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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study to Evaluate the Safety and Efficacy of Upadacitinib in Subjects With Non-Segmental Vitiligo

    Summary
    EudraCT number
    		 2021-000081-15
    Trial protocol
    		 FR  
    Global end of trial date
    29 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Sep 2024
    First version publication date
    12 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M19-051
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04927975
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2023
    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 safety and efficacy of upadacitinib for the treatment of adult subjects with non-segmental vitiligo.
    Protection of trial subjects
    Subjects signed and dated an informed consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2021
    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
    Japan: 15
    Country: Number of subjects enrolled
    United States: 94
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    France: 44
    Worldwide total number of subjects
    185
    EEA total number of subjects
    44
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    180
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who met eligibility criteria at Baseline were randomized in a 2:2:2:1:1 ratio to one of the five treatment groups. At Week 24, subjects who were randomized to placebo at Baseline were switched to either 22 mg (Group 4) or 11 mg (Group 5) upadacitinib in a blinded fashion per pre-specified randomization assignments.

    Period 1
    Period 1 title
    Period 1 (Baseline-Week 24)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Period 1
    Arm description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1.
    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
    Oral tablets

    Arm title
    		 Upa 6 mg Period 1
    Arm description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Upa 11 mg Period 1
    Arm description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Upa 22 mg Period 1
    Arm description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Number of subjects in period 1
    		Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Started
    46
    49
    47
    43
    Completed
    44
    46
    45
    38
    Not completed
    2
    3
    2
    5
         Death
    -
    -
    -
    1
         Lost to follow-up
    -
    2
    1
    -
         Withdrawal by subject
    2
    1
    1
    4
    Period 2
    Period 2 title
    Period 2 (Week 24-52)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo Period 1, Then Upa 11 mg Period 2
    Arm description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Placebo Period 1, Then Upa 22 mg Period 2
    Arm description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Upa 6 mg Period 1, Then Upa 6 mg Period 2
    Arm description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 6 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Upa 11 mg Period 1, Then Upa 11 mg Period 2
    Arm description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Arm title
    		 Upa 22 mg Period 1, Then Upa 22 mg Period 2
    Arm description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Upadacitinib
    Investigational medicinal product code
    ABT-494
    Other name
    RINVOQ
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral tablets

    Number of subjects in period 2 [1]
    		Placebo Period 1, Then Upa 11 mg Period 2 Placebo Period 1, Then Upa 22 mg Period 2 Upa 6 mg Period 1, Then Upa 6 mg Period 2 Upa 11 mg Period 1, Then Upa 11 mg Period 2 Upa 22 mg Period 1, Then Upa 22 mg Period 2
    Started
    21
    22
    45
    45
    33
    Completed
    19
    21
    39
    38
    30
    Not completed
    2
    1
    6
    7
    3
         Lost to follow-up
    1
    -
    2
    6
    2
         Withdrawal by subject
    1
    1
    4
    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: A total of 185 subjects were randomized and received the study drug (placebo or upadacitinib) in Period 1. A total of 166 subjects completed study drug in Period 1. A total of 166 subjects entered Period 2 and received randomized study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Period 1
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 6 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 11 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 22 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1 Total
    Number of subjects
    		 46 49 47 43 185
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.8 ( 10.48 ) 45.1 ( 11.68 ) 45.5 ( 11.90 ) 48.2 ( 11.13 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 26 34 26 115
        Male
    		 17 23 13 17 70
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 6 4 5 20
        Not Hispanic or Latino
    		 41 43 43 38 165
        Unknown or Not Reported
    		 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 1 1
        Asian
    		 6 6 7 6 25
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 0 1
        Black or African American
    		 4 3 3 1 11
        White
    		 34 35 36 33 138
        More than one race
    		 0 3 1 1 5
        Unknown or Not Reported
    		 2 1 0 1 4
    Total Vitiligo Area Scoring Index (T- VASI)
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. It is based on a composite estimate of the overall area of vitiligo patches, measured by the number of hand units (palm plus 5 digits = 1% body surface area [BSA]) multiplied by the degree of depigmentation within each affected area (0%, 10%, 25%, 50%, 75%, 90%, or 100%). The T-VASI is calculated using a formula that includes contributions from all body regions, with a possible range from 0 to 100, with higher scores indicating more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 21.014 ( 16.9516 ) 20.993 ( 15.9672 ) 22.322 ( 18.1784 ) 21.843 ( 15.9324 ) -
    Facial Vitiligo Area Scoring Index (F- VASI)
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. The F-VASI includes contributions from the face, with a possible range from 0 to 3, with higher scores indicating more severe disease.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 1.043 ( 0.6094 ) 1.154 ( 0.7655 ) 1.021 ( 0.5781 ) 1.159 ( 0.6585 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Period 1
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 6 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 11 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.

    Reporting group title
    Upa 22 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1.
    Reporting group title
    Placebo Period 1, Then Upa 11 mg Period 2
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

    Reporting group title
    Placebo Period 1, Then Upa 22 mg Period 2
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

    Reporting group title
    Upa 6 mg Period 1, Then Upa 6 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 6 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

    Reporting group title
    Upa 11 mg Period 1, Then Upa 11 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

    Reporting group title
    Upa 22 mg Period 1, Then Upa 22 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2.

    Primary: Percent Change From Baseline in Facial-Vitiligo Area Scoring Index (F-VASI) at Week 24

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    End point title
    		 Percent Change From Baseline in Facial-Vitiligo Area Scoring Index (F-VASI) at Week 24
    End point description
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. The F-VASI includes contributions from the face, with a possible range from 0 to 3, with higher scores indicating more severe disease. Negative changes from baseline indicate improvement. Analysis population: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; mixed model repeated measures analysis (MMRM) including observed measurements at all visits
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    43
    45
    43
    33
    Units: Percent change from baseline
        arithmetic mean (confidence interval 95%)
    -14.36 (-24.86 to -3.85)
    -21.96 (-32.18 to -11.75)
    -35.63 (-46.11 to -25.14)
    -33.96 (-45.41 to -22.50)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.304
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.18
         upper limit
    		 6.97
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -21.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.02
         upper limit
    		 -6.52
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.04
         upper limit
    		 -4.16

    Secondary: Percentage of Participants Achieving F-VASI 75 (≥75% Improvement in F-VASI From Baseline) at Week 24

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    End point title
    		 Percentage of Participants Achieving F-VASI 75 (≥75% Improvement in F-VASI From Baseline) at Week 24
    End point description
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. The F-VASI includes contributions from the face, with a possible range from 0 to 3, with higher scores indicating more severe disease. Analysis population: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; NRI-MI (non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    46
    49
    47
    43
    Units: percentage of participants
        number (confidence interval 95%)
    2.2 (0.0 to 6.4)
    8.2 (0.5 to 15.8)
    19.1 (7.9 to 30.4)
    14.0 (3.6 to 24.3)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 15.2
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    17.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.5
         upper limit
    		 29
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 21.9

    Secondary: Percentage of Participants Achieving F-VASI 50 (≥50% Improvement in F-VASI From Baseline) at Week 24

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    End point title
    		 Percentage of Participants Achieving F-VASI 50 (≥50% Improvement in F-VASI From Baseline) at Week 24
    End point description
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. The F-VASI includes contributions from the face, with a possible range from 0 to 3, with higher scores indicating more severe disease. Analysis population: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; NRI-MI (non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    46
    49
    47
    43
    Units: percentage of participants
        number (confidence interval 95%)
    10.9 (1.9 to 19.9)
    16.3 (6.0 to 26.7)
    38.3 (24.4 to 52.2)
    39.5 (24.9 to 54.1)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.327
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 19.7
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.8
         upper limit
    		 44.9
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    28.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.6
         upper limit
    		 44.7

    Secondary: Percentage of Participants Achieving Total Vitiligo Area Scoring Index (T-VASI) 50 (≥50% Improvement in T-VASI From Baseline) at Week 24

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    End point title
    		 Percentage of Participants Achieving Total Vitiligo Area Scoring Index (T-VASI) 50 (≥50% Improvement in T-VASI From Baseline) at Week 24
    End point description
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. It is based on a composite estimate of the overall area of vitiligo patches, measured by the number of hand units (palm plus 5 digits = 1% body surface area [BSA]) multiplied by the degree of depigmentation within each affected area (0%, 10%, 25%, 50%, 75%, 90%, or 100%). The T-VASI is calculated using a formula that includes contributions from all body regions, with a possible range from 0 to 100, with higher scores indicating more severe disease. Analysis population: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; NRI-MI (non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or any other missing data that can be reasonably assumed to be Missing at Random)
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    46
    49
    47
    43
    Units: percentage of participants
        number (confidence interval 95%)
    2.2 (0.0 to 6.4)
    6.1 (0.0 to 12.8)
    6.4 (0.0 to 13.4)
    11.6 (2.0 to 21.2)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 11.2
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.358
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 11.8
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    P-value calculated according to the Cochran-Mantel-Haenszel test adjusted for strata (age group [≤50 and > 50], baseline disease severity [T-VASI < 15 and ≥15], and status of active vitiligo [Yes/No])) for the comparison of two treatment groups. The calculations at each visit were based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 or non-responder imputation only if there were no missing data due to COVID-19.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Difference
    Point estimate
    9.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 17.2

    Secondary: Percent Change From Baseline in T-VASI at Week 24

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    End point title
    		 Percent Change From Baseline in T-VASI at Week 24
    End point description
    The vitiligo area scoring index (VASI) is a validated scoring method used to assess the areas of depigmentation due to vitiligo. It is based on a composite estimate of the overall area of vitiligo patches, measured by the number of hand units (palm plus 5 digits = 1% body surface area [BSA]) multiplied by the degree of depigmentation within each affected area (0%, 10%, 25%, 50%, 75%, 90%, or 100%). The T-VASI is calculated using a formula that includes contributions from all body regions, with a possible range from 0 to 100, with higher scores indicating more severe disease. Negative changes from baseline indicate improvement. Analysis popuation: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; mixed model repeated measures analysis (MMRM) including observed measurements at all visits.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    43
    45
    43
    33
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    -6.42 (-13.17 to 0.34)
    -13.87 (-20.45 to -7.29)
    -17.26 (-24.00 to -10.52)
    -20.69 (-28.05 to -13.32)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -7.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.86
         upper limit
    		 1.96
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -10.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.37
         upper limit
    		 -1.32
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -14.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.24
         upper limit
    		 -4.3

    Secondary: Change From Baseline in the Vitiligo Quality-of-Life (VitiQoL) Instrument Total Score at Week 24

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    End point title
    		 Change From Baseline in the Vitiligo Quality-of-Life (VitiQoL) Instrument Total Score at Week 24
    End point description
    The VitiQoL is a validated questionnaire used in clinical trials to assess stigma-related vitiligo impacts. The VitiQoL uses subject-elicited social, affective, and behavior items, asking the subject's appraisal of the vitiligo-related impacts over the last month. Fifteen items are scored on a 7-point scale ranging from 0 ("Not at all") to 6 ("All of the time"). Item scores (0 to 6) are summed to provide a total score range of 0 to 90; higher scores indicate greater impairment of quality of life (QoL). Negative changes from baseline indicate improvement. Analysis population: ITT_1: all randomized participants in Period 1, analyzed according to the treatment groups that they were randomized to; mixed model repeated measures analysis (MMRM) including observed measurements at all visits.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Period 1 Upa 6 mg Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1
    Number of subjects analysed
    40
    44
    44
    34
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -5.5 (-10.3 to -0.8)
    -7.5 (-12.0 to -3.0)
    -3.7 (-8.2 to 0.9)
    -6.6 (-11.6 to -1.6)
    Statistical analysis title
    		 Upa 6 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 6 mg Period 1
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.545
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 4.4
    Statistical analysis title
    		 Upa 11 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 11 mg Period 1
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.565
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 8.3
    Statistical analysis title
    		 Upa 22 mg Period 1 versus Placebo Period 1
    Statistical analysis description
    Repeated measures analysis was conducted using a mixed model including observed measurements at all visits. The model included categorical fixed effects of treatment, visit and treatment-by-visit interaction, and stratification factors (age [≤50 and > 50], Baseline disease severity [T-VASI < 15 and ≥15], active vitiligo [Yes/No]) derived from actual values, and the continuous fixed covariate of Baseline measurement. An unstructured variance covariance matrix was used.
    Comparison groups
    Placebo Period 1 v Upa 22 mg Period 1
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.754
    Method
    		 Mixed-Effect Model Repeat Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 5.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality/adverse events were collected from informed consent through the end of the study. Median time on follow-up was 168 days for all groups in Period 1.
    Adverse event reporting additional description
    Median time on follow-up for Period 2 was as follows: Placebo Period 1, Then Upa 11 mg Period 2 (198 days); Placebo Period 1, Then Upa 22 mg Period 2 and Upa 22 mg Period 1, Then Upa 22 mg Period 2 (212 days); Upa 6 mg Period 1, Then Upa 6 mg Period 2 (204 days); and Upa 11 mg Period 1, Then Upa 11 mg Period 2 (207 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo Period 1
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. AEs and SAEs were collected from the time of informed consent and during Period 1, as long as it did not exceed the start date of Period 2.

    Reporting group title
    Upa 11 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. AEs and SAEs were collected from the time of informed consent and during Period 1, as long as it did not exceed the start date of Period 2.

    Reporting group title
    Upa 22 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. AEs and SAEs were collected from the time of informed consent and during Period 1, as long as it did not exceed the start date of Period 2.

    Reporting group title
    Upa 22 mg Period 1, Then Upa 22 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 22 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. AEs and SAEs were collected from the start date of Period 2 to the end of the study.

    Reporting group title
    Placebo Period 1, Then Upa 22 mg Period 2
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 22 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. AEs and SAEs were collected from the start date of Period 2 to the end of the study.

    Reporting group title
    Upa 6 mg Period 1, Then Upa 6 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 6 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. AEs and SAEs were collected from the start date of Period 2 to the end of the study.

    Reporting group title
    Upa 11 mg Period 1, Then Upa 11 mg Period 2
    Reporting group description
    		 Participants received upadacitinib 11 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. AEs and SAEs were collected from the start date of Period 2 to the end of the study.

    Reporting group title
    Upa 6 mg Period 1
    Reporting group description
    		 Participants received upadacitinib 6 mg administered orally once a day (QD) as tablets for 24 weeks during Period 1. AEs and SAEs were collected from the time of informed consent and during Period 1, as long as it did not exceed the start date of Period 2.

    Reporting group title
    Placebo Period 1, Then Upa 11 mg Period 2
    Reporting group description
    		 Participants received Placebo for upadacitinib administered orally once a day (QD) as tablets for 24 weeks during Period 1. Participants then received upadacitinib 11 mg administered orally once a day (QD) as tablets for 28 weeks during Period 2. AEs and SAEs were collected from the start date of Period 2 to the end of the study.

    Serious adverse events
    		 Placebo Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1 Upa 22 mg Period 1, Then Upa 22 mg Period 2 Placebo Period 1, Then Upa 22 mg Period 2 Upa 6 mg Period 1, Then Upa 6 mg Period 2 Upa 11 mg Period 1, Then Upa 11 mg Period 2 Upa 6 mg Period 1 Placebo Period 1, Then Upa 11 mg Period 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    3 / 43 (6.98%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    2 / 45 (4.44%)
    1 / 49 (2.04%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    INVASIVE LOBULAR BREAST CARCINOMA
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    0 / 49 (0.00%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ARTERIOSCLEROSIS CORONARY ARTERY
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    1 / 49 (2.04%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    0 / 49 (0.00%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 43 (2.33%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 43 (2.33%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 43 (2.33%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (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
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Period 1 Upa 11 mg Period 1 Upa 22 mg Period 1 Upa 22 mg Period 1, Then Upa 22 mg Period 2 Placebo Period 1, Then Upa 22 mg Period 2 Upa 6 mg Period 1, Then Upa 6 mg Period 2 Upa 11 mg Period 1, Then Upa 11 mg Period 2 Upa 6 mg Period 1 Placebo Period 1, Then Upa 11 mg Period 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 46 (56.52%)
    28 / 47 (59.57%)
    23 / 43 (53.49%)
    17 / 33 (51.52%)
    11 / 22 (50.00%)
    12 / 45 (26.67%)
    22 / 45 (48.89%)
    19 / 49 (38.78%)
    9 / 21 (42.86%)
    Investigations
    WEIGHT INCREASED
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 47 (2.13%)
    3 / 43 (6.98%)
    2 / 33 (6.06%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    3
    2
    0
    0
    1
    0
    0
    BLOOD THYROID STIMULATING HORMONE DECREASED
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    3 / 45 (6.67%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    3
    0
    0
    Injury, poisoning and procedural complications
    SKIN LACERATION
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    4 / 46 (8.70%)
    9 / 47 (19.15%)
    2 / 43 (4.65%)
    2 / 33 (6.06%)
    1 / 22 (4.55%)
    2 / 45 (4.44%)
    5 / 45 (11.11%)
    0 / 49 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    11
    3
    2
    1
    2
    5
    0
    2
    General disorders and administration site conditions
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 47 (0.00%)
    1 / 43 (2.33%)
    2 / 33 (6.06%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    1 / 49 (2.04%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    1
    3
    0
    0
    1
    1
    0
    FATIGUE
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    5 / 43 (11.63%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    2 / 45 (4.44%)
    0 / 45 (0.00%)
    2 / 49 (4.08%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    5
    0
    0
    2
    0
    2
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    0
    0
    0
    0
    DIARRHOEA
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 47 (6.38%)
    1 / 43 (2.33%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    1 / 45 (2.22%)
    1 / 45 (2.22%)
    0 / 49 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    3
    1
    0
    0
    1
    1
    0
    1
    VOMITING
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    3 / 43 (6.98%)
    1 / 33 (3.03%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    1 / 49 (2.04%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    3
    1
    0
    0
    0
    1
    0
    NAUSEA
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 47 (4.26%)
    4 / 43 (9.30%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    2
    4
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    1 / 46 (2.17%)
    4 / 47 (8.51%)
    2 / 43 (4.65%)
    1 / 33 (3.03%)
    1 / 22 (4.55%)
    0 / 45 (0.00%)
    1 / 45 (2.22%)
    2 / 49 (4.08%)
    0 / 21 (0.00%)
         occurrences all number
    1
    4
    2
    1
    1
    0
    1
    2
    0
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    1 / 46 (2.17%)
    4 / 47 (8.51%)
    6 / 43 (13.95%)
    3 / 33 (9.09%)
    2 / 22 (9.09%)
    1 / 45 (2.22%)
    2 / 45 (4.44%)
    3 / 49 (6.12%)
    1 / 21 (4.76%)
         occurrences all number
    4
    4
    7
    3
    3
    2
    2
    3
    1
    DYSHIDROTIC ECZEMA
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 43 (0.00%)
    2 / 33 (6.06%)
    1 / 22 (4.55%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 47 (6.38%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    1 / 49 (2.04%)
    0 / 21 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    0
    1
    0
    INSOMNIA
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 47 (6.38%)
    0 / 43 (0.00%)
    0 / 33 (0.00%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 47 (4.26%)
    4 / 43 (9.30%)
    2 / 33 (6.06%)
    3 / 22 (13.64%)
    1 / 45 (2.22%)
    2 / 45 (4.44%)
    4 / 49 (8.16%)
    3 / 21 (14.29%)
         occurrences all number
    5
    2
    4
    2
    3
    1
    2
    4
    4
    COVID-19
         subjects affected / exposed
    8 / 46 (17.39%)
    9 / 47 (19.15%)
    9 / 43 (20.93%)
    5 / 33 (15.15%)
    5 / 22 (22.73%)
    7 / 45 (15.56%)
    12 / 45 (26.67%)
    7 / 49 (14.29%)
    1 / 21 (4.76%)
         occurrences all number
    8
    9
    9
    5
    5
    7
    12
    7
    1
    GASTROENTERITIS
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 47 (2.13%)
    1 / 43 (2.33%)
    1 / 33 (3.03%)
    0 / 22 (0.00%)
    0 / 45 (0.00%)
    0 / 45 (0.00%)
    0 / 49 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    1
    1
    0
    0
    0
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    0 / 43 (0.00%)
    3 / 33 (9.09%)
    0 / 22 (0.00%)
    1 / 45 (2.22%)
    4 / 45 (8.89%)
    3 / 49 (6.12%)
    3 / 21 (14.29%)
         occurrences all number
    1
    2
    0
    3
    0
    2
    4
    3
    3
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    2 / 43 (4.65%)
    0 / 33 (0.00%)
    3 / 22 (13.64%)
    2 / 45 (4.44%)
    1 / 45 (2.22%)
    1 / 49 (2.04%)
    0 / 21 (0.00%)
         occurrences all number
    3
    7
    3
    0
    3
    2
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2021
    Protocol Version 2.0 • Updated Synopsis and Section 2.1 to add "in some countries" to clarify the approval status of upadacitinib for the treatment of RA, PsA, and AS • Clarified that previous treatment with permanent skin bleaching agents to treat vitiligo is prohibited. • Clarified the approximate number of sites that will be selected and that subjects at participating sites will be required to participate after digital imaging platform is available for implementation at the site • Updated Section 5.3 to revise the dose for systemic corticosteroids from 1 mg/kg to 1 mg/kg/day • Updated Section 5.3 to change the wording regarding natural daily light exposure from "encouraged" to "allowed" • Updated Section 5.3 to add language prohibiting use throughout the study of any drugs considered to be strong CYP3A inhibitors or inducers, or herbal supplements or traditional medicines with unknown effects on CYP3A • Updated Section 5.5 to condense the wording regarding subject non-compliance with study procedures • Updated Section 5.5 to add "beginning at Week 8" to the discontinuation criterion regarding worsening vitiligo as defined by an increase of 25% or higher in T-VASI from Baseline • Updated Section 7.4 to clarify that categorical stratification factors will be adjusted in the models • Updated Appendix D to add respiratory rate and body temperature to vital signs

    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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