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

    Summary
    EudraCT number
    2016-000642-62
    Trial protocol
    NL   LV   PT   FI   DE   GR   SE   GB   AT   CZ   LT   IE   HU   ES   SK   PL   FR   HR   NO   IT   RO  
    Global end of trial date
    14 Jan 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Apr 2022
    First version publication date
    23 Jul 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Updated to correct erros in data for the following secondary endpoint: Percentage Of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8.

    Trial information

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    Trial identification
    Sponsor protocol code
    M14-675
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03653026
    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, AbbViw, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbViw, 001 800-633-9110, 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
    14 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy and safety of upadacitinib 45 mg once daily (QD) compared to placebo in inducing clinical remission (per the Adapted Mayo score) in subjects with moderately to severely active ulcerative colitis (UC) who have demonstrated inadequate response, loss of response, or intolerance to oral aminosalicylates, immunosuppressants, corticosteroids, and/or biologic therapies.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Dec 2018
    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: 7
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 2
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    China: 13
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Estonia: 13
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Japan: 81
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 10
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Norway: 22
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 117
    Worldwide total number of subjects
    522
    EEA total number of subjects
    151
    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)
    9
    Adults (18-64 years)
    466
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study included a Screening Period of up to 5 weeks, Part 1, and Part 2. Part 1 was a randomized, double-blind, placebo-controlled 8-week induction period. Part 2 was an open-label, 8 week extended treatment period for clinical non-responders from Part 1. A total of 522 subjects were randomized at 204 sites in 41 countries.

    Pre-assignment
    Screening details
    Participants were randomized in a 2:1 ratio to upadacitinib or placebo. Randomization was stratified by bio-IR status, corticosteroid use, and Adapted Mayo score at Baseline. Within bio-IR, randomization was further stratified by number of prior biologic treatments. Within non-bio-IR, randomization was further stratified by previous biologic use.

    Period 1
    Period 1 title
    Part 1: Placebo-controlled Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Upadacitinib 45 mg
    Arm description
    Participants received 45 mg upadacitinib once daily (QD) for 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Upadacitinib 45 mg administered orally once daily.

    Arm title
    Placebo
    Arm description
    Participants received placebo matching to upadacitinib once daily for 8 weeks.
    Arm type
    Placebo

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

    Number of subjects in period 1
    Upadacitinib 45 mg Placebo
    Started
    345
    177
    Received Treatment
    344
    177
    Completed
    334
    164
    Not completed
    11
    13
         Other
    -
    3
         Adverse event, non-fatal
    5
    6
         Consent withdrawn by subject
    6
    4
    Period 2
    Period 2 title
    Part 2: Open-label Extension
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Upadacitinib 45 mg / Upadacitinib 45 mg
    Arm description
    Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Upadacitinib 45 mg administered orally once daily.

    Arm title
    Placebo / Upadacitinib 45 mg
    Arm description
    Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period.
    Arm type
    Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Upadacitinib 45 mg administered orally once daily.

    Number of subjects in period 2 [1]
    Upadacitinib 45 mg / Upadacitinib 45 mg Placebo / Upadacitinib 45 mg
    Started
    68
    116
    Completed
    65
    111
    Not completed
    3
    5
         Other
    1
    2
         Adverse event, non-fatal
    1
    1
         Consent withdrawn by subject
    1
    2
    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: Part 2 was an open label, 8-week extended treatment period for subjects who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily (QD) for 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo matching to upadacitinib once daily for 8 weeks.

    Reporting group values
    Upadacitinib 45 mg Placebo Total
    Number of subjects
    345 177 522
    Age categorical
    Units: Subjects
        < 18 years
    6 3 9
        ≥ 18 years - < 40 years
    160 81 241
        ≥ 40 years - < 65 years
    146 79 225
        ≥ 65 years
    33 14 47
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.2 ± 14.73 42.2 ± 14.44 -
    Gender categorical
    Units: Subjects
        Female
    129 67 196
        Male
    216 110 326
    Race
    Units: Subjects
        White
    238 127 365
        Black or African American
    11 6 17
        Asian
    94 41 135
        American Indian or Alaska Native
    0 1 1
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Multiple
    2 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    26 16 42
        Not Hispanic or Latino
    319 161 480
    Biologic-inadequate Responder (Bio-IR) Status
    Biologic-inadequate responders (Bio-IR) are defined as subjects who had inadequate response, loss of response, or intolerance to biologic therapy. Non-biologic-inadequate responders (non-bio-IR) are defined as subjects who had inadequate response, loss of response, or intolerance to conventional therapy but had not failed biologic therapy.
    Units: Subjects
        Bio-IR
    175 91 266
        Non-Bio-IR
    170 86 256
    Baseline Corticosteroid Use
    Units: Subjects
        Yes
    123 75 198
        No
    222 102 324
    Adapted Mayo Score
    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.
    Units: Subjects
        ≤ 7
    205 104 309
        > 7
    138 73 211
        Missing
    2 0 2
    Bio-IR Subjects: Number of Prior Biologic Treatments
    Units: Subjects
        ≤ 1
    58 33 91
        > 1
    117 58 175
        NA (Non-bio-IR)
    170 86 256
    Non-Bio-IR Subjects: Prior Exposure to Biologic Therapy
    Units: Subjects
        Yes
    1 5 6
        No
    169 81 250
        NA (Bio-IR)
    175 91 266
    Disease Duration
    Data are available for 344 and 177 participants in each arm, respectively.
    Units: years
        arithmetic mean (standard deviation)
    7.273 ± 6.4459 7.584 ± 7.6701 -
    Adapted Mayo Score
    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 score ranges from 0 to 9 where higher scores represent more severe disease. Data were available for 343 ad 177 subjects in each arm, respectively.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.00 ± 1.216 7.05 ± 1.236 -

    End points

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    End points reporting groups
    Reporting group title
    Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily (QD) for 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo matching to upadacitinib once daily for 8 weeks.
    Reporting group title
    Upadacitinib 45 mg / Upadacitinib 45 mg
    Reporting group description
    Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period.

    Reporting group title
    Placebo / Upadacitinib 45 mg
    Reporting group description
    Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period.

    Primary: Percentage of Participants who Achieved Clinical Remission per Adapted Mayo Score at Week 8

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    End point title
    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. Clinical Remission is defined as an Adapted Mayo score ≤ 2, with SFS ≤ 1 and not higher than Baseline, RBS of 0, and endoscopic subscore ≤ 1. The Part 1 intent-to-treat population (ITT1) includes randomized subjects who received at least 1 dose of study drug in Part 1. The ITT1 population excludes 6 subjects from 1 site with non-compliance. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [1]
    174 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    33.5 (28.5 to 38.5)
    4.1 (1.1 to 7.1)
    Notes
    [1] - ITT1 population
    [2] - ITT1 population
    Statistical analysis title
    Primary Analysis
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.2
         upper limit
    34.7
    Notes
    [3] - 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).
    [4] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants with Endoscopic Improvement at Week 8

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    End point title
    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). The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [5]
    174 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    44.0 (38.8 to 49.3)
    8.3 (4.1 to 12.5)
    Notes
    [5] - ITT1 population
    [6] - ITT1 population
    Statistical analysis title
    Analysis of Endoscopic Improvement
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    35.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.6
         upper limit
    41.6
    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] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants with Endoscopic Remission at Week 8

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    End point title
    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). The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [9]
    174 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    18.2 (14.1 to 22.3)
    1.7 (0.0 to 3.7)
    Notes
    [9] - ITT1 population
    [10] - ITT1 population
    Statistical analysis title
    Analysis of Endoscopic Remission
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    15.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.4
         upper limit
    20.3
    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] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants Achieving Clinical Response per Adapted Mayo Score at Week 8

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    End point title
    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 with spontaneous bleeding, ulceration). The overall Adapted Mayo score ranges from 0 to 9 with higher scores representing more severe disease. Clinical response per the Adapted Mayo Score is defined as a decrease in Adapted Mayo score ≥ 2 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [13]
    174 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    74.5 (69.9 to 79.1)
    25.4 (18.9 to 31.8)
    Notes
    [13] - ITT1 population
    [14] - ITT1 population
    Statistical analysis title
    Analysis of Clinical Response
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.001 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    49.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    41.7
         upper limit
    57.1
    Notes
    [15] - 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).
    [16] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants Achieving Clinical Response per Partial Adapted Mayo Score at Week 2

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    End point title
    Percentage of Participants Achieving Clinical Response per Partial Adapted Mayo Score at Week 2
    End point description
    The Partial Adapted 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 Adapted Mayo score ranges from 0 to 6 with higher scores representing more severe disease. Clinical response per Partial Adapted Mayo Score is defined as a decrease in Partial Adapted Mayo score ≥ 1 point and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [17]
    174 [18]
    Units: percentage of participants
        number (confidence interval 95%)
    63.3 (58.2 to 68.5)
    25.9 (19.4 to 32.4)
    Notes
    [17] - ITT1 population
    [18] - ITT1 population
    Statistical analysis title
    Analysis of Clinical Response at Week 2
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.8
         upper limit
    45.1
    Notes
    [19] - 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).
    [20] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants Who Achieved Histologic-Endoscopic Mucosal Improvement at Week 8

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    End point title
    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. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [21]
    174 [22]
    Units: percentage of participants
        number (confidence interval 95%)
    36.7 (31.6 to 41.8)
    5.9 (2.3 to 9.4)
    Notes
    [21] - ITT1 population
    [22] - ITT1 population
    Statistical analysis title
    Analysis of Histologic-Endoscopic Improvement
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    < 0.001 [24]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    30.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.1
         upper limit
    36.2
    Notes
    [23] - 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).
    [24] - Cochran-Mantel-Haenszel test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants who Reported No Bowel Urgency at Week 8

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    End point title
    Percentage of Participants who Reported No Bowel Urgency at Week 8
    End point description
    Bowel urgency was assessed by participants in a subject diary completed once a day. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [25]
    174 [26]
    Units: percentage of participants
        number (confidence interval 95%)
    53.7 (48.4 to 59.0)
    25.9 (19.4 to 32.4)
    Notes
    [25] - ITT1 population
    [26] - ITT1 population
    Statistical analysis title
    Analysis of Bowel Urgency
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.001 [28]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    27.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19
         upper limit
    35.3
    Notes
    [27] - 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).
    [28] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (<= 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants who Reported No Abdominal Pain at Week 8

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    End point title
    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. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [29]
    174 [30]
    Units: percentage of participants
        number (confidence interval 95%)
    53.7 (48.4 to 59.0)
    24.1 (17.8 to 30.5)
    Notes
    [29] - ITT1 population
    [30] - ITT1 population
    Statistical analysis title
    Analysis of Abdominal Pain
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.001 [32]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    29.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.9
         upper limit
    37.4
    Notes
    [31] - 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).
    [32] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

    Secondary: Percentage of Participants Who Achieved Histologic Improvement at Week 8

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    End point title
    Percentage of Participants Who Achieved Histologic Improvement at Week 8
    End point description
    Histologic improvement is defined as a decrease from Baseline in Geboes score. 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. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [33]
    174 [34]
    Units: percentage of participants
        number (confidence interval 95%)
    62.2 (57.0 to 67.3)
    24.5 (18.0 to 30.9)
    Notes
    [33] - ITT1 population
    [34] - ITT1 population
    Statistical analysis title
    Analysis of Histologic Improvement
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    < 0.001 [36]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    37.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.8
         upper limit
    46.1
    Notes
    [35] - 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).
    [36] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

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

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    End point title
    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. The analysis was conducted in the ITT1 population with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases up to Week 8 was used except for measurements at or after the occurrence of UC-related corticosteroids intercurrent event were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    315 [37]
    156 [38]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    52.2 (48.57 to 55.92)
    21.1 (15.98 to 26.17)
    Notes
    [37] - ITT1 population with available data
    [38] - ITT1 population with available data
    Statistical analysis title
    Analysis of Change in IBDQ Total Score
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    471
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    < 0.001 [40]
    Method
    Mixed-effect model repeated measurement
    Parameter type
    Least Squares (LS) Mean Difference
    Point estimate
    31.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.98
         upper limit
    37.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.15
    Notes
    [39] - 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).
    [40] - Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and strata (Baseline corticosteroid use, Baseline Adapted Mayo score, bio-IR status) in the model.

    Secondary: Percentage of Participants Who Achieved Mucosal Healing at Week 8

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    End point title
    Percentage of Participants Who Achieved 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. The analysis was conducted in the ITT1 population; non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 was used.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    341 [41]
    174 [42]
    Units: percentage of participants
        number (confidence interval 95%)
    13.5 (9.9 to 17.1)
    1.7 (0.0 to 3.7)
    Notes
    [41] - ITT1 population
    [42] - ITT1 population
    Statistical analysis title
    Analysis of Mucosal Healing
    Comparison groups
    Upadacitinib 45 mg v Placebo
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    superiority [43]
    P-value
    < 0.001 [44]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Adjusted Response Rate Difference
    Point estimate
    11.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.2
         upper limit
    15.3
    Notes
    [43] - 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).
    [44] - Cochran-Mantel-Haenszel (CMH) test adjusted for strata (Baseline corticosteroid use (yes or no), Baseline Adapted Mayo score (≤ 7 or > 7), bio-IR status (bio-IR or non-bio-IR)) for the comparison of two treatment groups.

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

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    End point title
    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. The analysis was conducted in the ITT1 population with available data; a mixed effect model repeat measurement (MMRM) analysis with data from observed cases up to Week 8 was used except for measurements at or after the occurrence of UC-related corticosteroids intercurrent event were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 8
    End point values
    Upadacitinib 45 mg Placebo
    Number of subjects analysed
    312 [45]
    155 [46]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    9.4 (8.38 to 10.48)
    3.5 (2.02 to 4.92)
    Notes
    [45] - ITT1 population with available data
    [46] - ITT1 population with available data
    Statistical analysis title
    Analysis of Change in FACIT-F
    Comparison groups
    Placebo v Upadacitinib 45 mg
    Number of subjects included in analysis
    467
    Analysis specification
    Pre-specified
    Analysis type
    superiority [47]
    P-value
    < 0.001 [48]
    Method
    Mixed-effect model repeated measurement
    Parameter type
    LS Mean Difference
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.19
         upper limit
    7.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    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] - Mixed-Effect Model Repeat Measurement with Baseline, treatment, visit, treatment by visit interaction, and strata (Baseline corticosteroid use, Baseline Adapted Mayo score, bio-IR status) in the model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: From first dose of study drug up to 30 days after the last dose or until first dose of study drug in Part 2 or first dose of study drug in M14-234 (maintenance study) or M14-533 (long term extension).
    Adverse event reporting additional description
    Time Frame for Part 2: From the first dose of study drug in Part 2 up to 30 days after last dose or until first dose of study drug in M14-234 (maintenance study) or the first dose date of study drug in M14-533 (long-term extension study).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Part 1: Upadacitinib 45 mg
    Reporting group description
    Participants received 45 mg upadacitinib once daily (QD) for 8 weeks.

    Reporting group title
    Part 1: Placebo
    Reporting group description
    Participants received placebo matching to upadacitinib once daily for 8 weeks.

    Reporting group title
    Part 2: Upadacitinib 45 mg / Upadacitinib 45 mg
    Reporting group description
    Participants initially assigned to upadacitinib who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 additional weeks in the open-label extension period.

    Reporting group title
    Part 2: Placebo / Upadacitinib 45 mg
    Reporting group description
    Participants initially assigned to placebo who did not achieve clinical response per Adapted Mayo score at Week 8 in Part 1 received upadacitinib 45 mg once daily for 8 weeks in the open-label extension period.

    Serious adverse events
    Part 1: Upadacitinib 45 mg Part 1: Placebo Part 2: Upadacitinib 45 mg / Upadacitinib 45 mg Part 2: Placebo / Upadacitinib 45 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 344 (3.20%)
    8 / 177 (4.52%)
    1 / 68 (1.47%)
    4 / 116 (3.45%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    PELVIC VENOUS THROMBOSIS
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    GASTROINTESTINAL STOMA NECROSIS
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAND FRACTURE
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 344 (0.00%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 344 (0.29%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    ACUTE PSYCHOSIS
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 344 (0.00%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 344 (0.00%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    4 / 344 (1.16%)
    3 / 177 (1.69%)
    1 / 68 (1.47%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    PYODERMA GANGRENOSUM
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    MALNUTRITION
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 PNEUMONIA
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DENGUE FEVER
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 177 (0.00%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOCCAL INFECTION
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA INFECTION
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 177 (0.56%)
    0 / 68 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1: Upadacitinib 45 mg Part 1: Placebo Part 2: Upadacitinib 45 mg / Upadacitinib 45 mg Part 2: Placebo / Upadacitinib 45 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 344 (18.02%)
    18 / 177 (10.17%)
    11 / 68 (16.18%)
    19 / 116 (16.38%)
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    16 / 344 (4.65%)
    2 / 177 (1.13%)
    4 / 68 (5.88%)
    5 / 116 (4.31%)
         occurrences all number
    18
    2
    4
    5
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    13 / 344 (3.78%)
    3 / 177 (1.69%)
    4 / 68 (5.88%)
    3 / 116 (2.59%)
         occurrences all number
    13
    3
    4
    3
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    8 / 344 (2.33%)
    9 / 177 (5.08%)
    2 / 68 (2.94%)
    2 / 116 (1.72%)
         occurrences all number
    9
    10
    2
    3
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    8 / 344 (2.33%)
    3 / 177 (1.69%)
    4 / 68 (5.88%)
    4 / 116 (3.45%)
         occurrences all number
    8
    4
    4
    4
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    24 / 344 (6.98%)
    3 / 177 (1.69%)
    0 / 68 (0.00%)
    6 / 116 (5.17%)
         occurrences all number
    25
    3
    0
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2018
    Global amendment 1: ● Clarified the study objective to outline both the primary and secondary endpoints. ● Enhanced various sections of the protocol to clarify expectations and create better understanding of the content. ● Enhanced the description of the DMC review, the contacts list and signatories were updated to reflect changes in study team administration.
    24 Apr 2019
    Global amendment 2: ● Updating the study objective to include the secondary objectives. ● Updating the benefit risk language, modifying exclusion criterion #14 to allow for undetectable biologic levels to be measured via a commercially available assay as an alternative to the washout period, based on regulatory feedback. ● Adding the country-specific requirements in the inclusion/exclusion criteria (included 16 and 17-year-old subjects, where locally permitted). ● Adding, amending, and clarifying the study procedures. ● Adding justification for the use of placebo and further elaborating on the details of the DMC.
    29 Apr 2020
    Global amendment 3: ● Updated wording about re-testing of exclusionary laboratory values during the screening period. ● Clarified intervals for testing biologic drug levels. ● Updated the criteria of clinical response for entering extended treatment period for subjects with missing Week 8 endoscopy when endoscopies cannot be performed due to the COVID-19 pandemic. ● Moved non-ranked secondary efficacy variables to additional efficacy variables. ● Added criteria for failure of ustekinumab treatment, added wording to define borderline serum pregnancy test results, clarified that live vaccines should not be administered for at least 30 days prior to or after study drug administration. ● Excluded subjects with a history of gastrointestinal perforation (perforation due to mechanical injury should not exclude a subject from participation). ● Prohibited cytapheresis treatment for 60 days prior to screening. ● Excluded subjects with prior history of thrombotic events including deep vein thrombosis and pulmonary embolism or known inherited conditions that predispose to hypercoagulability. ● Added wording about gastric banding/segmentation to make clear that it is not an exclusion. ● Added wording to the washout requirements for all biologic therapies. ● Removed wording about women classified as non-childbearing potential. ● Updated ECG review requirements. ● Updated the type of QuantiFERON TB test used. ● Updated toxicity management for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), thrombosis events, and herpes zoster
    31 Jul 2020
    Global amendment 4: Updated information on the re-evaluation of the benefit and risk to subjects participating in the study, updated wording to allow for changes in visits and procedures affected by the COVID-19 pandemic and associated changes in global/local regulations.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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