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    Clinical Trial Results:
    A Phase 3b Multicenter, Randomized, Double-Blind, Double-Dummy, Active Controlled Study Comparing the Safety and Efficacy of Upadacitinib to Dupilumab in Adult Subjects With Moderate to Severe Atopic Dermatitis

    Summary
    EudraCT number
    		 2018-002264-57
    Trial protocol
    		 DE   FI   GB   NL   SE   FR   HU   NO   ES   HR   IT  
    Global end of trial date
    09 Dec 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Jul 2024
    First version publication date
    18 Dec 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M16-046
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03738397
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the efficacy and safety of upadacitinib versus dupilumab for the treatment of adult subjects with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2019
    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
    Australia: 68
    Country: Number of subjects enrolled
    Canada: 73
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czechia: 19
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Malaysia: 28
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    New Zealand: 27
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 179
    Worldwide total number of subjects
    673
    EEA total number of subjects
    230
    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)
    643
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized at 128 sites located in 22 countries (Australia, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Malaysia, Netherlands, New Zealand, Norway, Poland, Singapore, Spain, Taiwan, Ukraine, United Kingdom, and the United States).

    Pre-assignment
    Screening details
    		 Participants were randomly assigned in a 1:1 ratio to receive upadacitinib or dupilumab. Randomization was stratified by disease severity (Validated Investigator Global Assessment Scale for Atopic Dermatitis [vIGA-AD] moderate [3] vs severe [4]) and age (<40, ≥ 40 to < 65, ≥ 65 years).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dupilumab 300 mg EOW
    Arm description
    		 Participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection on Day 1 followed by 300 mg dupilumab SC every other week (EOW) until Week 22 and placebo to upadacitinib orally once a day (QD) up to Week 24.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo to upadacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    Dupixent®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as a subcutaneous injection every 2 weeks after a loading dose of 600 mg, starting at week 2 until Week 22.

    Arm title
    		 Upadacitinib 30 mg QD
    Arm description
    		 Participants received 30 mg upadacitinib orally once a day up to Week 24 and placebo to dupilumab SC EOW up to Week 22.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo to dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered as a subcutaneous injection every 2 weeks until Week 22.

    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
    Administered orally once a day

    Number of subjects in period 1
    		Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Started
    331
    342
    Completed
    308
    312
    Not completed
    23
    30
         Consent withdrawn by subject
    8
    11
         Adverse event, non-fatal
    3
    7
         Other
    4
    6
         COVID-19 logistical restrictions
    1
    1
         Lost to follow-up
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dupilumab 300 mg EOW
    Reporting group description
    		 Participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection on Day 1 followed by 300 mg dupilumab SC every other week (EOW) until Week 22 and placebo to upadacitinib orally once a day (QD) up to Week 24.

    Reporting group title
    Upadacitinib 30 mg QD
    Reporting group description
    		 Participants received 30 mg upadacitinib orally once a day up to Week 24 and placebo to dupilumab SC EOW up to Week 22.

    Reporting group values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD Total
    Number of subjects
    		 331 342 673
    Age categorical
    Units: Subjects
        < 40 years
    		 223 228 451
        ≥ 40 to < 65 years
    		 94 98 192
        ≥ 65 years
    		 14 16 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ( 13.81 ) 36.2 ( 14.42 ) -
    Gender categorical
    Units: Subjects
        Female
    		 139 159 298
        Male
    		 192 183 375
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 31 25 56
        Not Hispanic or Latino
    		 300 317 617
    Race
    Units: Subjects
        White
    		 231 229 460
        Black or African American
    		 15 25 40
        Asian
    		 78 77 155
        American Indian/Alaska Native
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 1 3 4
        Multiple
    		 5 6 11
    Disease Severity
    Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) was used to assess the severity of AD based on lesion appearance on the following scale: •0-Clear: No signs of AD; •1-Almost clear: Barely perceptible erythema, induration/papulation and/or lichenification; •2-Mild: Slight but definite erythema, induration/papulation and/or minimal lichenification. No oozing or crusting; •3-Moderate: Clearly perceptible erythema, induration/papulation and/or lichenification, possible oozing or crusting; •4-Severe: Marked erythema, induration/papulation and/or lichenification.
    Units: Subjects
        3 (Moderate)
    		 159 169 328
        4 (Severe)
    		 172 173 345
    Eczema Area and Severity Index (EASI) Score
    EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 29.21 ( 11.551 ) 30.96 ( 12.550 ) -
    Duration Since AD Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 25.474 ( 14.8251 ) 23.608 ( 14.7697 ) -

    End points

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    End points reporting groups
    Reporting group title
    Dupilumab 300 mg EOW
    Reporting group description
    		 Participants received a loading dose of 600 mg dupilumab by subcutaneous (SC) injection on Day 1 followed by 300 mg dupilumab SC every other week (EOW) until Week 22 and placebo to upadacitinib orally once a day (QD) up to Week 24.

    Reporting group title
    Upadacitinib 30 mg QD
    Reporting group description
    		 Participants received 30 mg upadacitinib orally once a day up to Week 24 and placebo to dupilumab SC EOW up to Week 22.

    Primary: Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index (EASI 75) at Week 16

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    End point title
    		 Percentage of Participants Achieving a 75% Reduction From Baseline in Eczema Area and Severity Index (EASI 75) at Week 16
    End point description
    EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected and the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, adjusting for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used in the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    331 [1]
    342
    Units: percentage of participants
        number (confidence interval 95%)
    62.6 (57.4 to 67.8)
    72.4 (67.6 to 77.2)
    Notes
    [1] - Intent-to-treat (ITT) population (all randomized participants)
    Statistical analysis title
    		 Analysis of EASI 75 Response at Week 16
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.007 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Response Rate Difference
    Point estimate
    9.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 16.7
    Notes
    [2] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [3] - Cochran-Mantel-Haenszel test adjusted for vIGA-AD categories (moderate [3] versus severe [4]).

    Secondary: Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16

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    End point title
    		 Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 16
    End point description
    The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement. The intent-to-treat population with non-missing Baseline and at least one post-baseline value was used in the analysis; missing data were handled using a mixed-effect model with repeated measurements (MMRM) including observed measurements at all visits, except that measurements after any rescue medication were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    239 [4]
    252 [5]
    Units: percent change
        least squares mean (standard error)
    -49.58 ( 1.986 )
    -67.78 ( 1.906 )
    Notes
    [4] - ITT population with non-missing percent change from Baseline values
    [5] - ITT population with non-missing percent change from Baseline values
    Statistical analysis title
    		 Analysis of Change in Pruritus NRS at Week 16
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    491
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001 [7]
    Method
    		 Mixed Effect Model Repeated Measurement
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -18.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.61
         upper limit
    		 -12.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.753
    Notes
    [6] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [7] - Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD categories in the model.

    Secondary: Percentage of Participants Who Achieved a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16

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    End point title
    		 Percentage of Participants Who Achieved a 100% Reduction From Baseline in EASI Score (EASI 100) at Week 16
    End point description
    EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected and the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, adjusting for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    331
    342
    Units: percentage of participants
        number (confidence interval 95%)
    7.9 (5.0 to 10.8)
    28.4 (23.6 to 33.2)
    Statistical analysis title
    		 Analysis of EASI 100 Response at Week 16
    Comparison groups
    Upadacitinib 30 mg QD v Dupilumab 300 mg EOW
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.001 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Response Rate Difference
    Point estimate
    20.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.8
         upper limit
    		 26
    Notes
    [8] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [9] - Cochran-Mantel-Haenszel test adjusted for vIGA-AD categories (moderate [3] versus severe [4]).

    Secondary: Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4

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    End point title
    		 Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 4
    End point description
    The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement. The intent-to-treat population with non-missing Baseline and at least one post-baseline value was used in the analysis; missing data were handled using a mixed-effect model with repeated measurements (MMRM) including observed measurements at all visits, except that measurements after any rescue medication were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    297 [10]
    327 [11]
    Units: percent change
        least squares mean (standard error)
    -32.39 ( 2.288 )
    -60.41 ( 2.204 )
    Notes
    [10] - ITT population with non-missing percent change from Baseline values
    [11] - ITT population with non-missing percent change from Baseline values
    Statistical analysis title
    		 Analysis of Change in Pruritus NRS at Week 4
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    624
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001 [13]
    Method
    		 Mixed Effect Model Repeated Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -28.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.25
         upper limit
    		 -21.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.177
    Notes
    [12] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [13] - Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD categories in the model.

    Secondary: Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2

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    End point title
    		 Percentage of Participants Achieving a 75% Reduction From Baseline in EASI Score at Week 2
    End point description
    EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected and the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, adjusting for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. Non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C) was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 2
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    331
    342
    Units: percentage of participants
        number (confidence interval 95%)
    18.2 (14.0 to 22.4)
    44.3 (39.1 to 49.6)
    Statistical analysis title
    		 Analysis of EASI 75 Response at Week 2
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.001 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Response Rate Difference
    Point estimate
    26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.3
         upper limit
    		 32.7
    Notes
    [14] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [15] - Cochran-Mantel-Haenszel test adjusted for vIGA-AD categories (moderate [3] versus severe [4]).

    Secondary: Percentage of Participants Achieving a 90% Reduction from Baseline in EASI Score (EASI 90) at Week 16

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    End point title
    		 Percentage of Participants Achieving a 90% Reduction from Baseline in EASI Score (EASI 90) at Week 16
    End point description
    EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected and the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, adjusting for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. Non-responder imputation incorporating multiple imputation (MI) to handle missing data due to COVID-19 (NRI-C) was used in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    331
    342
    Units: percentage of participants
        number (confidence interval 95%)
    40.3 (35.0 to 45.6)
    61.6 (56.4 to 66.8)
    Statistical analysis title
    		 Analysis of EASI 90 Response at Week 16
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.001 [17]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Response Rate Difference
    Point estimate
    21.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.8
         upper limit
    		 28.6
    Notes
    [16] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [17] - Cochran-Mantel-Haenszel test adjusted for vIGA-AD categories (moderate [3] versus severe [4]).

    Secondary: Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1

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    End point title
    		 Percent Change From Baseline in Worst Pruritus Numerical Rating Scale (NRS) Score at Week 1
    End point description
    The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch). The percent change from Baseline was calculated from a rolling weekly average; a negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 1
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    314 [18]
    331 [19]
    Units: percent change
        least squares mean (standard error)
    -8.94 ( 1.831 )
    -31.96 ( 1.772 )
    Notes
    [18] - ITT population with non-missing percent change from Baseline values
    [19] - ITT population with non-missing percent change from Baseline values
    Statistical analysis title
    		 Analysis of Change in Pruritus NRS at Week 1
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.001 [21]
    Method
    		 Mixed Effect Model Repeated Measurement
    Parameter type
    		 LS Mean Difference
    Point estimate
    -23.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.03
         upper limit
    		 -18.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.548
    Notes
    [20] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [21] - Mixed-effect model repeat measurement with Baseline, treatment, visit, treatment by visit interaction, and Baseline vIGA-AD categories in the model.

    Secondary: Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16

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    End point title
    		 Percentage of Participants Achieving a Reduction of ≥ 4 Points From Baseline in Worst Pruritus NRS at Week 16
    End point description
    The Worst Pruritus NRS is an assessment tool that participants used to report the intensity of their pruritus during a 24-hour recall period using an electronic hand-held device. Participants were asked to rate itch (pruritus) intensity at its worst during the past 24 hours on an 11-point scale from 0 (no itch) to 10 (worst imaginable itch).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Dupilumab 300 mg EOW Upadacitinib 30 mg QD
    Number of subjects analysed
    323 [22]
    334 [23]
    Units: percentage of participants
        number (confidence interval 95%)
    36.4 (31.1 to 41.6)
    56.1 (50.8 to 61.5)
    Notes
    [22] - Intent-to-treat population with Baseline worst pruritus NRS score ≥ 4
    [23] - Intent-to-treat population with Baseline worst pruritus NRS score ≥ 4
    Statistical analysis title
    		 Analysis of Worst Pruritus NRS Response
    Comparison groups
    Dupilumab 300 mg EOW v Upadacitinib 30 mg QD
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.001 [25]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted Response Rate Difference
    Point estimate
    19.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.4
         upper limit
    		 27.3
    Notes
    [24] - A multiple testing procedure was used to provide a strong control of the type I error rate at alpha = 0.05 (2-sided) across analyses comparing upadacitinib versus dupilumab with respect to the primary and ranked secondary endpoints.
    [25] - Cochran-Mantel-Haenszel test adjusted for vIGA-AD categories (moderate [3] versus severe [4]).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: from Day 1 to 12 weeks after last dose of study drug (34 weeks). Adverse events: From first dose of upadacitinib/dupilumab through 30 days following the last dose of upadacitinib or 84 days following the last dose of dupilumab (up to 34 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Upadacitinib 30 mg QD
    Reporting group description
    		 Participants received 30 mg upadacitinib orally once a day up to Week 24 and placebo to dupilumab SC EOW up to Week 22.

    Reporting group title
    Dupilumab 300 mg EOW
    Reporting group description
    		 Participants received a loading dose of 600 mg dupilumab by SC injection on Day 1 followed by 300 mg dupilumab SC EOW until Week 22 and placebo to upadacitinib orally QD up to Week 24.

    Serious adverse events
    		 Upadacitinib 30 mg QD Dupilumab 300 mg EOW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 342 (4.09%)
    7 / 331 (2.11%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARATHYROID TUMOUR BENIGN
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    TYPE I HYPERSENSITIVITY
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FOOD ALLERGY
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    INTENTIONAL SELF-INJURY
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT INJURY
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    LYMPHOPENIA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    GLAUCOMA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INCARCERATED UMBILICAL HERNIA
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ECZEMA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DERMATITIS ATOPIC
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BURSITIS
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    PELVIC ABSCESS
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    HERPES SIMPLEX
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 342 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BETA HAEMOLYTIC STREPTOCOCCAL INFECTION
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Upadacitinib 30 mg QD Dupilumab 300 mg EOW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 342 (48.83%)
    134 / 331 (40.48%)
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    26 / 342 (7.60%)
    10 / 331 (3.02%)
         occurrences all number
    27
    12
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    17 / 342 (4.97%)
    24 / 331 (7.25%)
         occurrences all number
    22
    32
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    64 / 342 (18.71%)
    11 / 331 (3.32%)
         occurrences all number
    72
    12
    DERMATITIS ATOPIC
         subjects affected / exposed
    36 / 342 (10.53%)
    32 / 331 (9.67%)
         occurrences all number
    52
    51
    Infections and infestations
    CONJUNCTIVITIS
         subjects affected / exposed
    5 / 342 (1.46%)
    35 / 331 (10.57%)
         occurrences all number
    6
    36
    FOLLICULITIS
         subjects affected / exposed
    22 / 342 (6.43%)
    4 / 331 (1.21%)
         occurrences all number
    22
    4
    NASOPHARYNGITIS
         subjects affected / exposed
    23 / 342 (6.73%)
    27 / 331 (8.16%)
         occurrences all number
    33
    31
    ORAL HERPES
         subjects affected / exposed
    17 / 342 (4.97%)
    9 / 331 (2.72%)
         occurrences all number
    21
    10
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    26 / 342 (7.60%)
    17 / 331 (5.14%)
         occurrences all number
    26
    20
    URINARY TRACT INFECTION
         subjects affected / exposed
    18 / 342 (5.26%)
    15 / 331 (4.53%)
         occurrences all number
    19
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2020
    Version 2, Global amendment added ranked secondary endpoints (Percent change from Baseline to Week 4 in Worst Pruritus NRS; Proportion of subjects achieving EASI 75 at Week 2; and Percent change from Baseline to Week 1 in Worst Pruritus NRS) to align with endpoints in other upadacitinib AD studies. To reflect the most recent updates to AESIs and toxicity management guidance in the Investigator Brochure, CTCAE v4.03 was retained for AE reporting in this global protocol amendment. An option to enroll in a separate open-label extension study of oral upadacitinib 30 mg in which they were to be treated for an additional 52 weeks was added for all countries.
    28 Oct 2020
    Version 3, Global Amendment updated the secondary endpoint to include Worst Pruritus NRS ≥ 4 at Week 16 (from an additional endpoint) and added the additional endpoint of daily Worst Pruritus NRS ≥ 4 up to Day 28 to harmonize with protocol Version 2.2.1. Modifications to the statistical analyses due to the COVID-19 pandemic were added.
    10 Nov 2020
    Version 4, Global Amendment clarified that the primary analysis was performed on the data from Week 24 database lock.

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34347860
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