
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0: 30 and 90 minutes postdose; Week 8: 1 hour postdose; Week 12, Week 20 and Week 24; predose
    End point values
    PK population 2 mg Baricitinib PK Population 4 mg Baricitinib
    Number of subjects analysed
    246
    245
    Units: nanograms per mL per hour (ng/mL*h)
        geometric mean (geometric coefficient of variation)
    637 ± 44.5
    1210 ± 47
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    I4V-MC-JADX
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    PLACEBO
    Reporting group description
    -

    Reporting group title
    Baricitinib 2 mg
    Reporting group description
    -

    Reporting group title
    Baricitinib 4 mg
    Reporting group description
    -

    Reporting group title
    Rescue
    Reporting group description
    -

    Reporting group title
    Placebo- Follow Up
    Reporting group description
    -

    Reporting group title
    Baricitinib 2 mg – Follow Up
    Reporting group description
    -

    Reporting group title
    Baricitinib 4 mg – Follow Up
    Reporting group description
    -

    Serious adverse events
    PLACEBO Baricitinib 2 mg Baricitinib 4 mg Rescue Placebo- Follow Up Baricitinib 2 mg – Follow Up Baricitinib 4 mg – Follow Up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 228 (5.70%)
    6 / 229 (2.62%)
    12 / 227 (5.29%)
    1 / 91 (1.10%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    animal bite
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    fall
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    patella fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    tibia fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    upper limb fracture
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    atrial fibrillation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    myocardial infarction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    ventricular tachycardia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    acute respiratory failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    allergic bronchitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    interstitial lung disease
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    pleural effusion
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    pulmonary embolism
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    migraine
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    subarachnoid haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    diverticulum intestinal
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    dyspepsia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    post-traumatic stress disorder
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    suicidal ideation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    renal failure
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis acute
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    psoriasis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    rash pruritic
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    subcutaneous emphysema
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    muscular weakness
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    myalgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    myositis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    polymyositis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    rheumatoid arthritis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    spinal pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    synovial cyst
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    bacterial infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    bronchitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    cellulitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    1 / 91 (1.10%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    disseminated tuberculosis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    gastroenteritis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    1 / 229 (0.44%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    lower respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    pelvic abscess
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 229 (0.44%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    urinary tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    1 / 91 (1.10%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    viral infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    wound infection staphylococcal
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    PLACEBO Baricitinib 2 mg Baricitinib 4 mg Rescue Placebo- Follow Up Baricitinib 2 mg – Follow Up Baricitinib 4 mg – Follow Up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 228 (46.05%)
    108 / 229 (47.16%)
    127 / 227 (55.95%)
    21 / 91 (23.08%)
    2 / 17 (11.76%)
    0 / 19 (0.00%)
    4 / 22 (18.18%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    10 / 229 (4.37%)
    6 / 227 (2.64%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    10
    6
    0
    0
    0
    0
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 228 (2.19%)
    2 / 229 (0.87%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    3
    5
    0
    0
    0
    0
    oedema peripheral
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    6 / 228 (2.63%)
    3 / 229 (1.31%)
    3 / 227 (1.32%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    3
    3
    0
    0
    0
    0
    pyrexia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 229 (0.44%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    7
    0
    1
    0
    0
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    7 / 228 (3.07%)
    0 / 229 (0.00%)
    1 / 227 (0.44%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    7
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    erectile dysfunction
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed [1]
    0 / 39 (0.00%)
    0 / 45 (0.00%)
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    vulvovaginal pruritus
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed [2]
    0 / 189 (0.00%)
    0 / 184 (0.00%)
    0 / 187 (0.00%)
    0 / 78 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    5 / 229 (2.18%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    6
    6
    0
    0
    0
    0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    3 / 229 (1.31%)
    6 / 227 (2.64%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    3
    7
    0
    0
    0
    0
    blood creatine phosphokinase increased
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    8 / 229 (3.49%)
    15 / 227 (6.61%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    8
    17
    0
    1
    0
    0
    Cardiac disorders
    sinus bradycardia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    6 / 228 (2.63%)
    6 / 229 (2.62%)
    4 / 227 (1.76%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    6
    4
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 228 (1.32%)
    9 / 229 (3.93%)
    9 / 227 (3.96%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    4
    11
    10
    0
    0
    0
    1
    dyspnoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    oropharyngeal pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    4 / 229 (1.75%)
    9 / 227 (3.96%)
    3 / 91 (3.30%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    4
    9
    3
    0
    0
    0
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 228 (1.75%)
    3 / 229 (1.31%)
    7 / 227 (3.08%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    3
    9
    0
    0
    0
    0
    headache
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 228 (3.51%)
    15 / 229 (6.55%)
    9 / 227 (3.96%)
    3 / 91 (3.30%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    10
    17
    10
    3
    0
    0
    0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    5 / 229 (2.18%)
    3 / 227 (1.32%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    5
    3
    0
    0
    0
    0
    abdominal pain upper
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    5 / 229 (2.18%)
    4 / 227 (1.76%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    5
    4
    0
    0
    0
    0
    constipation
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 228 (1.32%)
    7 / 229 (3.06%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    7
    5
    0
    0
    0
    0
    diarrhoea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    10 / 228 (4.39%)
    10 / 229 (4.37%)
    4 / 227 (1.76%)
    2 / 91 (2.20%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    11
    11
    5
    2
    1
    0
    0
    dyspepsia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 229 (0.44%)
    5 / 227 (2.20%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    5
    2
    0
    0
    0
    gastritis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    5 / 228 (2.19%)
    2 / 229 (0.87%)
    1 / 227 (0.44%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    2
    1
    2
    0
    0
    0
    lip disorder
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    mouth ulceration
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    5 / 229 (2.18%)
    3 / 227 (1.32%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    6
    3
    0
    0
    0
    0
    nausea
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    8 / 228 (3.51%)
    7 / 229 (3.06%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    9
    7
    5
    0
    0
    0
    0
    vomiting
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 228 (1.75%)
    7 / 229 (3.06%)
    4 / 227 (1.76%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    7
    4
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    acne
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    alopecia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 228 (1.75%)
    1 / 229 (0.44%)
    6 / 227 (2.64%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    1
    6
    0
    0
    0
    0
    dermatitis bullous
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 228 (1.32%)
    6 / 229 (2.62%)
    6 / 227 (2.64%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    8
    6
    0
    0
    0
    0
    back pain
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    10 / 228 (4.39%)
    9 / 229 (3.93%)
    5 / 227 (2.20%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    10
    9
    5
    0
    0
    0
    0
    Metabolism and nutrition disorders
    hypercholesterolaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    5 / 229 (2.18%)
    9 / 227 (3.96%)
    4 / 91 (4.40%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    5
    9
    4
    0
    0
    0
    hyperlipidaemia
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 229 (0.87%)
    6 / 227 (2.64%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    2
    6
    0
    0
    0
    0
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    11 / 228 (4.82%)
    6 / 229 (2.62%)
    7 / 227 (3.08%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    12
    7
    8
    2
    0
    0
    0
    gastroenteritis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 228 (0.44%)
    4 / 229 (1.75%)
    9 / 227 (3.96%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    4
    9
    0
    0
    0
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    18 / 228 (7.89%)
    10 / 229 (4.37%)
    18 / 227 (7.93%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    19
    10
    22
    0
    0
    0
    0
    pharyngitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    3 / 228 (1.32%)
    6 / 229 (2.62%)
    8 / 227 (3.52%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    6
    8
    0
    0
    0
    0
    rash pustular
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 228 (0.00%)
    0 / 229 (0.00%)
    0 / 227 (0.00%)
    0 / 91 (0.00%)
    1 / 17 (5.88%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    sinusitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    6 / 228 (2.63%)
    3 / 229 (1.31%)
    4 / 227 (1.76%)
    0 / 91 (0.00%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    3
    4
    0
    0
    0
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    18 / 228 (7.89%)
    14 / 229 (6.11%)
    24 / 227 (10.57%)
    2 / 91 (2.20%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    19
    16
    26
    2
    0
    0
    0
    urinary tract infection
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    4 / 228 (1.75%)
    12 / 229 (5.24%)
    9 / 227 (3.96%)
    3 / 91 (3.30%)
    0 / 17 (0.00%)
    0 / 19 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    13
    9
    3
    0
    0
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. 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 for the reporting group. 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.

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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