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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis

    Summary
    EudraCT number
    2016-000641-31
    Trial protocol
    SK   NL   FI   HU   CZ   SE   PL   IE   PT   DE   LV   LT   AT   GR   BE   EE   NO   ES   GB   FR   HR   RO  
    Global end of trial date
    13 Dec 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jun 2022
    First version publication date
    19 Jun 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    M14-234
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02819635
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was comprised of three substudies. Substudy 1 (SS1) was a Phase 2b dose-ranging study designed to evaluate the efficacy and safety of different doses of UPA (7.5, 15, 30, and 45 mg) compared to placebo as 8-week induction therapy in subjects with moderately to severely active ulcerative colitis (UC). Substudy 2 (SS2) was a two-part Phase 3 dose-confirming study designed to evaluate the efficacy and safety of oral administration of UPA 45 mg compared to placebo as induction therapy for up to 16 weeks in subjects with moderately to severely active UC. Substudy 3 (SS3) was a Phase 3 maintenance study designed to evaluate the efficacy and safety of UPA 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in subjects with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from SS1, SS2, or Study M14-675 (NCT03653026).
    Protection of trial subjects
    The investigator or his/her representative explained the nature of the study to the subject and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was to be reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. For US subjects: at Week 8 or Week 16 (Substudy 1 or 2 or Study M14-675), subjects who will continue into Substudy 3 were to sign and date a study specific Independent Ethics Committee/Institutional Review Board (IEC/IRB) approved Informed Consent Form before Substudy 3 procedures are performed. For adolescent subjects, the investigator or his/her representative explained the nature of the study and optional exploratory research samples to the subject and the subject's parent/legal guardian and answered all questions regarding this study. Adolescent subjects were to be included in all discussions in order to obtain verbal or written assent. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was to be reviewed, signed and dated by the subject's parent/legal guardian, the person who administered the informed consent, and any other signatories according to local requirements. Additionally, in keeping with each institution's IRB/IEC requirements, an informed assent form may also have been obtained by each subject prior to any study-related procedures being performed. If a subject attained legal age during the course of the study, that subject was to be re-consented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 4
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Canada: 114
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    China: 40
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Estonia: 24
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 63
    Country: Number of subjects enrolled
    Japan: 198
    Country: Number of subjects enrolled
    Korea, Republic of: 36
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Malaysia: 6
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 25
    Country: Number of subjects enrolled
    Norway: 29
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Portugal: 14
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Serbia: 31
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Slovakia: 16
    Country: Number of subjects enrolled
    South Africa: 35
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Switzerland: 34
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 273
    Worldwide total number of subjects
    1302
    EEA total number of subjects
    365
    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)
    6
    Adults (18-64 years)
    1183
    From 65 to 84 years
    113
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Intent-to-treat (ITT): Substudy 1 (randomized subjects who rcvd at least 1 dose of study drug in Substudy 1); Substudy 2 (randomized subjects who rcvd at least 1 dose of double-blinded study drug in Part 1 and those who rcvd at least 1 dose of upadacitinib 45 mg in Part 2); Substudy 3 (subjects who rcvd at least 1 dose of study drug in Substudy 3)

    Period 1
    Period 1 title
    Substudy 1 and Substudy 2, Part 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SS1: Placebo
    Arm description
    During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Arm title
    SS1: Upadacitinib 7.5 mg
    Arm description
    During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Arm title
    SS1: Upadacitinib 15 mg
    Arm description
    During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Arm title
    SS1: Upadacitinib 30 mg
    Arm description
    During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks during the Induction Phase. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Arm title
    SS1: Upadacitinib 45 mg
    Arm description
    During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks during the Induction Phase. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Arm title
    SS2: Placebo/Upadacitinib 45 mg
    Arm description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Arm title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Arm description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Arm title
    SS3: M14-675 Clinical Responders
    Arm description
    Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that\ study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were re-randomized and treated with placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were re-randomized and treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD for up to 52 weeks.

    Number of subjects in period 1
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg SS2: Placebo/Upadacitinib 45 mg SS2: Upadacitinib 45 mg/Upadacitinib 45 mg SS3: M14-675 Clinical Responders
    Started
    46
    47
    49
    117
    123
    155
    319
    446
    Completed
    41
    45
    45
    105
    113
    135
    306
    446
    Not completed
    5
    2
    4
    12
    10
    20
    13
    0
         COVID-19 Logistical Restrictions
    -
    -
    -
    -
    -
    -
    1
    -
         Other, not specified
    2
    1
    1
    7
    5
    7
    3
    -
         Withdrew consent
    -
    -
    -
    -
    1
    3
    2
    -
         Adverse event, non-fatal
    3
    1
    3
    5
    4
    9
    6
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    1
    -
    Period 2
    Period 2 title
    Substudy 3
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SS3: Placebo
    Arm description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo QD in Substudy 3 for up to 52 weeks.

    Arm title
    SS3: UPA 7.5 mg
    Arm description
    Participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3 for up to 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

    Arm title
    SS3: UPA 15 mg
    Arm description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

    Arm title
    SS3: UPA 30 mg
    Arm description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for up to 52 weeks.

    Number of subjects in period 2 [1]
    SS3: Placebo SS3: UPA 7.5 mg SS3: UPA 15 mg SS3: UPA 30 mg
    Started
    386
    20
    324
    316
    Completed
    140
    11
    218
    248
    Not completed
    246
    9
    106
    68
         COVID-19 Logistical Restrictions
    -
    -
    -
    1
         Other, not specified
    202
    5
    89
    39
         Withdrew consent
    11
    1
    4
    9
         Adverse event, non-fatal
    32
    3
    12
    18
         Lost to follow-up
    1
    -
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Substudy 3 was a Phase 3 maintenance study designed to evaluate the efficacy and safety of upadacitinib 15 and 30 mg once daily (QD) compared to placebo in achieving clinical remission per Adapted Mayo score in participants with moderately to severely active UC who achieved clinical response per Adapted Mayo score following induction therapy from Substudy 1, Substudy 2, or Study M14-675.
    Period 3
    Period 3 title
    Substudy 2, Part 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SS2: Placebo/Upadacitinib 45 mg
    Arm description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.

    Arm title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Arm description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    Other name
    ABT-494, RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.

    Number of subjects in period 3 [2]
    SS2: Placebo/Upadacitinib 45 mg SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Started
    85
    59
    Completed
    74
    47
    Not completed
    11
    12
         COVID-19 Logistical Restrictions
    -
    2
         Other, not specified
    4
    8
         Adverse event, non-fatal
    4
    -
         Withdrew consent
    3
    1
         Lost to follow-up
    -
    1
    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: Substudy 2 Part 2 was an open-label, 8-week extended treatment period for clinical non-responders from Part 1 of Substudy 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SS1: Placebo
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 7.5 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 15 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 30 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS1: Upadacitinib 45 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS2: Placebo/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS3: M14-675 Clinical Responders
    Reporting group description
    Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.

    Reporting group values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg SS2: Placebo/Upadacitinib 45 mg SS2: Upadacitinib 45 mg/Upadacitinib 45 mg SS3: M14-675 Clinical Responders Total
    Number of subjects
    46 47 49 117 123 155 319 446 1302
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.3 ± 13.29 41.7 ± 14.58 46.0 ± 13.58 42.9 ± 14.44 41.6 ± 14.19 44.3 ± 14.64 43.6 ± 14.04 42.1 ± 14.42 -
    Gender categorical
    Units: Subjects
        Female
    17 24 19 47 44 58 121 170 500
        Male
    29 23 30 70 79 97 198 276 802
    Race/Ethnicity
    Units: Subjects
        White
    37 36 38 88 90 101 206 302 898
        Black or African American
    0 3 1 3 2 4 12 15 40
        Asian
    8 7 10 23 28 46 95 124 341
        American Indian or Alaska Native
    0 0 0 1 0 2 0 1 4
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 1 1 2
        Multiple
    1 1 0 2 3 2 5 3 17
    Previous Biologic Use
    Units: Subjects
        Yes
    35 36 38 87 92 0 0 0 288
        No
    11 11 11 30 31 0 0 0 94
        Not recorded
    0 0 0 0 0 155 319 446 920
    Biologicinadequate Responder (BioIR) Status
    Biologic-inadequate responders (Bio-IR) are defined as participants who had inadequate response, loss of response, or intolerance to biologic therapy. Non-biologic-inadequate responders (non-bio-IR) are defined as participants who had inadequate response, loss of response, or intolerance to conventional therapy but had not failed biologic therapy.
    Units: Subjects
        Bio-IR
    0 0 0 0 0 79 168 221 468
        Non-Bio-IR
    0 0 0 0 0 76 151 225 452
        Not recorded
    46 47 49 117 123 0 0 0 382
    Baseline Corticosteroid Use
    Units: Subjects
        Yes
    26 24 27 51 53 62 124 173 540
        No
    20 23 22 66 70 93 195 273 762
    Average Stool Frequency Subscore
    Measure Description: Participants recorded stool frequency using an electronic subject diary on a daily basis. The stool frequency subscore (SFS) ranges from 0 to 3 according to the following scale: Score 0: Normal number of stools Score 1: 1 to 2 stools more than normal Score 2: 3 to 4 stools more than normal Score 3: 5 or more stools more than normal Participants with available data; Group 5 (n=122), Group 7 (n=318), Group 8 (n=445)
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.56 ± 0.667 2.62 ± 0.600 2.68 ± 0.565 2.61 ± 0.613 2.58 ± 0.648 2.52 ± 0.668 2.60 ± 0.624 2.55 ± 0.623 -
    Average Rectal Bleeding Subscore
    Participants recorded rectal bleeding in an electronic subject diary on a daily basis. The rectal bleeding subscore ranges from 0 to 3 according to the following scale: Score 0: No blood seen Score 1: Streaks of blood with stool less than half the time Score 2: Obvious blood with stool most of the time Score 3: Blood alone passed Participants with available data; Group 5 (n=122), Group 7 (n=318), Group 8 (n=445)
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.66 ± 1.034 1.61 ± 1.027 1.55 ± 0.915 1.51 ± 0.975 1.49 ± 0.960 1.76 ± 0.994 1.71 ± 1.046 1.77 ± 0.990 -
    Average Endoscopy Subscore
    Findings on endoscopy were scored according to the following: Score 0: Normal or inactive disease Score 1: Mild disease (erythema, decreased vascular pattern) Score 2: Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions) Score 3: Severe disease (spontaneous bleeding, ulceration)
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.8 ± 0.43 2.8 ± 0.40 2.8 ± 0.39 2.7 ± 0.47 2.7 ± 0.48 2.7 ± 0.47 2.7 ± 0.46 2.7 ± 0.47 -

    End points

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    End points reporting groups
    Reporting group title
    SS1: Placebo
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 7.5 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 15 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 30 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS1: Upadacitinib 45 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS2: Placebo/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS3: M14-675 Clinical Responders
    Reporting group description
    Participants in Study M14-675 (NCT03653026) who achieved clinical response defined by Adapted Mayo Score at Week 8 or Week 16 in that study and did not meet any study discontinuation criteria were eligible to enroll into Substudy 3. Participants were treated with a blinded treatment assignment (15 mg upadacitinib film-coated tablets once daily by mouth [QD], or 30 mg upadacitinib film-coated tablets QD, or placebo for upadacitinib film-coated tablets QD) for up to 52 weeks.
    Reporting group title
    SS3: Placebo
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.

    Reporting group title
    SS3: UPA 7.5 mg
    Reporting group description
    Participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3 for up to 52 weeks.

    Reporting group title
    SS3: UPA 15 mg
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.

    Reporting group title
    SS3: UPA 30 mg
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.
    Reporting group title
    SS2: Placebo/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.

    Reporting group title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks in Part 2 of the study.

    Subject analysis set title
    SS2: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Subject analysis set title
    SS2: Upadacitinib 45 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Subject analysis set title
    SS3: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at Week 8, while receiving upadacitinib 15, 30, or 45 mg QD and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.

    Subject analysis set title
    SS3: UPA 15 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at Week 8 while receiving upadacitinib 15, 30, or 45 mg QD and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks

    Subject analysis set title
    SS3: UPA 30 mg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at Week 8 while receiving upadacitinib 15, 30, or 45 mg QD and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks

    Primary: Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

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    End point title
    Substudy 1: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8 [1]
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 1, clinical remission is defined as SFS ≤ 1, RBS of 0, and endoscopic subscore ≤ 1.
    End point type
    Primary
    End point timeframe
    At Week 8
    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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [2]
    47 [3]
    49 [4]
    52 [5]
    56 [6]
    Units: percentage of participants
        number (not applicable)
    0
    8.5
    14.3
    13.5
    21.4
    Notes
    [2] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [3] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [4] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [5] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [6] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.049 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    8.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    16.8
    Notes
    [7] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [8] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.01 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    13.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.3
         upper limit
    23.8
    Notes
    [9] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [10] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.007 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    13.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.8
         upper limit
    23.9
    Notes
    [11] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [12] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    21.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.6
         upper limit
    33.6
    Notes
    [13] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [14] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Primary: Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 8
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal) 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed) 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration) The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 2, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In Substudy 2, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2. Participants were analyzed according to the treatment groups to which they were randomized.
    End point type
    Primary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [15]
    319 [16]
    Units: percentage of participants
        number (not applicable)
    4.8
    26.1
    Notes
    [15] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [16] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Upadacitinib 45 mg v SS2: Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    < 0.001 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    21.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.8
         upper limit
    27.4
    Notes
    [17] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [18] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes vs. no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Primary: Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52

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    End point title
    Substudy 3: Percentage Of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Week 52
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.
    End point type
    Primary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [19]
    148 [20]
    154 [21]
    Units: percentage of participants
        number (confidence interval 95%)
    12.1 (6.9 to 17.4)
    42.3 (34.3 to 50.3)
    51.7 (43.6 to 59.8)
    Notes
    [19] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [20] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [21] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    < 0.001 [23]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    30.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.7
         upper limit
    39.8
    Notes
    [22] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [23] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Baseline of Induction Study; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    < 0.001 [25]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.7
         upper limit
    48.2
    Notes
    [24] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [25] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Baseline of Induction Study; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8

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    End point title
    Substudy 1: Percentage Of Participants With Endoscopic Improvement at Week 8 [26]
    End point description
    Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [26] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [27]
    47 [28]
    49 [29]
    52 [30]
    56 [31]
    Units: percentage of participants
        number (not applicable)
    2.2
    14.9
    30.6
    26.9
    35.7
    Notes
    [27] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [28] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [29] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [30] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [31] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    P-value
    = 0.03 [33]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    13.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    25
    Notes
    [32] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [33] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [34]
    P-value
    < 0.001 [35]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    27.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.1
         upper limit
    42.1
    Notes
    [34] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [35] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    < 0.001 [37]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    26.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.3
         upper limit
    40.8
    Notes
    [36] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [37] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Upadacitinib 45 mg v SS1: Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    < 0.001 [39]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    35.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.2
         upper limit
    51.7
    Notes
    [38] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [39] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8

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    End point title
    Substudy 1: Percentage Of Participants Achieving Clinical Remission Per Full Mayo Score at Week 8 [40]
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1.
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [40] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [41]
    47 [42]
    49 [43]
    52 [44]
    56
    Units: percentage of participants
        number (not applicable)
    0
    10.6
    10.2
    11.5
    19.6
    Notes
    [41] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [42] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [43] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [44] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.021 [46]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.7
         upper limit
    20.4
    Notes
    [45] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [46] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    = 0.024 [48]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    9.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    18
    Notes
    [47] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [48] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [49]
    P-value
    = 0.015 [50]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    12.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.3
         upper limit
    22
    Notes
    [49] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [50] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [51]
    P-value
    = 0.001 [52]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    20.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8
         upper limit
    32.1
    Notes
    [51] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [52] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

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    End point title
    Substudy 1: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8 [53]
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [53] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [54]
    47 [55]
    49 [56]
    52 [57]
    56 [58]
    Units: percentage of participants
        number (not applicable)
    13.0
    29.8
    49.0
    46.2
    55.4
    Notes
    [54] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [55] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [56] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [57] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [58] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.038 [60]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    16.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    32.5
    Notes
    [59] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [60] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [61]
    P-value
    < 0.001 [62]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    35.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.5
         upper limit
    52.8
    Notes
    [61] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [62] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [63]
    P-value
    < 0.001 [64]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    33.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.3
         upper limit
    50.8
    Notes
    [63] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [64] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    < 0.001 [66]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    45.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    26.2
         upper limit
    63.9
    Notes
    [65] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [66] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

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    End point title
    Substudy 1: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2 [67]
    End point description
    The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
    End point type
    Secondary
    End point timeframe
    At Week 2
    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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [68]
    47 [69]
    49 [70]
    52 [71]
    56 [72]
    Units: percentage of participants
        number (not applicable)
    17.4
    23.4
    34.7
    36.5
    55.4
    Notes
    [68] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [69] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [70] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [71] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [72] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [73]
    P-value
    = 0.495 [74]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.1
         upper limit
    22.9
    Notes
    [73] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [74] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [75]
    P-value
    = 0.074 [76]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    15.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    33.4
    Notes
    [75] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [76] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    = 0.033 [78]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    19.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.6
         upper limit
    36.9
    Notes
    [77] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [78] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [79]
    P-value
    < 0.001 [80]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    40.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.5
         upper limit
    59.7
    Notes
    [79] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [80] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 1: Change in Full Mayo Score From Baseline to Week 8

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    End point title
    Substudy 1: Change in Full Mayo Score From Baseline to Week 8 [81]
    End point description
    The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy [confirmed by a central reader], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement. Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore > 1.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 8
    Notes
    [81] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    41 [82]
    43 [83]
    44 [84]
    44 [85]
    48 [86]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.741 ± 2.3302
    -2.870 ± 2.9685
    -3.589 ± 2.4984
    -4.211 ± 3.0886
    -4.606 ± 2.8976
    Notes
    [82] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
    [83] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
    [84] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
    [85] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
    [86] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; LOCF used for missing data
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority [87]
    P-value
    < 0.001 [88]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.142
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2323
         upper limit
    -1.052
    Notes
    [87] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [88] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    superiority [89]
    P-value
    < 0.001 [90]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.938
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.0284
         upper limit
    -1.8478
    Notes
    [89] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [90] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    superiority [91]
    P-value
    < 0.001 [92]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.736
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.8247
         upper limit
    -2.647
    Notes
    [91] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [92] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Upadacitinib 45 mg v SS1: Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority [93]
    P-value
    < 0.001 [94]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -4.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1252
         upper limit
    -2.9974
    Notes
    [93] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [94] - Stratified by previous biologic use, Baseline corticosteroid use, Baseline Adapted Mayo score (<= 7 and > 7)), and Baseline value as covariate.

    Secondary: Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8

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    End point title
    Substudy 1: Percentage Of Participants With Endoscopic Remission at Week 8 [95]
    End point description
    Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [95] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [96]
    47 [97]
    49 [98]
    52 [99]
    56 [100]
    Units: percentage of participants
        number (not applicable)
    0
    6.4
    4.1
    9.6
    17.9
    Notes
    [96] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [97] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [98] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [99] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [100] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [101]
    P-value
    = 0.075 [102]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    6.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    13.9
    Notes
    [101] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [102] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [103]
    P-value
    = 0.199 [104]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    9.6
    Notes
    [103] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [104] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [105]
    P-value
    = 0.015 [106]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    11.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.2
         upper limit
    20
    Notes
    [105] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [106] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [107]
    P-value
    = 0.004 [108]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    17.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.8
         upper limit
    29.9
    Notes
    [107] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [108] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

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    End point title
    Substudy 1: Percentage Of Participants Who Achieved Histologic Improvement at Week 8 [109]
    End point description
    The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score.
    End point type
    Secondary
    End point timeframe
    At Week 8
    Notes
    [109] - 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: This endpoint included Substudy 1, Part 1 participants.
    End point values
    SS1: Placebo SS1: Upadacitinib 7.5 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 30 mg SS1: Upadacitinib 45 mg
    Number of subjects analysed
    46 [110]
    47 [111]
    49 [112]
    52 [113]
    56 [114]
    Units: percentage of participants
        number (not applicable)
    6.5
    31.9
    51.0
    44.2
    48.2
    Notes
    [110] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [111] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [112] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [113] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    [114] - SS1 main subjects (ITT1A) randomized to ≥1 study drug dose during Pt 1; NRI used for missing values
    Statistical analysis title
    Substudy 1: Upadacitinib 7.5 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 7.5 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    superiority [115]
    P-value
    = 0.003 [116]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    25.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.9
         upper limit
    42.3
    Notes
    [115] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [116] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 15 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    superiority [117]
    P-value
    < 0.001 [118]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    43.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    25.4
         upper limit
    61.8
    Notes
    [117] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [118] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 30 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority [119]
    P-value
    < 0.001 [120]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    39.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.3
         upper limit
    57.5
    Notes
    [119] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [120] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)
    Statistical analysis title
    Substudy 1: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS1: Placebo v SS1: Upadacitinib 45 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority [121]
    P-value
    < 0.001 [122]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    43.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.4
         upper limit
    61.9
    Notes
    [121] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [122] - Stratified by previous biologic use, baseline corticosteroid use and baseline Adapted Mayo score (≤ 7 and > 7)

    Secondary: Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8

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    End point title
    Substudy 2: Percentage Of Participants With Endoscopic Improvement at Week 8
    End point description
    Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [123]
    319 [124]
    Units: percentage of participants
        number (confidence interval 95%)
    7.4 (3.2 to 11.5)
    36.3 (31.0 to 41.7)
    Notes
    [123] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [124] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [125]
    P-value
    < 0.001 [126]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    29.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    22.6
         upper limit
    35.9
    Notes
    [125] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [126] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8

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    End point title
    Substudy 2: Percentage Of Participants With Endoscopic Remission at Week 8
    End point description
    Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [127]
    319 [128]
    Units: percentage of participants
        number (confidence interval 95%)
    1.3 (0.0 to 3.1)
    13.7 (9.9 to 17.6)
    Notes
    [127] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [128] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Upadacitinib 45 mg v SS2: Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [129]
    P-value
    < 0.001 [130]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    12.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.4
         upper limit
    17
    Notes
    [129] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [130] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Achieving Clinical Response Per Adapted Mayo Score at Week 8
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [131]
    319 [132]
    Units: percentage of participants
        number (confidence interval 95%)
    27.3 (20.2 to 34.3)
    72.6 (67.7 to 77.5)
    Notes
    [131] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [132] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [133]
    P-value
    < 0.001 [134]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    46.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    38.4
         upper limit
    54.2
    Notes
    [133] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [134] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2

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    End point title
    Substudy 2: Percentage Of Participants Achieving Clinical Response Per Partial Mayo Score at Week 2
    End point description
    The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). The overall Partial Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Mayo Score is defined as a decrease from Baseline ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.
    End point type
    Secondary
    End point timeframe
    At Week 2
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [135]
    319 [136]
    Units: percentage of participants
        number (confidence interval 95%)
    27.3 (20.2 to 34.3)
    60.1 (54.7 to 65.5)
    Notes
    [135] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [136] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [137]
    P-value
    < 0.001 [138]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    33.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.8
         upper limit
    41.8
    Notes
    [137] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [138] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8
    End point description
    Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [139]
    319 [140]
    Units: percentage of participants
        number (confidence interval 95%)
    6.6 (2.6 to 10.5)
    30.1 (25.0 to 35.1)
    Notes
    [139] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [140] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [141]
    P-value
    < 0.001 [142]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    23.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.5
         upper limit
    30
    Notes
    [141] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [142] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Who Report No Bowel Urgency at Week 8
    End point description
    Bowel urgency was assessed by participants in a subject diary completed once a day.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [143]
    319 [144]
    Units: percentage of participants
        number (confidence interval 95%)
    21.4 (14.9 to 27.9)
    48.4 (42.9 to 53.9)
    Notes
    [143] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [144] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [145]
    P-value
    < 0.001 [146]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    27.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.2
         upper limit
    35.6
    Notes
    [145] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [146] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Who Reported No Abdominal Pain at Week 8
    End point description
    Abdominal pain was assessed by participants in a subject diary completed once a day.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [147]
    319 [148]
    Units: percentage of participants
        number (confidence interval 95%)
    23.4 (16.7 to 30.1)
    46.6 (41.1 to 52.1)
    Notes
    [147] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [148] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [149]
    P-value
    < 0.001 [150]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    23.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.1
         upper limit
    32.1
    Notes
    [149] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [150] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8

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    End point title
    Substudy 2: Percentage Of Participants Who Achieved Histologic Improvement at Week 8
    End point description
    The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration. Histologic improvement was defined as decrease from baseline in Geboes score.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [151]
    319 [152]
    Units: percentage of participants
        number (confidence interval 95%)
    22.5 (15.9 to 29.1)
    55.0 (49.5 to 60.5)
    Notes
    [151] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [152] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [153]
    P-value
    < 0.001 [154]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    32.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.8
         upper limit
    40.7
    Notes
    [153] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [154] - Stratified by bio-IR status (bio-IR vs. non-bio-IR), Baseline corticosteroid use (yes or no) and Baseline Adapted Mayo score (≤ 7 vs. > 7)

    Secondary: Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8

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    End point title
    Substudy 2: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 8
    End point description
    The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 1 (worst) to 7 (best). The total score ranges from 32 to 224 with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    125 [155]
    292 [156]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    21.7 (16.03 to 27.28)
    55.3 (51.54 to 59.15)
    Notes
    [155] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
    [156] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority [157]
    P-value
    < 0.001 [158]
    Method
    Mixed-effect model repeated measurement
    Parameter type
    LS Mean Difference
    Point estimate
    33.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.02
         upper limit
    40.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.39
    Notes
    [157] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [158] - MMRM with Baseline, treatment, visit, treatment-by-visit interaction, and strata (Baseline Adapted Mayo score, corticosteroid use, and bio-IR status).

    Secondary: Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8

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    End point title
    Substudy 2: Percentage Of Participants With Mucosal Healing at Week 8
    End point description
    Mucosal healing is defined as an endoscopic score of 0 and Geboes score < 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    154 [159]
    319 [160]
    Units: percentage of participants
        number (confidence interval 95%)
    1.3 (0.0 to 3.1)
    10.7 (7.3 to 14.1)
    Notes
    [159] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    [160] - SS2 (ITT1): randomized to ≥1 dose of study drug during Pt 1. NRI with MI due to COVID-19 (NRI-C)
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    superiority [161]
    P-value
    < 0.001 [162]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    9.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.7
         upper limit
    13.7
    Notes
    [161] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [162] - Stratified by Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), and bio-IR status (bio-IR or non-bio-IR)

    Secondary: Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8

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    End point title
    Substudy 2: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 8
    End point description
    The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 8
    End point values
    SS2: Placebo SS2: Upadacitinib 45 mg
    Number of subjects analysed
    125 [163]
    291 [164]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    2.8 (1.23 to 4.44)
    9.5 (8.44 to 10.61)
    Notes
    [163] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
    [164] - SS2 ITT1 w/ available data; MMRM anal; data after occurrence of UC-related corticosteroids event exc
    Statistical analysis title
    Substudy 2: Upadacitinib 45 mg vs Placebo
    Comparison groups
    SS2: Placebo v SS2: Upadacitinib 45 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    superiority [165]
    P-value
    < 0.001 [166]
    Method
    Mixed-effect model repeated measurement
    Parameter type
    LS Mean Difference
    Point estimate
    6.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.79
         upper limit
    8.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.97
    Notes
    [165] - The primary and ranked secondary efficacy endpoints were tested with multiplicity adjustment using a fixed-sequence multiple testing procedure to ensure a strong control of family-wise type I error rate at significance level alpha = 0.05 (2-sided).
    [166] - MMRM with Baseline, treatment, visit, treatment-by-visit interaction, and strata (Baseline Adapted Mayo score, corticosteroid use, and bio-IR status)

    Secondary: Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52

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    End point title
    Substudy 3: Percentage Of Participants With Endoscopic Improvement at Week 52
    End point description
    Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [167]
    148 [168]
    154 [169]
    Units: percentage of participants
        number (confidence interval 95%)
    14.5 (8.7 to 20.3)
    48.7 (40.5 to 56.8)
    61.6 (53.6 to 69.6)
    Notes
    [167] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [168] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [169] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [170]
    P-value
    < 0.001 [171]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    34.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    25.1
         upper limit
    43.7
    Notes
    [170] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [171] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [172]
    P-value
    < 0.001 [173]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    46.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    36.7
         upper limit
    55.8
    Notes
    [172] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [173] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

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    End point title
    Substudy 3: Percentage of Participants With Clinical Remission Per Adapted Mayo Score at Week 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    54 [174]
    47 [175]
    58 [176]
    Units: percentage of participants
        number (confidence interval 95%)
    22.2 (11.1 to 33.3)
    59.2 (45.1 to 73.4)
    69.7 (57.7 to 81.8)
    Notes
    [174] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [175] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [176] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [177]
    P-value
    < 0.001 [178]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    37.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.3
         upper limit
    54.6
    Notes
    [177] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [178] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [179]
    P-value
    < 0.001 [180]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    30.7
         upper limit
    63.3
    Notes
    [179] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [180] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment

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    End point title
    Substudy 3: Percentage of Participants Who Achieved Clinical Remission Per Adapted Mayo Score at Wk 52 and Were Corticosteroid Free for ≥ 90 Days Immediately Preceding Wk 52 Among Those Who Achieved Clinical Remission at the End of the Induction Treatment
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. For Substudy 3, clinical remission is defined as SFS ≤ 1 and not greater than Baseline, RBS of 0, and endoscopic subscore ≤ 1. In addition, evidence of friability during endoscopy in participants with otherwise "mild" endoscopic activity conferred an endoscopic subscore of 2.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    54 [181]
    47 [182]
    58 [183]
    Units: percentage of participants
        number (confidence interval 95%)
    22.2 (11.1 to 33.3)
    57.1 (42.9 to 71.3)
    68.0 (55.8 to 80.2)
    Notes
    [181] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [182] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [183] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority [184]
    P-value
    < 0.001 [185]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    35.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.2
         upper limit
    52.7
    Notes
    [184] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [185] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority [186]
    P-value
    < 0.001 [187]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    45.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.7
         upper limit
    61.6
    Notes
    [186] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [187] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment

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    End point title
    Substudy 3: Percentage of Participants With Endoscopic Improvement at Wk 52 Among Those Who Achieved Endoscopic Improvement at the End of the Induction Treatment
    End point description
    Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    73 [188]
    63 [189]
    79 [190]
    Units: percentage of participants
        number (confidence interval 95%)
    19.2 (9.9 to 28.4)
    61.6 (49.6 to 73.7)
    69.5 (59.1 to 80.0)
    Notes
    [188] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [189] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [190] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    superiority [191]
    P-value
    < 0.001 [192]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.8
         upper limit
    56.2
    Notes
    [191] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [192] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority [193]
    P-value
    < 0.001 [194]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    48.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.5
         upper limit
    61.7
    Notes
    [193] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [194] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52

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    End point title
    Substudy 3: Percentage Of Participants With Endoscopic Remission At Week 52
    End point description
    Endoscopic remission is defined as an endoscopic subscore of 0. Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [195]
    148
    154 [196]
    Units: percentage of participants
        number (confidence interval 95%)
    5.6 (1.8 to 9.3)
    24.2 (17.3 to 31.2)
    25.9 (18.8 to 33.0)
    Notes
    [195] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [196] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [197]
    P-value
    < 0.001 [198]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    18.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11
         upper limit
    26.4
    Notes
    [197] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [198] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [199]
    P-value
    < 0.001 [200]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    19.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.7
         upper limit
    27.2
    Notes
    [199] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [200] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment

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    End point title
    Substudy 3: Percentage Of Participants Who Maintained Clinical Response Per Adapted Mayo Score at Wk 52 Among Those Who Achieved Clinical Response at the End of the Induction Treatment
    End point description
    The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease. Clinical response is defined as a decrease from baseline in the Adapted Mayo score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    134 [201]
    135 [202]
    144 [203]
    Units: percentage of participants
        number (confidence interval 95%)
    18.8 (12.1 to 25.5)
    63.0 (54.8 to 71.1)
    76.6 (69.6 to 83.6)
    Notes
    [201] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [202] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [203] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority [204]
    P-value
    < 0.001 [205]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    44.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    34.5
         upper limit
    54.7
    Notes
    [204] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [205] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    superiority [206]
    P-value
    < 0.001 [207]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    56.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    47.2
         upper limit
    66
    Notes
    [206] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [207] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52

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    End point title
    Substudy 3: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 52
    End point description
    Histologic-endoscopic mucosal improvement is defined as an endoscopic subscore of 0 or 1 and a Geboes score ≤ 3.1. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [208]
    148 [209]
    154 [210]
    Units: percentage of participants
        number (confidence interval 95%)
    11.9 (6.7 to 17.2)
    35.0 (27.1 to 42.8)
    49.8 (41.5 to 58.0)
    Notes
    [208] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [209] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [210] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [211]
    P-value
    < 0.001 [212]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    23.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.8
         upper limit
    32.8
    Notes
    [211] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [212] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [213]
    P-value
    < 0.001 [214]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    37.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.8
         upper limit
    46.8
    Notes
    [213] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [214] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52

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    End point title
    Substudy 3: Change From Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 52
    End point description
    The Inflammatory Bowel Disease Questionnaire (IBDQ) is used to assess health-related quality of life (HRQoL) in patients with ulcerative colitis. It consists of 32 questions evaluating bowel and systemic symptoms, as well as emotional and social functions. Each question is answered on a scale from 1 (worst) to 7 (best). The total score ranges from 32 to 224 with higher scores indicating better health-related quality of life. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [215]
    148 [216]
    154 [217]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    17.9 (10.79 to 25.00)
    49.2 (42.59 to 55.89)
    58.9 (52.14 to 65.59)
    Notes
    [215] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    [216] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    [217] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [218]
    P-value
    < 0.001 [219]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    31.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.98
         upper limit
    40.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.77
    Notes
    [218] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [219] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [220]
    P-value
    < 0.001 [221]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.39
         upper limit
    50.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.88
    Notes
    [220] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [221] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

    Secondary: Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52

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    End point title
    Substudy 3: Percentage Of Participants With Mucosal Healing at Week 52
    End point description
    Mucosal healing is defined as an endoscopic score of 0 and Geboes score < 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration). The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [222]
    148 [223]
    154 [224]
    Units: percentage of participants
        number (confidence interval 95%)
    4.7 (1.3 to 8.2)
    17.6 (11.4 to 23.8)
    19.0 (12.6 to 25.4)
    Notes
    [222] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [223] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [224] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [225]
    P-value
    < 0.001 [226]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6
         upper limit
    20
    Notes
    [225] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [226] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [227]
    P-value
    < 0.001 [228]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    13.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    20.6
    Notes
    [227] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [228] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52

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    End point title
    Substudy 3: Percentage Of Participants Who Reported No Bowel Urgency at Week 52
    End point description
    Bowel urgency was assessed by participants in a subject diary completed once a day.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [229]
    148 [230]
    154 [231]
    Units: percentage of participants
        number (confidence interval 95%)
    17.4 (11.4 to 23.5)
    56.1 (48.1 to 64.1)
    63.6 (56.0 to 71.2)
    Notes
    [229] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [230] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [231] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [232]
    P-value
    < 0.001 [233]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    38.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.9
         upper limit
    48.5
    Notes
    [232] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [233] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [234]
    P-value
    < 0.001 [235]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    45.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.5
         upper limit
    54.8
    Notes
    [234] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [235] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52

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    End point title
    Substudy 3: Percentage Of Participants Who Reported No Abdominal Pain at Week 52
    End point description
    Abdominal pain was assessed by participants in a subject diary completed once a day.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [236]
    148 [237]
    154 [238]
    Units: percentage of participants
        number (confidence interval 95%)
    20.8 (14.2 to 27.3)
    45.9 (37.9 to 54.0)
    55.3 (47.4 to 63.2)
    Notes
    [236] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [237] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    [238] - SS3 ITT_A:1st 451 Upa 45 mg 8-wk responders; 52-wk tx Cohort 1, NRI with MI due to COVID-19- NRI-C
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [239]
    P-value
    < 0.001 [240]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    24.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.2
         upper limit
    34.5
    Notes
    [239] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [240] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [241]
    P-value
    < 0.001 [242]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted risk difference (%)
    Point estimate
    33.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.6
         upper limit
    43.9
    Notes
    [241] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [242] - Stratified by Bio-IR (Bio-IR/Non-Bio-IR) at Induction Study Baseline; clinical remission at Week 0 (yes/no); corticosteroid use at Week 0 (yes/no)

    Secondary: Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52

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    End point title
    Substudy 3: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 52
    End point description
    The FACIT fatigue questionnaire was developed to assess fatigue associated with anemia. It consists of 13 fatigue-related questions. Each question is answered on a 5-point Likert scale: 0 (not at all); 1 (a little bit); 2 (somewhat); 3 (quite a bit); and 4 (very much). The total score ranges from 0 to 52, where higher scores represent less fatigue, and a positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 52
    End point values
    SS3: Placebo SS3: UPA 15 mg SS3: UPA 30 mg
    Number of subjects analysed
    149 [243]
    148 [244]
    154 [245]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    3.7 (1.88 to 5.43)
    8.7 (7.01 to 10.49)
    9.5 (7.80 to 11.22)
    Notes
    [243] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    [244] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    [245] - SS3 ITT_A w/ available data; Baseline= last non-missing value prior to 1st induction dose; RTB-MI
    Statistical analysis title
    Substudy 3: Upadacitinib 15 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 15 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    superiority [246]
    P-value
    < 0.001 [247]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.67
         upper limit
    7.52
    Notes
    [246] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [247] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)
    Statistical analysis title
    Substudy 3: Upadacitinib 30 mg vs Placebo
    Comparison groups
    SS3: Placebo v SS3: UPA 30 mg
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    superiority [248]
    P-value
    < 0.001 [249]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.44
         upper limit
    8.27
    Notes
    [248] - The primary and ranked secondary efficacy endpoints were tested with graphical multiplicity adjustment to ensure a strong control of family-wise type I error rate at significance level α= 0.05 (2-sided).
    [249] - Stratified by corticosteroid use at Week 0 (yes/no); clinical remission status at Week 0 (yes/ no); Bio-IR status at Baseline (Bio-IR or Non-Bio-IR)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality from enrollment to study end: median follow-up was ≤ 57, 61, and 364 days (SS 1, 2, and 3). TEAEs/SAEs collected from 1st dose of study drug until 30 days after last dose; mean duration was ≤ 57, 56, and 364 days for SS 1, 2, and 3.
    Adverse event reporting additional description
    For safety analyses, participants were assigned to a treatment group based on the treatment actually received, regardless of the treatment randomized. The "as treated" group was determined by the most frequent dose regimen received in the analysis period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    SS1: Upadacitinib 7.5 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 7.5 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Placebo
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 30 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 30 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS1: Upadacitinib 15 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 15 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS1: Upadacitinib 45 mg
    Reporting group description
    During the 8-week induction phase in Substudy 1, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Additional participants were enrolled during the Substudy 1 analysis period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 4 weeks.

    Reporting group title
    SS2: Placebo
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS3: Upadacitinib 15 mg
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 15 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 15 mg QD in Substudy 3.

    Reporting group title
    SS3: Placebo
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to placebo QD in Substudy 3 for up to 52 weeks. In addition, participants who received double-blind placebo QD treatment for 8 weeks during Substudy 1, Substudy 2 Part 1, or Study M14-675 Part 1 and achieved clinical response at Week 8 continued to receive blinded placebo QD in Substudy 3 for up to 52 weeks.

    Reporting group title
    SS2: Upadacitinib 45 mg/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label expended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS2: Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks.

    Reporting group title
    SS2: Placebo/Upadacitinib 45 mg
    Reporting group description
    During the Substudy 2 Part 1 induction period, participants received placebo for upadacitinib film-coated tablets once daily by mouth (QD) for 8 weeks. Participants who did not achieve clinical response at Week 8 of Part 1 were enrolled in an open-label extended treatment period and received 45 mg upadacitinib film-coated tablets once daily by mouth (QD) for an additional 8 weeks.

    Reporting group title
    SS3: Upadacitinib 30 mg
    Reporting group description
    Participants who achieved clinical response in Substudy 1, Substudy 2, or Study M14-675 at either Week 8 or Week 16, while receiving upadacitinib 15, 30, or 45 mg QD and those who achieved clinical response while receiving upadacitinib 15 mg QD in Substudy 1 and were randomized to upadacitinib 30 mg QD in Substudy 3 for up to 52 weeks. In addition, participants who received upadacitinib 45 mg QD in Induction Phase and did not achieve clinical response and received upadacitinib 45 mg QD in Extended Treatment in Substudy 2 Part 2 or in Study M14-675 Part 2 and achieved clinical response at Week 16 and were randomized to upadacitinib 30 mg QD in Substudy 3.

    Reporting group title
    SS3: Upadacitinib 7.5 mg
    Reporting group description
    Participants who received double-blinded treatment of upadacitinib 7.5 mg QD for 8 weeks during Substudy 1 and achieved clinical response at Week 8 continued to receive blinded treatment of upadacitinib 7.5 mg QD in Substudy 3 for up to 52 weeks.

    Serious adverse events
    SS1: Upadacitinib 7.5 mg SS1: Placebo SS1: Upadacitinib 30 mg SS1: Upadacitinib 15 mg SS1: Upadacitinib 45 mg SS2: Placebo SS3: Upadacitinib 15 mg SS3: Placebo SS2: Upadacitinib 45 mg/Upadacitinib 45 mg SS2: Upadacitinib 45 mg SS2: Placebo/Upadacitinib 45 mg SS3: Upadacitinib 30 mg SS3: Upadacitinib 7.5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    5 / 46 (10.87%)
    5 / 117 (4.27%)
    2 / 49 (4.08%)
    6 / 123 (4.88%)
    9 / 155 (5.81%)
    24 / 323 (7.43%)
    32 / 385 (8.31%)
    2 / 59 (3.39%)
    8 / 319 (2.51%)
    2 / 85 (2.35%)
    25 / 316 (7.91%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    1 / 59 (1.69%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    2 / 323 (0.62%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INVASIVE BREAST CARCINOMA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    SMALL CELL CARCINOMA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEVICE INTOLERANCE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    1 / 319 (0.31%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    MENTAL DISORDER
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    CERVICAL DYSPLASIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    2 / 316 (0.63%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HIP FRACTURE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    PULMONARY CONTUSION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    SKIN LACERATION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    NONINFECTIVE BRONCHITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    2 / 323 (0.62%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    2 / 85 (2.35%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CARPAL TUNNEL SYNDROME
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    ANAL FISTULA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    1 / 155 (0.65%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    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
    0 / 0
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 46 (4.35%)
    4 / 117 (3.42%)
    1 / 49 (2.04%)
    3 / 123 (2.44%)
    5 / 155 (3.23%)
    1 / 323 (0.31%)
    9 / 385 (2.34%)
    1 / 59 (1.69%)
    2 / 319 (0.63%)
    1 / 85 (1.18%)
    3 / 316 (0.95%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
    0 / 1
    1 / 3
    3 / 6
    0 / 1
    4 / 9
    0 / 1
    0 / 2
    0 / 1
    0 / 3
    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
    0 / 0
    0 / 0
    0 / 0
    COLON DYSPLASIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    1 / 123 (0.81%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    DIAPHRAGMATIC HERNIA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    1 / 155 (0.65%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 117 (0.85%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    CYSTITIS HAEMORRHAGIC
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    1 / 117 (0.85%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    LIVER DISORDER
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    1 / 316 (0.32%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA NODOSUM
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    PANNICULITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    0 / 323 (0.00%)
    1 / 385 (0.26%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRITIS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 46 (0.00%)
    0 / 117 (0.00%)
    0 / 49 (0.00%)
    0 / 123 (0.00%)
    0 / 155 (0.00%)
    1 / 323 (0.31%)
    0 / 385 (0.00%)
    0 / 59 (0.00%)
    0 / 319 (0.00%)
    0 / 85 (0.00%)
    0 / 316 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0