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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Study Comparing Upadacitinib (ABT-494) to Placebo in Subjects With Active Psoriatic Arthritis Who Have a History of Inadequate Response to at Least One Biologic Disease Modifying Anti-Rheumatic Drug (bDMARD)

    Summary
    EudraCT number
    		 2016-004152-30
    Trial protocol
    		 BE   CZ   GB   NL   FR   GR   PT   HU   ES   IT  
    Global end of trial date
    30 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M15-554
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03104374
    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
    30 Sep 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a Phase 3 multicenter study that included two periods. Period 1 was designed to compare the safety, tolerability, and efficacy of upadacitinib 15 mg once daily (QD) and 30 mg QD versus placebo in subjects with moderately to severely active Psoriatic Arthritis (PsA) who have an inadequate response to Biological Disease Modifying Anti-Rheumatic Drug (bDMARDs). Period 2 evaluated the safety, tolerability and efficacy of upadacitinib 15 mg QD and 30 mg QD in subjects with PsA who have completed Period 1. Upon approval of protocol amendment 8, subjects receiving upadacitinib 30 mg QD in Period 2 were switched to upadacitinib 15 mg QD for the remainder of the study.
    Protection of trial subjects
    Prior to the initiation of any screening or study-specific procedures, the investigator or his or her representative explained the nature of the study to the subject or his or her representative and answered all questions regarding this study. The informed consent statement was reviewed and signed and dated by the subject and/or the subject's legal guardian and the person who administered the informed consent. For subjects in Japan only: if a subject is under 20 years of age, then the subject and their parent or legal guardian must voluntarily sign and date an informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2017
    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
    Belgium: 5
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Chile: 49
    Country: Number of subjects enrolled
    Czechia: 32
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 41
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Puerto Rico: 30
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 354
    Worldwide total number of subjects
    642
    EEA total number of subjects
    115
    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)
    518
    From 65 to 84 years
    124
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Randomization was stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA), current use of at least 1 DMARD, and number of prior failed biologic DMARDs (1 vs > 1), except for participants from Japan, for whom randomization was stratified by extent of psoriasis (≥ 3% BSA or < 3% BSA) only.

    Pre-assignment
    Screening details
    		 For assessment of the primary and secondary endpoints, all subjects from Period 1 who received Placebo for the first 24 weeks were pooled for data analysis.

    Period 1
    Period 1 title
    Period 1 (Week 1 to Week 56)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    When the last subject completed the last visit of Period 1 (Week 56), study drug assignment in both periods was unblinded to the sites, and subjects were dispensed study drug in an open-label fashion until the completion of Period 2.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Upadacitinib 15 mg
    Arm description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 15 mg once daily for Week 25 to Week 56.
    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
    It is administered once daily.

    Investigational medicinal product name
    Upadacitinib 15 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg administered once daily.

    Arm title
    		 Placebo / Upadacitinib 30 mg
    Arm description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 30 mg once daily for Week 25 to Week 56.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Upadacitinib 30 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg administered once daily.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It is administered once daily.

    Arm title
    		 Upadacitinib 15 mg
    Arm description
    		 Participants randomized to receive Upadacitinib 15 mg once daily from Week 1 to Week 56 in Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 15 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It is administered once daily.

    Arm title
    		 Upadacitinib 30 mg
    Arm description
    		 Subjects were randomized to receive Upadacitinib 30 mg once daily from Week 1 to Week 56 in Period 1. One randomized subject did not qualify per inclusion/exclusion criteria and discontinued prior to treatment. This subject is not included in the disposition table.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 30 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    It is administered once daily.

    Number of subjects in period 1 [1]
    		Placebo / Upadacitinib 15 mg Placebo / Upadacitinib 30 mg Upadacitinib 15 mg Upadacitinib 30 mg
    Started
    106
    106
    211
    218
    Received Study Drug
    106
    106
    211
    218
    Completed Week 24
    81
    92
    192
    195
    Completed
    69
    77
    167
    166
    Not completed
    37
    29
    44
    52
         Consent withdrawn by subject
    18
    9
    10
    17
         Adverse event, non-fatal
    7
    7
    12
    14
         Not Specified
    2
    2
    4
    7
         Lost to follow-up
    4
    4
    6
    8
         Lack of efficacy
    6
    7
    12
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One randomized subject did not qualify per inclusion/exclusion criteria and discontinued prior to treatment.
    Period 2
    Period 2 title
    Period 2 (Week 56 to End-of-Study)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    In order to maintain the blind, the upadacitinib/placebo tablets provided for the study will be identical in appearance. The Interactive Response Technology (IRT) will provide access to unblinded subject treatment information in the case of medical emergency. When the last subject completed the last visit of Period 1 (Week 56), study drug assignment in both periods was unblinded to the sites, and subjects were dispensed study drug in an open-label fashion until the completion of Period 2.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo / Upadacitinib 15 mg
    Arm description
    		 In Period 1, participants who were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 15 mg once daily for Week 25 to Week 56. In Period 2, participants received Upadacitinib 15 mg from Week 56 to EOS.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 15 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg by mouth once daily.

    Arm title
    		 Placebo / Upadacitinib 30 mg
    Arm description
    		 In Period 1, participants who were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 30 mg once daily for Week 25 to Week 56. In Period 2, participants received Upadacitinib 30 mg from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 30 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg by mouth once daily.

    Arm title
    		 Upadacitinib 15 mg
    Arm description
    		 In Period 2, participants in this arm continued to receive Upadacitinib 15 mg once daily from Week 56 to EOS.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 15 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg by mouth once daily.

    Arm title
    		 Upadacitinib 30 mg
    Arm description
    		 In Period 2, participants in this arm continued to receive Upadacitinib 30 mg once daily from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib 30 mg
    Investigational medicinal product code
    Other name
    ABT-494
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg by mouth once daily.

    Number of subjects in period 2 [2]
    		Placebo / Upadacitinib 15 mg Placebo / Upadacitinib 30 mg Upadacitinib 15 mg Upadacitinib 30 mg
    Started
    69
    77
    167
    165
    Switched to 15mg QD Upa Dosing in Per 2
    0 [3]
    28 [4]
    0 [5]
    59 [6]
    Completed
    55
    55
    131
    126
    Not completed
    14
    22
    36
    39
         Consent withdrawn by subject
    3
    7
    13
    16
         Adverse event, non-fatal
    4
    7
    10
    10
         Not Specified
    3
    2
    2
    4
         COVID-19 Infection
    -
    -
    1
    -
         Lost to follow-up
    2
    2
    3
    5
         Lack of efficacy
    2
    4
    7
    4
    Notes
    [2] - 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: One participant who completed Period 1 did not enter Period 2.
    [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: The milestone indicates the number of subjects who switched from 30mg QD to 15mg QD Upa Dosing in Period 2. This milestone is not applicable to this arm.
    [4] - 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: The milestone indicates the number of subjects who switched from 30mg QD to 15mg QD Upa Dosing in Period 2.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone indicates the number of subjects who switched from 30mg QD to 15mg QD Upa Dosing in Period 2. This milestone is not applicable to this arm.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone indicates the number of subjects who switched from 30mg QD to 15mg QD Upa Dosing in Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo / Upadacitinib 15 mg
    Reporting group description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 15 mg once daily for Week 25 to Week 56.

    Reporting group title
    Placebo / Upadacitinib 30 mg
    Reporting group description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 30 mg once daily for Week 25 to Week 56.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    		 Participants randomized to receive Upadacitinib 15 mg once daily from Week 1 to Week 56 in Period 1.

    Reporting group title
    Upadacitinib 30 mg
    Reporting group description
    		 Subjects were randomized to receive Upadacitinib 30 mg once daily from Week 1 to Week 56 in Period 1. One randomized subject did not qualify per inclusion/exclusion criteria and discontinued prior to treatment. This subject is not included in the disposition table.

    Reporting group values
    		 Placebo / Upadacitinib 15 mg Placebo / Upadacitinib 30 mg Upadacitinib 15 mg Upadacitinib 30 mg Total
    Number of subjects
    		 106 106 211 218 641
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ( 11.65 ) 56.0 ( 11.16 ) 53.0 ( 12.02 ) 53.0 ( 11.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 57 63 113 115 348
        Male
    		 49 43 98 103 293
    Extent of Psoriasis
    The extent of psoriasis was measured by the physician as the total body surface area (BSA) involved with psoriasis. For purposes of clinical estimation, the total surface of the participant's palm and five digits was assumed to be approximately equivalent to 1% of BSA.
    Units: Subjects
        < 3% BSA
    		 41 40 81 87 249
        ≥ 3% BSA
    		 65 66 130 131 392
    Number of Prior Failed Biologic DMARDs
    Failed treatment with prior biologic DMARD is defined as lack of efficacy after a minimum 12 week duration of therapy. The zero category includes participants with intolerance but not inadequate response to a biologic DMARD.
    Units: Subjects
        bDMARDS (0)
    		 12 6 16 17 51
        bDMARD (1)
    		 65 70 126 130 391
        bDMARDS (2)
    		 18 17 35 46 116
        bDMARDS (≥ 3 )
    		 11 13 34 25 83
    Duration of Psoriatic Arthritis Symptoms
    Units: years
        arithmetic mean (standard deviation)
    		 13.8 ( 11.65 ) 15.3 ( 11.75 ) 12.2 ( 8.81 ) 13.3 ( 10.84 ) -
    Duration of PsA Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 10.3 ( 9.97 ) 11.6 ( 10.68 ) 9.6 ( 8.36 ) 9.7 ( 8.71 ) -
    Tender Joint Count
    A total of 68 joints were assessed for the presence or absence of tenderness.
    Units: joints
        arithmetic mean (standard deviation)
    		 26.1 ( 18.01 ) 24.4 ( 17.27 ) 24.9 ( 17.27 ) 24.2 ( 15.87 ) -
    Swollen Joint Count
    A total of 66 joints were assessed for the presence or absence of swelling.
    Units: joints
        arithmetic mean (standard deviation)
    		 11.8 ( 9.04 ) 12.3 ( 8.70 ) 11.3 ( 8.19 ) 12.9 ( 9.41 ) -
    Patient's Assessment of Pain
    Participants were asked to indicate the severity of their arthritis pain within the previous week on a numeric rating scale (NRS) from 0 to 10. A score of 0 indicates "no pain" and a score of 10 indicates "worst possible pain." Measure Analysis Population Description: Participants with available data
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 6.6 ( 2.06 ) 6.5 ( 2.20 ) 6.4 ( 2.13 ) 6.2 ( 2.21 ) -
    Patient's Global Assessment of Disease Activity
    The participant was asked to rate their current psoriatic arthritis disease activity on a 0 to 10 NRS, where 0 indicates no disease activity and 10 indicates severe disease activity. Measure Analysis Population Description: Participants with available data
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 7.0 ( 1.84 ) 6.7 ( 2.23 ) 6.8 ( 1.91 ) 6.7 ( 2.15 ) -
    Physician's Global Assessment of Disease Activity
    The physician rated the participant's current global psoriatic arthritis disease activity (independently from the participant's assessment) on a 0 to 10 NRS where 0 indicates no disease activity and 10 indicates severe disease activity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 6.5 ( 1.91 ) 6.5 ( 1.61 ) 6.5 ( 1.80 ) 6.6 ( 1.73 ) -
    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 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. Analysis Population Description: Participants with available data.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 1.26 ( 0.721 ) 1.19 ( 0.661 ) 1.10 ( 0.61 ) 1.19 ( 0.662 ) -
    High-sensitivity Creactive Protein (hsCRP)
    Units: mg/L
        arithmetic mean (standard deviation)
    		 11.83 ( 22.06 ) 8.98 ( 13.929 ) 11.16 ( 18.55 ) 10.53 ( 17.21 ) -
    Subject analysis sets

    Subject analysis set title
    Placebo (Pooled Week 1 - Week 24)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set; 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. Participants received placebo once daily for 24 weeks.

    Subject analysis sets values
    		 Placebo (Pooled Week 1 - Week 24)
    Number of subjects
    212
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.1 ( 11.53 )
    Gender categorical
    Units: Subjects
        Female
    120
        Male
    92
    Extent of Psoriasis
    The extent of psoriasis was measured by the physician as the total body surface area (BSA) involved with psoriasis. For purposes of clinical estimation, the total surface of the participant's palm and five digits was assumed to be approximately equivalent to 1% of BSA.
    Units: Subjects
        < 3% BSA
    81
        ≥ 3% BSA
    131
    Number of Prior Failed Biologic DMARDs
    Failed treatment with prior biologic DMARD is defined as lack of efficacy after a minimum 12 week duration of therapy. The zero category includes participants with intolerance but not inadequate response to a biologic DMARD.
    Units: Subjects
        bDMARDS (0)
    18
        bDMARD (1)
    135
        bDMARDS (2)
    35
        bDMARDS (≥ 3 )
    24
    Duration of Psoriatic Arthritis Symptoms
    Units: years
        arithmetic mean (standard deviation)
    14.6 ( 11.70 )
    Duration of PsA Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    11.0 ( 10.33 )
    Tender Joint Count
    A total of 68 joints were assessed for the presence or absence of tenderness.
    Units: joints
        arithmetic mean (standard deviation)
    25.3 ( 17.62 )
    Swollen Joint Count
    A total of 66 joints were assessed for the presence or absence of swelling.
    Units: joints
        arithmetic mean (standard deviation)
    12.0 ( 8.85 )
    Patient's Assessment of Pain
    Participants were asked to indicate the severity of their arthritis pain within the previous week on a numeric rating scale (NRS) from 0 to 10. A score of 0 indicates "no pain" and a score of 10 indicates "worst possible pain." Measure Analysis Population Description: Participants with available data
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.6 ( 2.12 )
    Patient's Global Assessment of Disease Activity
    The participant was asked to rate their current psoriatic arthritis disease activity on a 0 to 10 NRS, where 0 indicates no disease activity and 10 indicates severe disease activity. Measure Analysis Population Description: Participants with available data
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.8 ( 2.04 )
    Physician's Global Assessment of Disease Activity
    The physician rated the participant's current global psoriatic arthritis disease activity (independently from the participant's assessment) on a 0 to 10 NRS where 0 indicates no disease activity and 10 indicates severe disease activity.
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.5 ( 1.76 )
    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 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. Analysis Population Description: Participants with available data.
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.23 ( 0.691 )
    High-sensitivity Creactive Protein (hsCRP)
    Units: mg/L
        arithmetic mean (standard deviation)
    10.40 ( 18.46 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo / Upadacitinib 15 mg
    Reporting group description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 15 mg once daily for Week 25 to Week 56.

    Reporting group title
    Placebo / Upadacitinib 30 mg
    Reporting group description
    		 Participants were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 30 mg once daily for Week 25 to Week 56.

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    		 Participants randomized to receive Upadacitinib 15 mg once daily from Week 1 to Week 56 in Period 1.

    Reporting group title
    Upadacitinib 30 mg
    Reporting group description
    		 Subjects were randomized to receive Upadacitinib 30 mg once daily from Week 1 to Week 56 in Period 1. One randomized subject did not qualify per inclusion/exclusion criteria and discontinued prior to treatment. This subject is not included in the disposition table.
    Reporting group title
    Placebo / Upadacitinib 15 mg
    Reporting group description
    		 In Period 1, participants who were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 15 mg once daily for Week 25 to Week 56. In Period 2, participants received Upadacitinib 15 mg from Week 56 to EOS.

    Reporting group title
    Placebo / Upadacitinib 30 mg
    Reporting group description
    		 In Period 1, participants who were randomized to receive placebo once daily up to Week 24 followed by Upadacitinib 30 mg once daily for Week 25 to Week 56. In Period 2, participants received Upadacitinib 30 mg from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment

    Reporting group title
    Upadacitinib 15 mg
    Reporting group description
    		 In Period 2, participants in this arm continued to receive Upadacitinib 15 mg once daily from Week 56 to EOS.

    Reporting group title
    Upadacitinib 30 mg
    Reporting group description
    		 In Period 2, participants in this arm continued to receive Upadacitinib 30 mg once daily from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment

    Subject analysis set title
    Placebo (Pooled Week 1 - Week 24)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set; 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. Participants received placebo once daily for 24 weeks.

    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 [1]
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: - ≥ 20% improvement in 68-tender joint count; - ≥ 20% improvement in 66-swollen joint count; and - ≥ 20% improvement in at least 3 of the 5 following parameters: -Physician global assessment of disease activity -Patient global assessment of disease activity -Patient assessment of pain -Health Assessment Questionnaire - Disability Index (HAQ-DI) -High-sensitivity C-reactive protein (hsCRP).
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    211 [2]
    218 [3]
    212 [4]
    Units: percentage
        number (confidence interval 95%)
    56.9 (50.2 to 63.6)
    63.8 (57.4 to 70.1)
    24.1 (18.3 to 29.8)
    Notes
    [2] - Full analysis set
    [3] - Full analysis set
    [4] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    32.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24
         upper limit
    		 41.6
    Notes
    [5] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [6] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    39.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.1
         upper limit
    		 48.3
    Notes
    [7] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [8] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

    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 [9]
    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. Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 12 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    199 [10]
    204 [11]
    180 [12]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -0.30 (-0.37 to -0.24)
    -0.41 (-0.47 to -0.35)
    -0.10 (-0.16 to -0.03)
    Notes
    [10] - Full analysis set participants with available data
    [11] - Full analysis set participants with available data
    [12] - Full analysis set participants with available data
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed Effect Model Repeated Measurement
    Parameter type
    		 Response Rate Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 -0.12
    Notes
    [13] - Mixed Effect Model Repeated Measurement test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed Effect Model Repeated Measurement
    Parameter type
    		 Response Rate Difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.22
    Notes
    [14] - [Mixed Effect Model Repeated Measurement test adjusted for the main stratification factor of current DMARD use (yes/no).

    Secondary: Percentage of Participants Achieving a Static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 1 and at Least a 2-point Improvement From Baseline (sIGA 0/1) at Week 16

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    End point title
    		 Percentage of Participants Achieving a Static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 1 and at Least a 2-point Improvement From Baseline (sIGA 0/1) at Week 16 [15]
    End point description
    The sIGA is a 5 point scale ranging from 0 to 4, based on the investigator's assessment of the average elevation, erythema, and scaling of all psoriatic lesions at the current visit. A lower score indicates less severe psoriasis (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe). Analysis Population Description: Full analysis set participants with a Baseline sIGA score ≥ 2; participants who prematurely discontinued from study drug prior to Week 16 or for whom sIGA data were missing at Week 16 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    171 [16]
    164 [17]
    163 [18]
    Units: percentage of participants
        number (confidence interval 95%)
    36.8 (29.6 to 44.1)
    40.2 (32.7 to 47.7)
    9.2 (4.8 to 13.6)
    Notes
    [16] - Full analysis set participants with a Baseline sIGA score ≥ 2
    [17] - Full analysis set participants with a Baseline sIGA score ≥ 2
    [18] - Full analysis set participants with a Baseline sIGA score ≥ 2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    27.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.2
         upper limit
    		 36.1
    Notes
    [19] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path
    [20] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.0001 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.3
         upper limit
    		 39.8
    Notes
    [21] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [22] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

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

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    End point title
    		 Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 [23]
    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 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. Analysis Population Description: Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 12 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    201 [24]
    206 [25]
    185 [26]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    5.15 (4.14 to 6.15)
    7.06 (6.07 to 8.06)
    1.62 (0.58 to 2.67)
    Notes
    [24] - Full analysis set participants with available data
    [25] - Full analysis set participants with available data
    [26] - Full analysis set participants with available data
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    386
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    3.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.07
         upper limit
    		 4.98
    Notes
    [27] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [28] - MMRM analysis including treatment, visit, treatment-by-visit interaction, current DMARD use (yes/no) as fixed factors and Baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    5.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.99
         upper limit
    		 6.88
    Notes
    [29] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [30] - MMRM analysis including treatment, visit, treatment-by-visit interaction, current DMARD use (yes/no) as fixed factors and Baseline value as covariate.

    Secondary: Percentage of Participants Achieving Psoriasis Area Severity Index (PASI) 75 Response at Week 16

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    End point title
    		 Percentage of Participants Achieving Psoriasis Area Severity Index (PASI) 75 Response at Week 16 [31]
    End point description
    PASI is a composite score based on the percentage of the body surface area (BSA) affected by psoriasis and the intensity of erythema (reddening), induration (thickening or hardening of the skin), and desquamation (peeling of the skin) of lesions assessed at 4 anatomic sites (head, upper extremities, trunk, and lower extremities). At each location, the percentage of BSA involvement is assigned a score from 0 (no involvement) to 6 (90% to 100% involvement), and erythema, induration, and desquamation are scored on a scale from 0 (no symptoms) to 4 (very marked). The PASI score ranges from 0 (no psoriasis) to 72 (very severe psoriasis). A PASI-75 response is the percentage of participants who achieved at least a 75% reduction (improvement) from Baseline in PASI score. Analysis Population Description: Full analysis set participants with Baseline psoriasis BSA involvement ≥ 3%; participants who prematurely discontinued from study drug prior to Week 16 or for whom PASI data were missing
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    130 [32]
    131 [33]
    131 [34]
    Units: percentage of participants
        number (confidence interval 95%)
    52.3 (43.7 to 60.9)
    56.5 (48.0 to 65.0)
    16.0 (9.7 to 22.3)
    Notes
    [32] - Full analysis set participants with Baseline psoriasis BSA involvement ≥ 3%
    [33] - Full analysis set participants with Baseline psoriasis BSA involvement ≥ 3%
    [34] - Full analysis set participants with Baseline psoriasis BSA involvement ≥ 3%
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    36.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.6
         upper limit
    		 46.9
    Notes
    [35] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [36] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.0001 [38]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    40.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.9
         upper limit
    		 51
    Notes
    [37] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [38] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

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

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    End point title
    		 Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 12 [39]
    End point description
    The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days, including physical fatigue (e.g., I feel tired), functional fatigue (e.g., trouble finishing things), emotional fatigue (e.g., frustration), and social consequences of fatigue (e.g., limits social activity). Participants respond to the questions on a scale from 0 'not at all' to 4 'very much'. The FACIT Fatigue score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from Baseline indicates improvement. Analysis Population Description: Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 12 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    201 [40]
    206 [41]
    184 [42]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    5.0 (3.8 to 6.1)
    6.1 (4.9 to 7.2)
    1.3 (0.1 to 2.5)
    Notes
    [40] - Full analysis set participants with available data
    [41] - Full analysis set participants with available data
    [42] - Full analysis set participants with available data
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 < 0.0001 [44]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 5.4
    Notes
    [43] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [44] - MMRM analysis including treatment, visit, treatment-by-visit interaction, current DMARD use (yes/no) as fixed factors and Baseline value as covariate.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 < 0.0001 [46]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 6.4
    Notes
    [45] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [46] - MMRM analysis including treatment, visit, treatment-by-visit interaction, current DMARD use (yes/no) as fixed factors and Baseline value as covariate.

    Secondary: Percentage of Participants Achieving Minimal Disease Activity (MDA) at Week 24

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    End point title
    		 Percentage of Participants Achieving Minimal Disease Activity (MDA) at Week 24 [47]
    End point description
    A participant was classified as achieving MDA if 5 of the following 7 criteria were met: - Tender joint count (out of 68 joints) ≤ 1 - Swollen joint count (out of 66 joints) ≤ 1 - PASI score ≤ 1 (score ranges from 0 - 72) or percent BSA involved with psoriasis ≤ 3% - Patient's assessment of pain ≤ 1.5 (NRS from 0 to 10) - Patient's Global Assessment of disease activity ≤ 2 (NRS from 0 to 10) - HAQ-DI score ≤ 0.5 (index score ranges from 0 to 3) Analysis Population Description: Full analysis set; participants who prematurely discontinued from study drug prior to Week 24 or for whom data were missing at Week 24, or who met rescue criteria at Week 16 were considered non-responders. - Leeds Enthesitis Index ≤ 1 (assesses the presence or absence of enthesitis at 3 bilateral sites, with an overall score range from 0 to 6)
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    211 [48]
    218 [49]
    212 [50]
    Units: percentage of participants
        number (confidence interval 95%)
    25.1 (19.3 to 31.0)
    28.9 (22.9 to 34.9)
    2.8 (0.6 to 5.1)
    Notes
    [48] - Full analysis set
    [49] - Full analysis set
    [50] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 < 0.0001 [52]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    22.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16
         upper limit
    		 28.6
    Notes
    [51] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [52] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.0001 [54]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.7
         upper limit
    		 32.5
    Notes
    [53] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [54] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no

    Secondary: Change From Baseline in Self-Assessment of Psoriasis Symptoms (SAPS) Score at Week 16

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    End point title
    		 Change From Baseline in Self-Assessment of Psoriasis Symptoms (SAPS) Score at Week 16 [55]
    End point description
    The SAPS is an 11-item self-assessment of psoriasis symptoms that includes questions on: pain, itching, redness, scaling, flaking, bleeding, burning, stinging, tenderness, pain due to skin cracking, and joint pain. Each item is scored from 0 to 10, with 0 being least severe and 10 being most severe. The total score is generated by summing the 11 items and ranges from 0 to 110 (worst). A negative change from Baseline in the total score indicates improvement. Analysis Population Description: Full analysis set participants with available data; a mixed effect model repeat measurement (MMRM) analysis with longitudinal data from observed cases up to Week 16 was used.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    191 [56]
    200 [57]
    182 [58]
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -24.4 (-27.5 to -21.2)
    -29.7 (-32.8 to -26.6)
    -1.5 (-4.7 to 1.8)
    Notes
    [56] - Full analysis set participants with available data
    [57] - Full analysis set participants with available data
    [58] - Full analysis set participants with available data
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 < 0.0001 [60]
    Method
    		 Mixed models analysis
    Parameter type
    		 Response Rate Difference
    Point estimate
    -22.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.4
         upper limit
    		 -18.4
    Notes
    [59] - The overall type I error rate of primary and ranked key secondary endpoints was strongly controlled using a graphical multiple testing procedure starting with the primary endpoint using α/2 for each dose followed by a prespecified α transfer path.
    [60] - MMRM analysis including treatment, visit, treatment-by-visit interaction, current DMARD use (yes/no) as fixed factors 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 [61]
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR50 response criteria: - ≥ 50% improvement in 68-tender joint count; - ≥ 50% improvement in 66-swollen joint count; and - ≥ 50% improvement in at least 3 of the 5 following parameters: - Physician global assessment of disease activity - Patient global assessment of disease activity - Patient assessment of pain - Health Assessment Questionnaire - Disability Index (HAQ-DI) - High-sensitivity C-reactive protein (hsCRP). Analysis Population Description: Full analysis set; 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
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    211 [62]
    218 [63]
    212 [64]
    Units: percentage of participants
        number (confidence interval 95%)
    31.8 (25.5 to 38.0)
    37.6 (31.2 to 44.0)
    4.7 (1.9 to 7.6)
    Notes
    [62] - Full analysis set
    [63] - Full analysis set
    [64] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [65]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.1
         upper limit
    		 33.9
    Notes
    [65] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [66]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.9
         upper limit
    		 39.9
    Notes
    [66] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

    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 [67]
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR70 response criteria: - ≥ 70% improvement in 68-tender joint count; - ≥ 70% improvement in 66-swollen joint count; and - ≥ 70% improvement in at least 3 of the 5 following parameters: - Physician global assessment of disease activity - Patient global assessment of disease activity - Patient assessment of pain - Health Assessment Questionnaire - Disability Index (HAQ-DI) - High-sensitivity C-reactive protein (hsCRP). Analysis Population Description: Full analysis set; 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
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    211 [68]
    218 [69]
    212 [70]
    Units: percentage of participants
        number (confidence interval 95%)
    8.5 (4.8 to 12.3)
    16.5 (11.6 to 21.4)
    0.5 (0.0 to 1.4)
    Notes
    [68] - Full analysis set
    [69] - Full analysis set
    [70] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [71]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 11.9
    Notes
    [71] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [72]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11
         upper limit
    		 21.1
    Notes
    [72] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

    Secondary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 2

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    End point title
    		 Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 2 [73]
    End point description
    Participants who met the following 3 conditions for improvement from Baseline were classified as meeting the ACR20 response criteria: - ≥ 20% improvement in 68-tender joint count; - ≥ 20% improvement in 66-swollen joint count; and - ≥ 20% improvement in at least 3 of the 5 following parameters: - Physician global assessment of disease activity - Patient global assessment of disease activity - Patient assessment of pain - Health Assessment Questionnaire - Disability Index (HAQ-DI) - High-sensitivity C-reactive protein (hsCRP). Analysis Population Description: Full analysis set; participants who prematurely discontinued from study drug prior to Week 2 or for whom ACR data were missing at Week 2 were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2
    Notes
    [73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses are reported as planned in the protocol/SAP.
    End point values
    		 Upadacitinib 15 mg Upadacitinib 30 mg Placebo (Pooled Week 1 - Week 24)
    Number of subjects analysed
    211 [74]
    218 [75]
    212 [76]
    Units: percentage of participants
        number (confidence interval 95%)
    32.7 (26.4 to 39.0)
    33.5 (27.2 to 39.8)
    10.8 (6.7 to 15.0)
    Notes
    [74] - Full analysis set
    [75] - Full analysis set
    [76] - Full analysis set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Upadacitinib 15 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [77]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    21.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.3
         upper limit
    		 29.4
    Notes
    [77] - Cochran-Mantel-Haenszel test adjusting for the main stratification factor of current DMARD use (yes/no).
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Upadacitinib 30 mg v Placebo (Pooled Week 1 - Week 24)
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [78]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    22.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.1
         upper limit
    		 30.2
    Notes
    [78] - Cochran-Mantel-Haenszel (CMH) test adjusted for the main stratification factor of current DMARD use (yes/no).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and adverse event tables include events reported from enrollment to the end of the study (EOS).
    Adverse event reporting additional description
    The median time subjects were followed ranged from 190 to 415 days (Period 1) and 672 to 712 days (Period 2). Subjects receiving Upadacitinib 30 mg once daily (QD) were switched to Upadacitinib 15 mg QD during Period 2. Following the switch, adverse events for these subjects were pooled to EOS (median follow-up = 223 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Period 1: Upadacitinib 15mg (ICF to Week 56)
    Reporting group description
    		 Participants randomized to receive Upadacitinib 15 mg once daily to Week 56.

    Reporting group title
    Period 1: Upadacitinib 30mg (ICF to Week 56)
    Reporting group description
    		 Participants randomized to receive Upadacitinib 30 mg once daily to Week 56.

    Reporting group title
    Period 1: Pooled Placebo (ICF to Week 24)
    Reporting group description
    		 This group includes all participants in Period 1 who were randomized to receive Placebo to Week 24.

    Reporting group title
    Period 1: Placebo / Upadacitinib 15mg (Week 24 to Week 56)
    Reporting group description
    		 Participants were randomized to receive placebo once daily for 24 weeks followed by Upadacitinib 15 mg once daily to Week 56. AEs in this group were reported while participants received 15 mg Upadacitinib between Week 24 to Week 56.

    Reporting group title
    Period 1: Placebo / Upadacitinib 30mg (Week 24 to Week 56)
    Reporting group description
    		 Participants weree randomized to receive placebo once daily for 24 weeks followed by Upadacitinib 30 mg once daily to Week 56. AEs in this group were reported while participants received 30 mg Upadacitinib between Week 24 to Week 56.

    Reporting group title
    Period 2: Upadacitinib 30mg (Week 56 to EOS)
    Reporting group description
    		 Participants randomized to receive Upadacitinib 30 mg once daily in Period 2 from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment.

    Reporting group title
    Period 2: Upadacitinib 15mg (Week 56 to EOS)
    Reporting group description
    		 Participants randomized to receive Upadacitinib 15 mg once daily in Period 2 from Week 56 to EOS.

    Reporting group title
    Period 2: Placebo / Upadacitinib 30mg (Week 56 to Week EOS)
    Reporting group description
    		 Participants from the Period 1 Placebo / Upadacitinib 30 mg group received 30 mg upadacitinib from Week 56 to EOS. Participants in this group were switched to upadacitinib 15mg QD during Period 2 after week 116, following a protocol amendment.

    Reporting group title
    Period 2: Placebo / Upadacitinib 15mg (Week 56 to Week EOS)
    Reporting group description
    		 Participants from the Period 1 Placebo / Upadacitinib 15 mg group received 15 mg upadacitinib from Week 56 to EOS.

    Reporting group title
    Period 2: Pooled Upadacitinib (Switched From 30mg to 15mg P2)
    Reporting group description
    		 All participants in Period 2 who switched from 30 mg to 15 mg Upadacitinib to EOS during Period 2. This group includes all participants who received any upadacitinib 30 mg in Period 2 and switched dose to upadacitinib 15 mg once daily during Period 2 (following a protocol amendment, after week 116). The AEs in this group were reported while participants received 15 mg upadacitinib once daily.

    Serious adverse events
    		 Period 1: Upadacitinib 15mg (ICF to Week 56) Period 1: Upadacitinib 30mg (ICF to Week 56) Period 1: Pooled Placebo (ICF to Week 24) Period 1: Placebo / Upadacitinib 15mg (Week 24 to Week 56) Period 1: Placebo / Upadacitinib 30mg (Week 24 to Week 56) Period 2: Upadacitinib 30mg (Week 56 to EOS) Period 2: Upadacitinib 15mg (Week 56 to EOS) Period 2: Placebo / Upadacitinib 30mg (Week 56 to Week EOS) Period 2: Placebo / Upadacitinib 15mg (Week 56 to Week EOS) Period 2: Pooled Upadacitinib (Switched From 30mg to 15mg P2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 211 (10.43%)
    25 / 219 (11.42%)
    5 / 212 (2.36%)
    3 / 79 (3.80%)
    6 / 90 (6.67%)
    18 / 165 (10.91%)
    24 / 167 (14.37%)
    12 / 77 (15.58%)
    7 / 69 (10.14%)
    5 / 87 (5.75%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
    5
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANOGENITAL WARTS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL CANCER METASTATIC
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRADUCTAL PAPILLARY BREAST NEOPLASM
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL CARCINOMA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA STAGE III
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUROENDOCRINE CARCINOMA OF THE SKIN
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    OVARIAN CANCER
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OROPHARYNGEAL SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OVARIAN THECA CELL TUMOUR
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PARATHYROID TUMOUR BENIGN
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    ABORTION SPONTANEOUS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ECTOPIC PREGNANCY
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    CERVICAL DYSPLASIA
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMOTHORAX
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    DISORIENTATION
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    DEVICE DISLOCATION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CERVICAL VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKULL FRACTURED BASE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL BILE LEAK
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRAUMATIC HAEMOTHORAX
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AORTIC VALVE STENOSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    2 / 167 (1.20%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    1 / 79 (1.27%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR FIBRILLATION
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    BRAIN OEDEMA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CAROTID ARTERY INSUFFICIENCY
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERALISED TONIC-CLONIC SEIZURE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FACIAL PARALYSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPEECH DISORDER
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT GLOBAL AMNESIA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    BLOOD LOSS ANAEMIA
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Eye disorders
    RETINAL DETACHMENT
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINE ULCER
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SUBCUTANEOUS EMPHYSEMA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    2 / 211 (0.95%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    GOITRE
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYSTEMIC LUPUS ERYTHEMATOSUS
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RAPIDLY PROGRESSIVE OSTEOARTHRITIS
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PSORIATIC ARTHROPATHY
         subjects affected / exposed
    2 / 211 (0.95%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    2 / 167 (1.20%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHIOLITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    1 / 79 (1.27%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    4 / 167 (2.40%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    BURSITIS INFECTIVE STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    2 / 165 (1.21%)
    1 / 167 (0.60%)
    2 / 77 (2.60%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    2 / 167 (1.20%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EXTRADURAL ABSCESS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LIVER ABSCESS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIV INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 211 (0.47%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA INFLUENZAL
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    3 / 211 (1.42%)
    3 / 219 (1.37%)
    0 / 212 (0.00%)
    1 / 79 (1.27%)
    0 / 90 (0.00%)
    2 / 165 (1.21%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    1 / 79 (1.27%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    1 / 167 (0.60%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METABOLIC ACIDOSIS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    0 / 165 (0.00%)
    0 / 167 (0.00%)
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TYPE 1 DIABETES MELLITUS
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    1 / 165 (0.61%)
    0 / 167 (0.00%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Period 1: Upadacitinib 15mg (ICF to Week 56) Period 1: Upadacitinib 30mg (ICF to Week 56) Period 1: Pooled Placebo (ICF to Week 24) Period 1: Placebo / Upadacitinib 15mg (Week 24 to Week 56) Period 1: Placebo / Upadacitinib 30mg (Week 24 to Week 56) Period 2: Upadacitinib 30mg (Week 56 to EOS) Period 2: Upadacitinib 15mg (Week 56 to EOS) Period 2: Placebo / Upadacitinib 30mg (Week 56 to Week EOS) Period 2: Placebo / Upadacitinib 15mg (Week 56 to Week EOS) Period 2: Pooled Upadacitinib (Switched From 30mg to 15mg P2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 211 (52.61%)
    139 / 219 (63.47%)
    87 / 212 (41.04%)
    32 / 79 (40.51%)
    34 / 90 (37.78%)
    97 / 165 (58.79%)
    110 / 167 (65.87%)
    49 / 77 (63.64%)
    40 / 69 (57.97%)
    34 / 87 (39.08%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 211 (2.37%)
    11 / 219 (5.02%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    4 / 90 (4.44%)
    6 / 165 (3.64%)
    6 / 167 (3.59%)
    2 / 77 (2.60%)
    3 / 69 (4.35%)
    0 / 87 (0.00%)
         occurrences all number
    5
    13
    1
    0
    4
    6
    7
    2
    3
    0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    9 / 211 (4.27%)
    22 / 219 (10.05%)
    4 / 212 (1.89%)
    2 / 79 (2.53%)
    4 / 90 (4.44%)
    8 / 165 (4.85%)
    13 / 167 (7.78%)
    6 / 77 (7.79%)
    5 / 69 (7.25%)
    2 / 87 (2.30%)
         occurrences all number
    10
    29
    4
    3
    5
    8
    15
    7
    5
    2
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    8 / 211 (3.79%)
    10 / 219 (4.57%)
    10 / 212 (4.72%)
    4 / 79 (5.06%)
    3 / 90 (3.33%)
    11 / 165 (6.67%)
    19 / 167 (11.38%)
    7 / 77 (9.09%)
    5 / 69 (7.25%)
    1 / 87 (1.15%)
         occurrences all number
    9
    10
    12
    4
    3
    11
    20
    8
    5
    1
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    8 / 211 (3.79%)
    15 / 219 (6.85%)
    12 / 212 (5.66%)
    3 / 79 (3.80%)
    3 / 90 (3.33%)
    4 / 165 (2.42%)
    5 / 167 (2.99%)
    2 / 77 (2.60%)
    1 / 69 (1.45%)
    4 / 87 (4.60%)
         occurrences all number
    8
    18
    13
    4
    3
    7
    5
    2
    1
    4
    NAUSEA
         subjects affected / exposed
    8 / 211 (3.79%)
    12 / 219 (5.48%)
    7 / 212 (3.30%)
    0 / 79 (0.00%)
    1 / 90 (1.11%)
    10 / 165 (6.06%)
    4 / 167 (2.40%)
    0 / 77 (0.00%)
    0 / 69 (0.00%)
    1 / 87 (1.15%)
         occurrences all number
    8
    12
    8
    0
    1
    10
    5
    0
    0
    1
    Hepatobiliary disorders
    HEPATIC STEATOSIS
         subjects affected / exposed
    1 / 211 (0.47%)
    3 / 219 (1.37%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    3 / 165 (1.82%)
    5 / 167 (2.99%)
    5 / 77 (6.49%)
    1 / 69 (1.45%)
    1 / 87 (1.15%)
         occurrences all number
    1
    3
    1
    0
    0
    3
    5
    5
    1
    1
    Musculoskeletal and connective tissue disorders
    PSORIATIC ARTHROPATHY
         subjects affected / exposed
    13 / 211 (6.16%)
    7 / 219 (3.20%)
    11 / 212 (5.19%)
    2 / 79 (2.53%)
    3 / 90 (3.33%)
    16 / 165 (9.70%)
    11 / 167 (6.59%)
    8 / 77 (10.39%)
    9 / 69 (13.04%)
    8 / 87 (9.20%)
         occurrences all number
    14
    8
    12
    2
    3
    18
    14
    8
    9
    8
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    17 / 211 (8.06%)
    15 / 219 (6.85%)
    5 / 212 (2.36%)
    5 / 79 (6.33%)
    4 / 90 (4.44%)
    8 / 165 (4.85%)
    15 / 167 (8.98%)
    4 / 77 (5.19%)
    4 / 69 (5.80%)
    2 / 87 (2.30%)
         occurrences all number
    20
    16
    5
    7
    4
    10
    17
    5
    4
    2
    COVID-19
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 219 (0.00%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    12 / 165 (7.27%)
    22 / 167 (13.17%)
    7 / 77 (9.09%)
    7 / 69 (10.14%)
    14 / 87 (16.09%)
         occurrences all number
    0
    0
    0
    0
    0
    12
    22
    7
    7
    17
    HERPES ZOSTER
         subjects affected / exposed
    8 / 211 (3.79%)
    13 / 219 (5.94%)
    2 / 212 (0.94%)
    2 / 79 (2.53%)
    5 / 90 (5.56%)
    13 / 165 (7.88%)
    10 / 167 (5.99%)
    5 / 77 (6.49%)
    3 / 69 (4.35%)
    1 / 87 (1.15%)
         occurrences all number
    8
    13
    2
    2
    5
    13
    10
    5
    3
    1
    INFLUENZA
         subjects affected / exposed
    14 / 211 (6.64%)
    13 / 219 (5.94%)
    3 / 212 (1.42%)
    2 / 79 (2.53%)
    2 / 90 (2.22%)
    6 / 165 (3.64%)
    3 / 167 (1.80%)
    1 / 77 (1.30%)
    2 / 69 (2.90%)
    0 / 87 (0.00%)
         occurrences all number
    16
    14
    3
    2
    3
    6
    4
    1
    2
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    24 / 211 (11.37%)
    29 / 219 (13.24%)
    17 / 212 (8.02%)
    5 / 79 (6.33%)
    6 / 90 (6.67%)
    11 / 165 (6.67%)
    14 / 167 (8.38%)
    6 / 77 (7.79%)
    7 / 69 (10.14%)
    5 / 87 (5.75%)
         occurrences all number
    29
    34
    18
    5
    8
    12
    17
    6
    8
    6
    PNEUMONIA
         subjects affected / exposed
    1 / 211 (0.47%)
    4 / 219 (1.83%)
    3 / 212 (1.42%)
    2 / 79 (2.53%)
    0 / 90 (0.00%)
    4 / 165 (2.42%)
    2 / 167 (1.20%)
    4 / 77 (5.19%)
    1 / 69 (1.45%)
    1 / 87 (1.15%)
         occurrences all number
    1
    4
    3
    2
    0
    5
    2
    6
    1
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    22 / 211 (10.43%)
    29 / 219 (13.24%)
    10 / 212 (4.72%)
    6 / 79 (7.59%)
    2 / 90 (2.22%)
    9 / 165 (5.45%)
    15 / 167 (8.98%)
    6 / 77 (7.79%)
    4 / 69 (5.80%)
    3 / 87 (3.45%)
         occurrences all number
    27
    34
    13
    7
    2
    13
    15
    7
    4
    3
    TOOTH INFECTION
         subjects affected / exposed
    3 / 211 (1.42%)
    3 / 219 (1.37%)
    1 / 212 (0.47%)
    0 / 79 (0.00%)
    2 / 90 (2.22%)
    4 / 165 (2.42%)
    2 / 167 (1.20%)
    0 / 77 (0.00%)
    4 / 69 (5.80%)
    0 / 87 (0.00%)
         occurrences all number
    3
    4
    1
    0
    2
    4
    2
    0
    4
    0
    SINUSITIS
         subjects affected / exposed
    8 / 211 (3.79%)
    9 / 219 (4.11%)
    9 / 212 (4.25%)
    3 / 79 (3.80%)
    2 / 90 (2.22%)
    7 / 165 (4.24%)
    7 / 167 (4.19%)
    6 / 77 (7.79%)
    2 / 69 (2.90%)
    0 / 87 (0.00%)
         occurrences all number
    9
    10
    11
    4
    2
    7
    9
    8
    4
    0
    URINARY TRACT INFECTION
         subjects affected / exposed
    19 / 211 (9.00%)
    16 / 219 (7.31%)
    12 / 212 (5.66%)
    4 / 79 (5.06%)
    4 / 90 (4.44%)
    14 / 165 (8.48%)
    17 / 167 (10.18%)
    9 / 77 (11.69%)
    8 / 69 (11.59%)
    3 / 87 (3.45%)
         occurrences all number
    24
    18
    14
    4
    4
    22
    24
    12
    11
    3
    Metabolism and nutrition disorders
    DYSLIPIDAEMIA
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 219 (0.46%)
    0 / 212 (0.00%)
    0 / 79 (0.00%)
    0 / 90 (0.00%)
    4 / 165 (2.42%)
    2 / 167 (1.20%)
    4 / 77 (5.19%)
    1 / 69 (1.45%)
    0 / 87 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    4
    2
    4
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2017
    Amendment 1: The protocol amendment includes various updates focused on enhancing subject safety, ensuring adherence to local guidelines, and improving communication. Key updates are: Contact Information: The Title Page now contains updated Sponsor/Emergency Contact fax numbers with country codes, providing sites with current and complete contact information. Safety Enhancements: The Inclusion Criteria, Exclusion Criteria, and Prohibited Therapies sections are revised to enhance subject safety during the study. Hepatitis Screening Compliance: Updates to relevant sections ensure that subjects in Japan with positive HBs Ab+ and/or HBc Ab+ at Screening undergo required testing per local guidelines. Adverse Event Reporting: The Serious Adverse Event and Malignancy Reporting section is updated to include country codes in the contact numbers for the Immunology Safety Team and Therapeutic Area Medical Director, aiding clear communication during emergencies. Study Activities Table: Appendix C revisions ensure: Correct footnotes for FSH testing; Accurate completion timing for subject questionnaires at Week 2; Annual frequency of activities noted in footnotes; Necessary testing for Japanese subjects with certain hepatitis markers per footnote. These amendments aim to maintain thorough and consistent communication across study sites, enhance participant safety, and adhere to locale-specific guidelines, ensuring efficient and compliant study operation.
    03 Mar 2017
    Amendment 2: This protocol amendment includes updates focused on enhancing subject safety, improving clarity, and removing redundant information. Key updates are: Subject Safety Improvements: Section 1.2 (Synopsis), Section 5.1 (Overall Study Design and Plan), and Table 2 (Clinical Laboratory Tests) have been revised to enhance safety measures for participants. The Inclusion Criteria in Section 5.2.1 are updated to further ensure subject safety. Removal of Redundancies: Duplicate information has been removed from the Exclusion Criteria in Section 5.2.2, streamlining the protocol. Clarifications: Footnote "h" in Table 2 and footnote "s" in Appendix C have been updated to clarify the reporting period for protocol deviations. Section 9.3 (Subject Information and Consent) now provides clearer procedures on subject withdrawal concerning optional exploratory samples. Overall, these amendments aim to maintain high safety standards, ensure precise procedural guidance, and create a more efficient and clear protocol for study conduct.
    07 Jul 2017
    Amendment 3: The amendment outlines updates focusing on clarifications, error corrections, methodological adjustments, and modifications in criteria. Key changes include: Title Page and Synopsis: Added the generic name of ABT-494 and corrected typos. Clarified the sponsor's role and enrollment criteria. Methodology Changes: Adjustments were made to allow the addition or modification of non-biologic DMARDs and oral corticosteroids. Non-responder criteria for rescue therapy and discontinuation were clarified. Exclusion and Safety Criteria: Added details on HBV testing requirements based on local regulations and updated safety information. Certain medical conditions previously listed as exclusions have been clarified or removed. Therapy and Drug Guidelines: Provided updates to permitted and prohibited therapies, including allowances for the modification of some medications and clarifications on live vaccine prohibition. Contraception Recommendations: Clarified requirements for contraception, particularly concerning surgically sterile or post-menopausal women, and updates regarding vasectomized partners. Study Procedures: Clarified procedures like informed consent, physical exams, pregnancy tests, and TB testing. Adjusted guidelines for ECGs and CXR assessments. Adverse Events and Toxicity Management: Updated classifications and management guidelines for adverse events and toxicity, including the handling of gastrointestinal events and ECG abnormalities. Study Activities and Appendices: Revised the timeframe and details for follow-up visits. Removed an outdated appendix and updated local requirement guidelines. These updates aim to enhance the study's clarity, ensure regulatory compliance, and improve participant safety and protocol adherence.
    23 Mar 2018
    Amendment 4: This protocol amendment includes administrative updates to enhance consistency, readability, and clarity. Sponsor information for non-EU countries is updated on the title page, and the emergency contact number is prominently added. Stratification will be based on the number of prior biologics a subject has failed. Inclusion criteria changes include shortening washout periods for certain drugs to reduce flare rates and removing male contraception requirements due to new studies showing upadacitinib poses no reproductive risk for males. Exclusion criteria adjustments permit enrollment in non-interventional studies and refine conditions around organ transplant histories, psoriasis treatments, and pregnancy post-study drug use. Study methodologies for TB testing and hepatitis screening are updated for consistency with safety standards, including specific PCR testing guidelines. Adverse event classifications are revised, removing subtypes of malignancies and adding embolic and thrombotic events. Contraception guidelines for males are updated based on new data showing no reproductive effects from upadacitinib. Sections on therapy options provide clarity: permitted changes in background DMARDs are preferred but not mandatory, responding flexibly to subject safety needs. Randomization methods emphasize stratification based on prior biologics. Adverse event severity grading is specified for investigators, with updated management for AST and ALT abnormalities and HBV testing procedures to manage potential reactivation risks. Further revisions include updated guidelines for protocol signatories, study activities related to TB, requirements for specific testing, and the prohibition of certain therapies. The revisions reflect efforts to align the protocol with current findings and maintain participant safety throughout the study.
    14 Jan 2019
    Amendment 5: This amendment to the clinical study protocol includes administrative and methodological updates aimed at enhancing consistency and clarity. Key updates involve defining stratification enrollment limits based on psoriasis involvement and prior biologic DMARD failures. These limits ensure a balanced study population, similar to past studies, and sufficiently power skin-related efficacy endpoints without altering study conduct or analysis. Key sections revised include the overall study design and discontinuation criteria to improve clarity. Male contraception requirements are removed, aligning with previous amendments, thereby eliminating the need to discuss pregnancy avoidance for female partners of male subjects. TB testing procedures are updated to allow retesting of QuantiFERON-TB Gold in low-risk subjects both initially and annually, and IGRA blood tests are now permitted for TB screening. Language across clinical laboratory tests is clarified for consistency with toxicity management guidelines. Randomization and drug assignment updates specify stratification limits, ensuring a comparative and balanced study population. Drug accountability requirements are aligned with revised sponsor guidelines. Serious adverse event reporting is refined to exclude USA-specific SUSAR references, applicable only to EU countries. Table 4 updates specify that ALT/AST toxicity-related symptoms must be new from baseline, with appropriate eCRFs provided for hepatic and renal situations. Protocol deviations include address updates, and Appendix changes reflect updates to protocol signatories and study activities, ensuring alignment across sections. Overall, these amendments streamline protocol management while maintaining focus on study integrity and participant safety.
    04 Oct 2019
    Amendment 6: This amendment involves numerous updates to the clinical study protocol, aimed at enhancing clarity, consistency, and accuracy. Key changes include: Administrative Revisions: Improved consistency and readability across the protocol, correcting descriptions of key terms and adding definitions such as PsO. Updates include adjustments in the efficacy section for FACIT-F and PsARC descriptions. Risk and Safety Updates: Updated safety information covers thromboembolic events and embryofetal effects, with toxicity management guidelines adding herpes zoster, skin cancer screening, and thrombosis considerations in line with Rinvoq® labeling. Procedural Adjustments: Changes in study procedures detail the removal of unnecessary ECG monitoring requirements, clarify who needs annual chest X-rays, and refine TB prophylaxis initiation processes. Prohibited therapy terminology is updated to reflect common usage (rifampicin for rifampin). Subjects may request withdrawal from both study drug or the study. Study Design and Variable Clarifications: Adjustments to secondary and additional efficacy variables align with new data, ensuring accurate reflections in sections on key secondary variables. Multiplicity control methods are revised for endpoint evaluations. Adverse Event Criteria: Specifies using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version for adverse event severity. Laboratory data analysis now uses CTCAE grades rather than simple categories. Appendices and Signatory Updates: Protocol signatories are updated, and study activities clarify requirements for specific tests and evaluations during follow-ups. Overall, these changes ensure the study protocol is up-to-date with current safety and efficacy standards while providing clear guidelines for subject management and data analysis, maintaining the integrity and reliability of study outcomes.
    01 Apr 2020
    Amendment 7: This amendment involves several updates to enhance protocol clarity, subject safety, and consistency: Administrative Updates: Text revisions enhance consistency and readability throughout the protocol. Safety Information: Updated information regarding risk of pregnancy for female partners of male subjects. Permitted Therapy: Section 5.2.3.2 is updated to ensure oral corticosteroid doses do not exceed prednisone ≤ 10 mg/day, per inclusion criteria. Hepatitis Screening: Clarifications in Section 5.3.1.1 allow HBV DNA PCR testing at unscheduled visits where mandated every 12 weeks. Similar updates apply to Figure 2's footnote. Subject Discontinuation and Safety Precautions: Section 5.4.1 clarifies that gastrointestinal perforations from appendicitis or mechanical injury do not require study drug discontinuation. It also adds precautions due to thrombotic risks associated with the JAK inhibitor class. Drug Accountability: Section 5.5.7 notes that drug receipt verification is through IRT systems, eliminating paper records. Toxicity Management: Updates in Section 6.1.7 clarify handling gastrointestinal perforations and add thrombotic risk precautions. It specifies additional eCRFs for certain lab abnormalities. Toxicity Guidelines: Table 4 updates provide clearer guidelines on managing laboratory value abnormalities to ensure subject safety. Cardiovascular Assessment: Section 6.1.9 clarifies that the Cardiovascular Adjudication Committee evaluates embolic and thrombotic adverse events. Protocol Signatories and Activities: Appendix B sees a title update, while Appendix C removes 'X' marks for Week 12 and 24 to clarify Hepatitis B testing applicability for Japan or where required. Footnotes clarify unscheduled HBV DNA PCR testing permissions. These amendments aim to improve the study's procedural clarity and ensure ongoing participant safety in light of new insights and regulatory mandates.
    29 Jan 2021
    Amendment 8: The protocol amendment includes administrative changes to improve consistency and clarity, replacing "ABT-494" with "upadacitinib" as the drug's generic name. Subjects on upadacitinib 30 mg daily now shift to 15 mg daily in Period 2 following approval, deemed optimal for active psoriatic arthritis and proposed for global marketing. Updates provide flexibility for study procedures amid emergencies/pandemics, allowing study visits via phone/week and subject/caregiver assessments. Vital signs, weight, physical exams, chest X-rays (CXR), and TB tests adapt to emergencies. If TB test seroconversion occurs without risk factors, CXR should follow ASAP; investigators consult AbbVie TA MD regarding continued drug use. Local labs ensure safety during emergencies. Direct-to-patient drug shipment aids compliance. Patient questionnaires and case report forms include phone interviews to gather patient-reported outcomes (PRO) during emergencies. Gastrointestinal perforation definition changes, with added toxicity management guidelines for COVID-19 suspicions to direct study drug interruption and data collection. AST/ALT guidelines are revised. Dose change impacts are noted in the Statistical Analysis Plan (SAP). Ethical study conduct adapts for protocol-specific hurdles and allows verbal consent for substantial study changes in emergencies. Remote monitoring is enabled; vendors and protocol signatories updated. COVID-19 impacts require supplemental case report forms and specific event data collection. Clarified that subjects should complete a discontinuation visit preferably prior to initiation of another therapy. Overall, these amendments boost protocol consistency, flexibility, safety, and response adaptivity during emergencies/pandemics, ensuring ethical and effective study management.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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