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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo in Subjects with Moderately to Severely Active Rheumatoid Arthritis Who Are on a Stable Dose of Conventional Synthetic Disease-Modifying Anti Rheumatic Drugs (csDMARDs) and Have an Inadequate Response to csDMARDs

    Summary
    EudraCT number
    		 2015-003332-13
    Trial protocol
    		 SK   ES   BG   CZ   DK   BE   IE   PT   GB   PL   LV   FI   NO   LT   HU   GR   AT   RO   HR   IT  
    Global end of trial date
    10 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2023
    First version publication date
    08 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M13-549
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02675426
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to compare the efficacy, safety, and tolerability of upadacitinib 30 mg once daily (QD) and 15 mg QD versus placebo for the treatment of signs and symptoms of adults with moderately to severely active rheumatoid arthritis who were on a stable dose of csDMARDs and had an inadequate response to csDMARDs.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2015
    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
    Czechia: 24
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 22
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Kazakhstan: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Country: Number of subjects enrolled
    Latvia: 5
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Poland: 38
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 31
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 255
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 10
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Croatia: 19
    Worldwide total number of subjects
    661
    EEA total number of subjects
    220
    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)
    509
    From 65 to 84 years
    151
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized at 149 centers in 35 countries in North America, eastern and western Europe, Asia, South America, Australia, New Zealand, and South Africa. The study included a 12-week placebo-controlled, double-blind period (Period 1), and a 5-year (248 week) double-blind extension (Period 2).

    Pre-assignment
    Screening details
    		 Participants were randomly assigned in a 1:1:2:2 ratio to receive either placebo for 12 weeks followed by upadacitinib 15 mg or 30 mg from week 12 onwards, or to receive upadacitinib 15 mg or 30 mg. Randomization was stratified by prior exposure to biologic disease-modifying anti-rheumatic drug (bDMARD) and geographical region.

    Period 1
    Period 1 title
    Period 1: Week 1 to Week 12
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Within the placebo group, 110 participants were assigned to receive placebo followed by upadacitinib 15 mg from Week 12 onwards and 111 participants were assigned to receive placebo followed by upadacitinib 30 mg from Week 12 onwards.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo once daily for 12 weeks in Period 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Arm title
    		 Upadacitinib 15 mg
    Arm description
    		 Participants received upadacitinib 15 mg once daily for 12 weeks in Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Arm title
    		 Upadacitinib 30 mg
    Arm description
    		 Participants received upadacitinib 30 mg once daily for 12 weeks in Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Number of subjects in period 1
    		Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Started
    221
    221
    219
    Received Study Drug
    221
    221
    219
    Completed
    208
    213
    201
    Not completed
    13
    8
    18
         Consent withdrawn by subject
    3
    5
    5
         Adverse event, non-fatal
    6
    3
    9
         Other
    3
    -
    2
         Lost to follow-up
    1
    -
    2
    Period 2
    Period 2 title
    Period 2: Week 12 to Week 260
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Subjects who were assigned to upadacitinib in Period 1 continued to receive blinded upadacitinib per original randomization assignment. Subjects assigned to placebo in Period 1 received upadacitinib 15 mg QD or 30 mg QD from Week 12 onward in a blinded fashion per pre-specified randomization assignments. Study sites and subjects remained blinded until implementation of Protocol Amendment 6.0, when all subjects received upadacitinib 15 mg QD, with the earliest switch occurring at Week 168 visit.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Upadacitinib 15 mg
    Arm description
    		 Participants originally randomized to placebo then upadacitinib 15 mg received upadacitinib 15 mg once daily from Week 12 to Week 260.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Arm title
    		 Placebo / Upadacitinib 30 mg
    Arm description
    		 Participants originally randomized to placebo then upadacitinib 30 mg received upadacitinib 30 mg once daily from Week 12 to Week 260. After Protocol Amendment 6 participants still on study were switched to receive upadacitinib 15 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Arm title
    		 Upadacitinib 15 mg / Upadacitinib 15 mg
    Arm description
    		 Participants originally randomized to receive upadacitinib 15 mg continued to receive upadacitinib 15 mg once daily for an additional 248 weeks in Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Arm title
    		 Upadacitinib 30 mg / Upadacitinib 30 mg
    Arm description
    		 Participants originally randomized to receive upadacitinib 30 mg continued to receive upadacitinib 30 mg for an additional 248 weeks or until implementation of Protocol Amendment 6 at which time participants were switched to receive upadacitinib 15 mg once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Number of subjects in period 2 [1]
    		Placebo / Upadacitinib 15 mg Placebo / Upadacitinib 30 mg Upadacitinib 15 mg / Upadacitinib 15 mg Upadacitinib 30 mg / Upadacitinib 30 mg
    Started
    103
    103
    212
    200
    Received Study Drug
    103
    102
    207
    199
    Switched to Upadacitinib 15 mg
    0 [2]
    53
    0 [3]
    126
    Completed
    61
    49
    130
    120
    Not completed
    42
    54
    82
    80
         Consent withdrawn by subject
    14
    21
    31
    30
         Coronavirus Disease – 2019 (COVID-19) Infection
    1
    -
    -
    1
         Adverse event, non-fatal
    13
    16
    17
    30
         Other
    8
    12
    23
    15
         COVID-19 Logistic Restrictions
    1
    -
    1
    -
         Lost to follow-up
    5
    5
    10
    4
    Notes
    [1] - 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: Four participants completed the Week 12 visit but did not continue into Period 2.
    [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: Not applicable - participants in this group did not switch doses.
    [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: Not applicable - participants in this group did not switch doses.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once daily for 12 weeks in Period 1.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    		 Participants received upadacitinib 15 mg once daily for 12 weeks in Period 1.

    Reporting group title
    Upadacitinib 30 mg
    Reporting group description
    		 Participants received upadacitinib 30 mg once daily for 12 weeks in Period 1.

    Reporting group values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg Total
    Number of subjects
    		 221 221 219 661
    Age categorical
    Units: Subjects
        < 40 years
    		 21 23 22 66
        40 to 64 years
    		 145 153 145 443
        ≥ 65 years
    		 55 45 52 152
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.0 ± 12.22 55.3 ± 11.47 55.8 ± 11.29 -
    Gender categorical
    Units: Subjects
        Female
    		 166 182 172 520
        Male
    		 55 39 47 141
    Race
    Units: Subjects
        White
    		 187 188 186 561
        Black or African American
    		 10 13 8 31
        American Indian / Alaskan Native
    		 1 0 1 2
        Asian
    		 19 19 21 59
        Multiple
    		 4 1 3 8
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 27 23 30 80
        Not Hispanic or Latino
    		 194 198 189 581
    Geographical Region
    Other includes Australia, New Zealand, and South Africa.
    Units: Subjects
        North America
    		 90 88 89 267
        South/Central America
    		 8 10 11 29
        Western Europe
    		 24 22 23 69
        Eastern Europe
    		 74 76 73 223
        Asia
    		 16 17 15 48
        Other
    		 9 8 8 25
    Prior Biological DMARD Use
    Units: Subjects
        Yes
    		 29 27 28 84
        No
    		 192 194 191 577
    Conventional Synthetic DMARD (csDMARD) Use at Baseline
    Units: Subjects
        Methotrexate alone
    		 141 122 136 399
        Methotrexate and other csDMARD
    		 49 47 39 135
        csDMARD other than methotrexate
    		 30 51 44 125
        Missing
    		 1 1 0 2
    Duration of Rheumatoid Arthritis (RA) Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 7.2 ± 7.45 7.3 ± 7.89 7.3 ± 7.86 -
    Tender Joint Count
    A total of 68 joints were assessed for the presence or absence of tenderness.
    Units: tender joints
        arithmetic mean (standard deviation)
    		 24.7 ± 14.96 25.2 ± 13.80 26.2 ± 14.26 -
    Swollen Joint Count
    A total of 66 joints were assessed for the presence or absence of swelling.
    Units: swollen joints
        arithmetic mean (standard deviation)
    		 15.4 ± 9.24 16.0 ± 10.04 16.2 ± 10.55 -
    Patient's Assessment of Pain
    Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 100. A score of 0 indicates "no pain" and a score of 100 indicates "worst possible pain." There were 221, 217, and 219 subjects with available data in each treatment group respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 61.5 ± 20.80 64.1 ± 19.45 64.0 ± 19.77 -
    Patient’s Global Assessment of Disease Activity
    The participant was asked to rate their current RA disease activity over the past 24 hours ranging from 0 to 100 using a VAS, where 0 indicates very low disease activity and 100 indicates very high disease activity. There were 221, 217, and 219 subjects with available data in each treatment group respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 60.3 ± 20.50 63.1 ± 21.86 62.8 ± 20.32 -
    Physician's Global Assessment of Disease Activity
    The physician rated the participant's current global RA disease activity (independently from the participant's assessment) on a VAS scale from 0 to 100, where 0 indicates very low disease activity and 100 indicates very high disease activity. There were 211, 209, and 213 subjects with available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 64.4 ± 17.67 64.3 ± 16.22 63.0 ± 17.99 -
    Health Assessment Questionnaire – Disability Index (HAQ-DI)
    The HAQ-DI is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 (no disability) to 3 (very severe, high-dependency disability). There were 221, 216, and 219 subjects with available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 1.4 ± 0.63 1.5 ± 0.61 1.5 ± 0.61 -
    High-sensitivity C-reactive Protein (hsCRP)
    Units: mg/L
        arithmetic mean (standard deviation)
    		 12.6 ± 13.96 16.6 ± 19.17 14.8 ± 16.86 -
    Disease Activity Score Based on CRP (DAS28 [CRP])
    The DAS28 (CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. There were 221, 217, and 219 participants with available data in each treatment group, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 5.6 ± 0.84 5.7 ± 0.97 5.7 ± 0.90 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once daily for 12 weeks in Period 1.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    		 Participants received upadacitinib 15 mg once daily for 12 weeks in Period 1.

    Reporting group title
    Upadacitinib 30 mg
    Reporting group description
    		 Participants received upadacitinib 30 mg once daily for 12 weeks in Period 1.
    Reporting group title
    Placebo / Upadacitinib 15 mg
    Reporting group description
    		 Participants originally randomized to placebo then upadacitinib 15 mg received upadacitinib 15 mg once daily from Week 12 to Week 260.

    Reporting group title
    Placebo / Upadacitinib 30 mg
    Reporting group description
    		 Participants originally randomized to placebo then upadacitinib 30 mg received upadacitinib 30 mg once daily from Week 12 to Week 260. After Protocol Amendment 6 participants still on study were switched to receive upadacitinib 15 mg.

    Reporting group title
    Upadacitinib 15 mg / Upadacitinib 15 mg
    Reporting group description
    		 Participants originally randomized to receive upadacitinib 15 mg continued to receive upadacitinib 15 mg once daily for an additional 248 weeks in Period 2.

    Reporting group title
    Upadacitinib 30 mg / Upadacitinib 30 mg
    Reporting group description
    		 Participants originally randomized to receive upadacitinib 30 mg continued to receive upadacitinib 30 mg for an additional 248 weeks or until implementation of Protocol Amendment 6 at which time participants were switched to receive upadacitinib 15 mg once daily.

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

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    End point title
    		 Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12
    End point description
    The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was low disease activity, based on a Disease Activity Score 28 (DAS28)-CRP score of ≤ 3.2 at Week 12. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A DAS28 score less than or equal to 3.2 indicates low disease activity. The full analysis set (FAS) included all randomized participants who received at least one dose of study drug. Participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 data were missing at Week 12 were considered non-responders.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [1]
    221 [2]
    219 [3]
    Units: percentage of participants
        number (confidence interval 95%)
    17.2 (12.2 to 22.2)
    48.4 (41.8 to 55.0)
    47.9 (41.3 to 54.6)
    Notes
    [1] - Full analysis set
    [2] - Full analysis set
    [3] - Full analysis set
    Statistical analysis title
    		 Analysis of LDA Based on DAS28(CRP)
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    31.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23
         upper limit
    		 39.5
    Notes
    [4] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [5] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.
    Statistical analysis title
    		 Analysis of LDA Based on DAS28(CRP)
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    30.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.5
         upper limit
    		 39
    Notes
    [6] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [7] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.

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

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    End point title
    		 Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
    End point description
    The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 12. Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: i) Physician global assessment of disease activity; ii) Patient global assessment of disease activity; iii) Patient assessment of pain; iv) Health Assessment Questionnaire - Disability Index (HAQ-DI); v) High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [8]
    221 [9]
    219 [10]
    Units: percentage of participant
        number (confidence interval 95%)
    35.7 (29.4 to 42.1)
    63.8 (57.5 to 70.1)
    66.2 (59.9 to 72.5)
    Notes
    [8] - Full analysis set
    [9] - Full analysis set
    [10] - Full analysis set
    Statistical analysis title
    		 Analysis of ACR20 Response at Week 12
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    28.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.1
         upper limit
    		 37
    Notes
    [11] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [12] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.
    Statistical analysis title
    		 Analysis of ACR20 Response at Week 12
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    30.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.6
         upper limit
    		 39.4
    Notes
    [13] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [14] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.

    Secondary: Change From Baseline in in Disease Activity Score 28 (CRP) at Week 12

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    End point title
    		 Change From Baseline in in Disease Activity Score 28 (CRP) at Week 12
    End point description
    The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. A negative change from Baseline in DAS28 (CRP) indicates improvement in disease activity. Multiple imputation was used for missing data in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    220 [15]
    217 [16]
    219 [17]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -1.02 (-1.22 to -0.82)
    -2.20 (-2.40 to -2.00)
    -2.34 (-2.54 to -2.14)
    Notes
    [15] - Full analysis set participants with available data at Baseline
    [16] - Full analysis set participants with available data at Baseline
    [17] - Full analysis set participants with available data at Baseline
    Statistical analysis title
    		 Analysis of Change from Baseline in DAS28 (CRP)
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.001 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 -0.94
    Notes
    [18] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [19] - Analysis of covariance (ANCOVA) model with treatment, prior bDMARD use and Baseline value as covariates.
    Statistical analysis title
    		 Analysis of Change from Baseline in DAS28 (CRP)
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.001 [21]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.56
         upper limit
    		 -1.08
    Notes
    [20] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [21] - ANCOVA model with treatment, prior bDMARD use and Baseline value as covariates.

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

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    End point title
    		 Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12
    End point description
    The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Baseline in the overall score indicates improvement. Multiple imputation was used for missing data in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    220 [22]
    216 [23]
    219 [24]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -0.25 (-0.34 to -0.17)
    -0.59 (-0.67 to -0.51)
    -0.54 (-0.62 to -0.46)
    Notes
    [22] - Full analysis set participants with available data at Baseline
    [23] - Full analysis set participants with available data at Baseline
    [24] - Full analysis set participants with available data at Baseline
    Statistical analysis title
    		 Analysis of Change from Baseline in HAQ-DI
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.001 [26]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 -0.24
    Notes
    [25] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [26] - ANCOVA model with treatment, prior bDMARD use and Baseline value as covariates.
    Statistical analysis title
    		 Analysis of Change from Baseline in HAQ-DI
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.001 [28]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.18
    Notes
    [27] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [28] - ANCOVA model with treatment, prior bDMARD use and Baseline value as covariates.

    Secondary: Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary (PCS) Score at Week 12

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    End point title
    		 Change From Baseline in Short-Form 36 (SF-36) Physical Component Summary (PCS) Score at Week 12
    End point description
    The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component summary score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from Baseline score indicates an improvement. A mixed effect model repeat measurement (MMRM) with data from observed cases to Week 12 was used in this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    207 [29]
    209 [30]
    197 [31]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    3.03 (1.88 to 4.18)
    7.58 (6.43 to 8.74)
    8.01 (6.84 to 9.18)
    Notes
    [29] - Full analysis set participants with available data
    [30] - Full analysis set participants with available data
    [31] - Full analysis set participants with available data
    Statistical analysis title
    		 Analysis of Change from Baseline in SF-36 PCS
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 < 0.001 [33]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.13
         upper limit
    		 5.98
    Notes
    [32] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [33] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Statistical analysis title
    		 Analysis of Change from Baseline in SF-36 PCS
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 < 0.001 [35]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.54
         upper limit
    		 6.42
    Notes
    [34] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [35] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.

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

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    End point title
    		 Percentage of Participants Achieving Clinical Remission Based on DAS28 (CRP) at Week 12
    End point description
    Clinical remission (CR) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than 2.6. DAS28 (CRP) is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. Participants who prematurely discontinued from study drug prior to Week 12 or for whom DAS28 (CRP) data were missing at Week 12 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [36]
    221 [37]
    219 [38]
    Units: percentage of participants
        number (confidence interval 95%)
    10.0 (6.0 to 13.9)
    30.8 (24.7 to 36.9)
    28.3 (22.3 to 34.3)
    Notes
    [36] - Full analysis set
    [37] - Full analysis set
    [38] - Full analysis set
    Statistical analysis title
    		 Analysis of Clinical Remission Based on DAS28(CRP)
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.001 [40]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    20.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.6
         upper limit
    		 28.1
    Notes
    [39] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [40] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.
    Statistical analysis title
    		 Analysis of Clinical Remission Based on DAS28(CRP)
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.001 [42]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    18.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.2
         upper limit
    		 25.5
    Notes
    [41] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [42] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.

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

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    End point title
    		 Percentage of Participants Achieving Low Disease Activity Based on CDAI at Week 12
    End point description
    Low disease activity based on the clinical disease activity index (CDAI) is defined as a CDAI score ≤ 10. CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm. The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity. Participants who prematurely discontinued from study drug prior to Week 12 or for whom CDAI data were missing at Week 12 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [43]
    221 [44]
    219 [45]
    Units: percentage of participants
        number (confidence interval 95%)
    19.0 (13.8 to 24.2)
    40.3 (33.8 to 46.7)
    42.0 (35.5 to 48.5)
    Notes
    [43] - Full analysis set
    [44] - Full analysis set
    [45] - Full analysis set
    Statistical analysis title
    		 Analysis of LDA Based on CDAI
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 < 0.001 [47]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    21.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13
         upper limit
    		 29.5
    Notes
    [46] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [47] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.
    Statistical analysis title
    		 Analysis of LDA Based on CDAI
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 < 0.001 [49]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.7
         upper limit
    		 31.3
    Notes
    [48] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [49] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use.

    Secondary: Change From Baseline in Duration of Morning Stiffness at Week 12

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    End point title
    		 Change From Baseline in Duration of Morning Stiffness at Week 12
    End point description
    Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days. A mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    202 [50]
    207 [51]
    197 [52]
    Units: minutes
        least squares mean (confidence interval 95%)
    -34.27 (-54.63 to -13.91)
    -85.28 (-105.61 to -64.95)
    -85.13 (-105.65 to -64.62)
    Notes
    [50] - Full analysis set participants with available data
    [51] - Full analysis set participants with available data
    [52] - Full analysis set participants with available data
    Statistical analysis title
    		 Analysis of Change in Morning Stiffness
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.001 [54]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -51.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78.14
         upper limit
    		 -23.87
    Notes
    [53] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [54] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Statistical analysis title
    		 Analysis of Change in Morning Stiffness
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.001 [56]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -50.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -78.19
         upper limit
    		 -23.53
    Notes
    [55] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [56] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.

    Secondary: Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12

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    End point title
    		 Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) at Week 12
    End point description
    The FACIT-Fatigue scale is a 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a five point Likert scale from 0 (not at all) to 4 (very much). The FACIT-Fatigue scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better the quality of life. A positive change from Baseline indicates improvement. A mixed effect model repeat measurement (MMRM) analysis with data from observed cases to Week 12 was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    207 [57]
    207 [58]
    197 [59]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    2.96 (1.62 to 4.30)
    7.91 (6.56 to 9.27)
    7.74 (6.38 to 9.11)
    Notes
    [57] - Full analysis set participants with available data
    [58] - Full analysis set participants with available data
    [59] - Full analysis set participants with available data
    Statistical analysis title
    		 Analysis of Change in FACIT-Fatigue
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 < 0.001 [61]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.31
         upper limit
    		 6.6
    Notes
    [60] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [61] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.
    Statistical analysis title
    		 Analysis of Change in FACIT-Fatigue
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [62]
    P-value
    		 < 0.001 [63]
    Method
    		 Mixed Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.12
         upper limit
    		 6.44
    Notes
    [62] - The overall type I error rate of the primary and ranked key secondary endpoints for the two doses was controlled using a graphical multiple testing procedure. The adjusted p-value under multiplicity control is reported, with significance achieved if the adjusted p-value is less than 0.05.
    [63] - MMRM model with fixed effects of treatment, visit, and treatment-by-visit interaction, previous bDMARD use, and Baseline value as covariate.

    Secondary: Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12

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    End point title
    		 Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: 1. ≥ 50% improvement in 68-tender joint count; 2. ≥ 50% improvement in 66-swollen joint count; and 3. ≥ 50% improvement in at least 3 of the 5 following parameters: i) Physician global assessment of disease activity; ii) Patient global assessment of disease activity; iii) Patient assessment of pain; iv) Health Assessment Questionnaire - Disability Index (HAQ-DI); v) High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [64]
    221 [65]
    219 [66]
    Units: percentage of participants
        number (confidence interval 95%)
    14.9 (10.2 to 19.6)
    38.0 (31.6 to 44.4)
    43.4 (36.8 to 49.9)
    Notes
    [64] - Full analysis set
    [65] - Full analysis set
    [66] - Full analysis set
    Statistical analysis title
    		 Analysis of ACR50 Response
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [67]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    23.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.1
         upper limit
    		 31
    Notes
    [67] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.
    Statistical analysis title
    		 Analysis of ACR50 Response
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [68]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    28.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.4
         upper limit
    		 36.5
    Notes
    [68] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.

    Secondary: Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12

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    End point title
    		 Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: 1. ≥ 70% improvement in 68-tender joint count; 2. ≥ 70% improvement in 66-swollen joint count; and 3. ≥ 70% improvement in at least 3 of the 5 following parameters: i) Physician global assessment of disease activity; ii) Patient global assessment of disease activity; iii) Patient assessment of pain; iv) Health Assessment Questionnaire - Disability Index (HAQ-DI); v) High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 12 or for whom ACR data were missing at Week 12 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [69]
    221 [70]
    219 [71]
    Units: percentage of participants
        number (confidence interval 95%)
    5.9 (2.8 to 9.0)
    20.8 (15.5 to 26.2)
    26.5 (20.6 to 32.3)
    Notes
    [69] - Full analysis set
    [70] - Full analysis set
    [71] - Full analysis set
    Statistical analysis title
    		 Analysis of ACR70 Response
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [72]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    14.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.7
         upper limit
    		 21.1
    Notes
    [72] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.
    Statistical analysis title
    		 Analysis of ACR70 Response
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [73]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    20.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14
         upper limit
    		 27.2
    Notes
    [73] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.

    Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 1

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    End point title
    		 Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 1
    End point description
    Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: 1. ≥ 20% improvement in 68-tender joint count; 2. ≥ 20% improvement in 66-swollen joint count; and 3. ≥ 20% improvement in at least 3 of the 5 following parameters: i) Physician global assessment of disease activity; ii) Patient global assessment of disease activity; iii) Patient assessment of pain; iv) Health Assessment Questionnaire - Disability Index (HAQ-DI); v) High-sensitivity C-reactive protein (hsCRP). Participants who prematurely discontinued from study drug prior to Week 1 or for whom ACR data were missing at Week 1 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1
    End point values
    		 Placebo Upadacitinib 15 mg Upadacitinib 30 mg
    Number of subjects analysed
    221 [74]
    221 [75]
    219 [76]
    Units: percentage of participants
        number (confidence interval 95%)
    8.6 (4.9 to 12.3)
    22.2 (16.7 to 27.6)
    28.3 (22.3 to 34.3)
    Notes
    [74] - Full analysis set
    [75] - Full analysis set
    [76] - Full analysis set
    Statistical analysis title
    		 Analysis of ACR20 Response at Week 1
    Comparison groups
    Upadacitinib 15 mg v Placebo
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [77]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    13.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 20.2
    Notes
    [77] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.
    Statistical analysis title
    		 Analysis of ACR20 Response at Week 1
    Comparison groups
    Upadacitinib 30 mg v Placebo
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [78]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    19.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.7
         upper limit
    		 26.7
    Notes
    [78] - Cochran-Mantel-Haenszel test adjusted for the stratification factor of prior biological disease-modifying anti-rheumatoid drug use. The unadjusted p-value is reported.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Period 1: From first dose of study drug up to Week 12 or up to 30 days after last dose for participants who discontinued study drug prior to Week 12. Period 1+2: From first dose of upadacitinib up to 30 days after last dose (maximum of 264 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Period 1: Placebo
    Reporting group description
    		 Participants received placebo once daily for 12 weeks in Period 1.

    Reporting group title
    Period 1: Upadacitinib 15 mg
    Reporting group description
    		 Participants received upadacitinib 15 mg once daily for 12 weeks in Period 1.

    Reporting group title
    Period 1: Upadacitinib 30 mg
    Reporting group description
    		 Participants received upadacitinib 30 mg once daily for 12 weeks in Period 1.

    Reporting group title
    Period 1+2: Upadacitinib 15 mg
    Reporting group description
    		 Participants originally randomized to upadacitinib 15 mg received upadacitinib 15 mg for 260 weeks and participants originally randomized to placebo followed by upadacitinib 15 mg received upadacitinib 15 mg from Week 12 to Week 260.

    Reporting group title
    Period 1+2: Upadacitinib 30 mg
    Reporting group description
    		 Participants originally randomized to upadacitinib 30 mg received upadacitinib 30 mg up to Week 260 or implementation of Protocol Amendment 6 (December 2019) and participants originally randomized to placebo followed by upadacitinib 30 mg received upadacitinib 30 mg from Week 12 up to Week 260 or implementation of Protocol Amendment 6.

    Reporting group title
    Period 2: Upadacitinib 15 mg After Switch
    Reporting group description
    		 Participants who were receiving upadacitinib 30 mg in Period 2 were switched to upadacitinib 15 mg once daily after implementation of Protocol Amendment 6 (December 2019) up to Week 260.

    Serious adverse events
    		 Period 1: Placebo Period 1: Upadacitinib 15 mg Period 1: Upadacitinib 30 mg Period 1+2: Upadacitinib 15 mg Period 1+2: Upadacitinib 30 mg Period 2: Upadacitinib 15 mg After Switch
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 221 (2.26%)
    10 / 221 (4.52%)
    7 / 219 (3.20%)
    91 / 324 (28.09%)
    102 / 321 (31.78%)
    19 / 179 (10.61%)
         number of deaths (all causes)
    1
    0
    0
    4
    7
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACROCHORDON
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADENOCARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    ANAL CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-CELL SMALL LYMPHOCYTIC LYMPHOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC LYMPHOCYTIC LEUKAEMIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CLEAR CELL RENAL CELL CARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CUTANEOUS T-CELL LYMPHOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    HEPATIC CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    INVASIVE BREAST CARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHANGIOSIS CARCINOMATOSA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO SPINE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    NON-HODGKIN'S LYMPHOMA STAGE IV
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN GERM CELL TERATOMA BENIGN
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAPILLARY THYROID CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PITUITARY TUMOUR BENIGN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER STAGE II
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RENAL CANCER STAGE I
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEMINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN SQUAMOUS CELL CARCINOMA RECURRENT
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF LUNG
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSITIONAL CELL CARCINOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THERAPY CHANGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTHETIC CARDIAC VALVE STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    3 / 321 (0.93%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VASCULAR STENT OCCLUSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    GENITAL PROLAPSE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CYST
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE PROLAPSE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    3 / 324 (0.93%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    BRONCHIECTASIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMPHYSEMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ORGANISING PNEUMONIA
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    3 / 324 (0.93%)
    2 / 321 (0.62%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY MASS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    BEHAVIOUR DISORDER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HALLUCINATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE BREAKAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEVICE MATERIAL ISSUE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIVER FUNCTION TEST INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCUS TEST POSITIVE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TROPONIN INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WEIGHT INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ACETABULUM FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA POSTOPERATIVE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK INJURY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMMINUTED FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONTUSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    3 / 324 (0.93%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FRACTURE DISPLACEMENT
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAND FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INCISIONAL HERNIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION POSTOPERATIVE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE INJURIES
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL DISCHARGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL FISTULA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TIBIA FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETHRAL INJURY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    2 / 221 (0.90%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    5 / 321 (1.56%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    4 / 324 (1.23%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOLFF-PARKINSON-WHITE SYNDROME
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROSPINAL FLUID LEAKAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR RADICULOPATHY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBOSACRAL RADICULOPATHY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT GLOBAL AMNESIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOCAL CORD PARALYSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA MACROCYTIC
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD LOSS ANAEMIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHADENITIS
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    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
    Eye disorders
    CORNEAL DECOMPENSATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETINAL TEAR
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ULCERATIVE KERATITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL FISSURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS ISCHAEMIC
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSBIOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOPERITONEUM
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    RETROPERITONEAL HAEMORRHAGE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UMBILICAL HERNIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    4 / 321 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATIC STEATOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATOMEGALY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DERMAL CYST
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STRESS URINARY INCONTINENCE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URETHRAL STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FASCIITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FISTULA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOOT DEFORMITY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC DEGENERATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    JOINT INSTABILITY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    3 / 324 (0.93%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    1 / 219 (0.46%)
    6 / 324 (1.85%)
    8 / 321 (2.49%)
    2 / 179 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 11
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEONECROSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOPOROTIC FRACTURE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ROTATOR CUFF SYNDROME
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPONDYLOLISTHESIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENOSYNOVITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VERTEBRAL FORAMINAL STENOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VERTEBRAL OSTEOPHYTE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS LIMB
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BONE TUBERCULOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS VIRAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    6 / 324 (1.85%)
    2 / 321 (0.62%)
    4 / 179 (2.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 6
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    CELLULITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHORIORETINITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLONIC ABSCESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENDOCARDITIS STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    0 / 221 (0.00%)
    1 / 221 (0.45%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EXTRADURAL ABSCESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EXTRAPULMONARY TUBERCULOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GROIN ABSCESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS B REACTIVATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER CUTANEOUS DISSEMINATED
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    2 / 321 (0.62%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METAPNEUMOVIRUS INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MUSCLE ABSCESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECROTISING FASCIITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 221 (0.45%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    6 / 324 (1.85%)
    11 / 321 (3.43%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    4 / 6
    10 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SALPINGO-OOPHORITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    4 / 321 (1.25%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    SIALOADENITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    2 / 324 (0.62%)
    2 / 321 (0.62%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VARICELLA
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VESTIBULAR NEURONITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    1 / 219 (0.46%)
    0 / 324 (0.00%)
    3 / 321 (0.93%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    YERSINIA INFECTION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LACTIC ACIDOSIS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    0 / 324 (0.00%)
    1 / 321 (0.31%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OBESITY
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    1 / 324 (0.31%)
    0 / 321 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Period 1: Placebo Period 1: Upadacitinib 15 mg Period 1: Upadacitinib 30 mg Period 1+2: Upadacitinib 15 mg Period 1+2: Upadacitinib 30 mg Period 2: Upadacitinib 15 mg After Switch
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 221 (30.77%)
    83 / 221 (37.56%)
    74 / 219 (33.79%)
    241 / 324 (74.38%)
    233 / 321 (72.59%)
    51 / 179 (28.49%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 221 (2.26%)
    1 / 221 (0.45%)
    5 / 219 (2.28%)
    36 / 324 (11.11%)
    33 / 321 (10.28%)
    2 / 179 (1.12%)
         occurrences all number
    5
    1
    5
    42
    41
    2
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    6 / 221 (2.71%)
    2 / 221 (0.90%)
    3 / 219 (1.37%)
    33 / 324 (10.19%)
    25 / 321 (7.79%)
    3 / 179 (1.68%)
         occurrences all number
    6
    2
    3
    44
    31
    3
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 221 (0.00%)
    5 / 221 (2.26%)
    7 / 219 (3.20%)
    36 / 324 (11.11%)
    32 / 321 (9.97%)
    1 / 179 (0.56%)
         occurrences all number
    0
    5
    7
    55
    46
    1
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 221 (0.45%)
    2 / 221 (0.90%)
    2 / 219 (0.91%)
    21 / 324 (6.48%)
    17 / 321 (5.30%)
    5 / 179 (2.79%)
         occurrences all number
    1
    2
    3
    28
    19
    5
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    4 / 221 (1.81%)
    3 / 221 (1.36%)
    2 / 219 (0.91%)
    41 / 324 (12.65%)
    27 / 321 (8.41%)
    4 / 179 (2.23%)
         occurrences all number
    4
    3
    2
    45
    29
    4
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    12 / 221 (5.43%)
    9 / 221 (4.07%)
    8 / 219 (3.65%)
    21 / 324 (6.48%)
    21 / 321 (6.54%)
    2 / 179 (1.12%)
         occurrences all number
    14
    9
    9
    24
    24
    2
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 221 (0.45%)
    2 / 219 (0.91%)
    20 / 324 (6.17%)
    10 / 321 (3.12%)
    0 / 179 (0.00%)
         occurrences all number
    1
    1
    2
    24
    14
    0
    LEUKOPENIA
         subjects affected / exposed
    1 / 221 (0.45%)
    4 / 221 (1.81%)
    4 / 219 (1.83%)
    17 / 324 (5.25%)
    20 / 321 (6.23%)
    2 / 179 (1.12%)
         occurrences all number
    1
    4
    4
    26
    34
    2
    NEUTROPENIA
         subjects affected / exposed
    0 / 221 (0.00%)
    4 / 221 (1.81%)
    6 / 219 (2.74%)
    13 / 324 (4.01%)
    26 / 321 (8.10%)
    3 / 179 (1.68%)
         occurrences all number
    0
    4
    6
    21
    35
    3
    General disorders and administration site conditions
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    2 / 219 (0.91%)
    18 / 324 (5.56%)
    15 / 321 (4.67%)
    1 / 179 (0.56%)
         occurrences all number
    0
    0
    2
    23
    20
    2
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    9 / 221 (4.07%)
    5 / 221 (2.26%)
    2 / 219 (0.91%)
    22 / 324 (6.79%)
    15 / 321 (4.67%)
    0 / 179 (0.00%)
         occurrences all number
    10
    5
    2
    24
    15
    0
    NAUSEA
         subjects affected / exposed
    7 / 221 (3.17%)
    15 / 221 (6.79%)
    3 / 219 (1.37%)
    30 / 324 (9.26%)
    18 / 321 (5.61%)
    1 / 179 (0.56%)
         occurrences all number
    8
    17
    3
    40
    20
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 221 (0.90%)
    9 / 221 (4.07%)
    3 / 219 (1.37%)
    24 / 324 (7.41%)
    26 / 321 (8.10%)
    0 / 179 (0.00%)
         occurrences all number
    2
    9
    3
    28
    33
    0
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    2 / 221 (0.90%)
    1 / 221 (0.45%)
    5 / 219 (2.28%)
    6 / 324 (1.85%)
    21 / 321 (6.54%)
    2 / 179 (1.12%)
         occurrences all number
    2
    1
    5
    7
    23
    2
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    2 / 221 (0.90%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    23 / 324 (7.10%)
    10 / 321 (3.12%)
    1 / 179 (0.56%)
         occurrences all number
    2
    0
    0
    28
    10
    1
    BACK PAIN
         subjects affected / exposed
    2 / 221 (0.90%)
    6 / 221 (2.71%)
    2 / 219 (0.91%)
    31 / 324 (9.57%)
    21 / 321 (6.54%)
    3 / 179 (1.68%)
         occurrences all number
    2
    7
    2
    37
    22
    3
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    10 / 221 (4.52%)
    4 / 221 (1.81%)
    4 / 219 (1.83%)
    36 / 324 (11.11%)
    30 / 321 (9.35%)
    8 / 179 (4.47%)
         occurrences all number
    11
    4
    5
    54
    41
    8
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    5 / 221 (2.26%)
    4 / 221 (1.81%)
    5 / 219 (2.28%)
    35 / 324 (10.80%)
    42 / 321 (13.08%)
    2 / 179 (1.12%)
         occurrences all number
    5
    4
    5
    55
    58
    2
    COVID-19
         subjects affected / exposed
    0 / 221 (0.00%)
    0 / 221 (0.00%)
    0 / 219 (0.00%)
    20 / 324 (6.17%)
    2 / 321 (0.62%)
    16 / 179 (8.94%)
         occurrences all number
    0
    0
    0
    21
    2
    16
    HERPES ZOSTER
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 221 (0.45%)
    1 / 219 (0.46%)
    27 / 324 (8.33%)
    44 / 321 (13.71%)
    4 / 179 (2.23%)
         occurrences all number
    1
    1
    1
    29
    46
    4
    INFLUENZA
         subjects affected / exposed
    2 / 221 (0.90%)
    1 / 221 (0.45%)
    3 / 219 (1.37%)
    15 / 324 (4.63%)
    22 / 321 (6.85%)
    0 / 179 (0.00%)
         occurrences all number
    2
    1
    3
    18
    23
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    9 / 221 (4.07%)
    12 / 221 (5.43%)
    13 / 219 (5.94%)
    60 / 324 (18.52%)
    45 / 321 (14.02%)
    3 / 179 (1.68%)
         occurrences all number
    10
    13
    14
    105
    75
    3
    PHARYNGITIS
         subjects affected / exposed
    0 / 221 (0.00%)
    2 / 221 (0.90%)
    2 / 219 (0.91%)
    18 / 324 (5.56%)
    9 / 321 (2.80%)
    0 / 179 (0.00%)
         occurrences all number
    0
    2
    2
    19
    10
    0
    SINUSITIS
         subjects affected / exposed
    1 / 221 (0.45%)
    6 / 221 (2.71%)
    1 / 219 (0.46%)
    28 / 324 (8.64%)
    22 / 321 (6.85%)
    1 / 179 (0.56%)
         occurrences all number
    1
    6
    1
    40
    23
    2
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    9 / 221 (4.07%)
    12 / 221 (5.43%)
    12 / 219 (5.48%)
    64 / 324 (19.75%)
    57 / 321 (17.76%)
    4 / 179 (2.23%)
         occurrences all number
    10
    12
    13
    111
    84
    5
    URINARY TRACT INFECTION
         subjects affected / exposed
    8 / 221 (3.62%)
    8 / 221 (3.62%)
    6 / 219 (2.74%)
    55 / 324 (16.98%)
    46 / 321 (14.33%)
    4 / 179 (2.23%)
         occurrences all number
    8
    8
    6
    89
    71
    4
    Metabolism and nutrition disorders
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    1 / 221 (0.45%)
    1 / 221 (0.45%)
    2 / 219 (0.91%)
    12 / 324 (3.70%)
    17 / 321 (5.30%)
    0 / 179 (0.00%)
         occurrences all number
    1
    1
    2
    12
    17
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2015
    - Updated the study design to add a blinded long-term extension (Period 2). - Revised inclusion criteria: Clarified requirements for subjects who had been receiving csDMARD therapy prior to study entry. Provided acceptable csDMARDS and dose requirements for inclusion. Modified dose requirement of methotrexate for inclusion. Updated hsCRP value requirement at screening. Updated contraception requirements for females and males. - Added the following exclusion criteria: subjects who are considered inadequate responders to bDMARD therapy; subjects with a history of gastrointestinal (GI) perforation or a history of associated GI diseases; subjects with conditions that could interfere with drug absorption; subjects who have received an organ transplant; and subjects who had clinically relevant or significant electrocardiogram (ECG) abnormalities. - Added an interim data analysis after the completion of Period 1.
    01 Apr 2016
    - Addition of CDAI calculation at Week 24 to determine LDA. - Clarified that starting at Week 24, subjects who do not show 20% improvement in tender joint count (TJC) and swollen joint count (SJC) compared to baseline at 2 consecutive visits should discontinue study drug.
    31 Mar 2017
    - Revised contraception recommendations for males including sperm donation time frame and clarified follicle-stimulating hormone testing requirements for females. - Added/updated key secondary endpoints, additional endpoints. - Updated statistical sections for accuracy and clarity. - Incorporated Canada and South Korea country-specific requirements.
    21 Jun 2017
    - Revised contraception recommendations for females if childbearing potential status changed during the course of the study. - Updated examples of commonly used strong CYP3A inhibitors and inducers, to include rifapentine. - Updated statistical sections for accuracy and clarity.
    26 Oct 2017
    - Updated female contraception recommendation language to clarify that injectable hormonal contraception was allowed. Clarified that verbal confirmation of vasectomized partner was an acceptable form of contraception. - Clarified that live vaccines were prohibited up to 30 days following last dose of study drug. - Updated study procedures to prevent unnecessary initiation of tuberculosis (TB) prophylaxis in subject with indeterminate QuantiFERON-TB test results by allowing local testing. - Updated study procedures to prevent unnecessary pregnancy test for women who become post-menopausal or surgically sterile during the study. - Added wording to study procedures for management of subjects with hepatitis B core antibody (Ab)+ (irrespective of hepatitis B surface Ab status) and negative hepatitis B virus DNA at screening and elevated levels of transaminases during study that may indicate active hepatitis which would require hepatitis B virus DNA polymerase chain reaction testing for confirmation. - Clarified a radiologist or pulmonologist may perform assessment of chest x-ray. - Updated the adverse events of special interest (AESI) that was to be monitored during the study to align in content and presentation with the current version of the Product Safety SAP.
    16 Dec 2019
    - Changed length of study from 240 weeks to 260 weeks throughout protocol to collect long-term safety data up to 5 years. - Changed dosing for all subjects to 15 mg QD open-label throughout protocol. - Added verbiage to explain that unblinded hsCRP results will be sent to site. - Clarified that restart of study drug after an interruption of > 30 consecutive days is at the discretion of the Investigator. - Clarified concurrent use of JAK inhibitors is prohibited during the study. Updated excluded biologic therapies to be consistent with current available biologic therapies in RA. Added allowance of high potency opiates for analgesic care related to AEs or SAEs. Added guidance for use of live vaccine administration during Period 2. - Removed male contraception requirements. - Provided guidance for interpretation of positive TB testing results in low risk subjects and added the ability to retest locally to confirm central laboratory result as a false-positive result is more likely in low risk subjects. Added use of Interferon Gamma Release Assay as a substitute for local TB testing. Clarification on test method to be used for annual TB testing. Specified that only subjects with newly identified TB risks are subject to chest x-rays. - Added an additional safety precaution for subjects regarding risk of venous thromboembolic events (VTE). - Specified the DMC concluded its oversight of the study after reviewing the unblinded safety data at the end of Period 1. - Updated study drug accountability requirements according to the revised sponsor guidelines. - Clarified throughout Medical Complaints section that all cardiac, embolic and thrombotic events will be adjudicated. - Added herpes zoster and recommendation for skin examination under Toxicity Management and updated AST or ALT parameters for management. - Added text to clarify what happens to optional exploratory research samples in the event a subject withdraws from the main study.
    15 Jul 2020
    - Updated allowance for administration of live vaccines during Period 2 with the following guidance: if a live vaccine must be administered during study participation, study drug must be held for at least 30 days prior to the vaccination and at least 30 days after the vaccination (or longer if required locally). - Clarified that contraception recommendations related to use of background csDMARDs including methotrexate, as well as concomitant therapies prescribed per standard of care, should be based on the local label.
    25 Nov 2020
    - Added an evaluation of the benefit and risk to subjects participating in the study relative to COVID-19. - Added provisions for virtual or alternative locations for study visits in the event of a pandemic situation like COVID-19 or any state of emergency to ensure the safety of subjects and site staff, while maintaining the integrity of the study. - Updated list of examples of commonly used strong cytochrome 3A inducers. - Added clarifications on study activities that can be performed by phone/video conference or at local clinic/hospital/laboratory or through the optional home healthcare service in the event study visits are impacted by any state of emergency or pandemic, as permitted by IRB/IEC. - Specified activities not eligible for completion by virtual interview in the event that an onsite visit cannot be performed due to a pandemic or state of emergency and should be completed at the next earliest feasible visit. - Added provision allowing Direct-to-Patient (DTP) shipment of study drug and study ancillaries due to state of emergency or pandemic situations. - Clarified that subjects will have to discontinue study drug treatment immediately if they develop a gastrointestinal perforation with the exception of appendicitis or mechanical injury. Added mitigation strategies regarding study discontinuation. - Clarified and updated the list of the adverse events of special interest. - Added supplemental COVID-19 case report forms. - Updated text to define Pregnancy and Product Complaint reporting timeline as 24 hours from site staff awareness. - Added guidance for investigators on the management of subjects with suspected or confirmed COVID-19 infection during the study. - Added option for verbal consent in the event of a pandemic situation. - Clarified that clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29908669
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