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    Clinical Trial Results:
    A Phase 3b, Open-Label Treatment Extension Study of Upadacitinib for the Treatment of Adult Subjects with Moderate to Severe Atopic Dermatitis Who Completed Treatment in Study M16-046

    Summary
    EudraCT number
    		 2019-001227-12
    Trial protocol
    		 IE   FI   HU   CZ   ES   NL   FR   GB   HR   IT   NO  
    Global end of trial date
    11 Sep 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Jan 2025
    First version publication date
    21 Sep 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Clarifying text made to end point description and timeframe.

    Trial information

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    Trial identification
    Sponsor protocol code
    M19-850
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04195698
    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, Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 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
    11 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study for adults (18-75 years) who have successfully completed treatment either with Dupilumab or with Upadacitinib in the study M16-046. At the end of M16-046, they have the option to receive Upadacitinib with a duration of 52 weeks beyond the timeframe of Study M16-046. There will be a 30 day follow-up visit after the treatment period is completed. Main objective of this study is to assess long-term safety, tolerability and efficacy of upadacitinib in participants with moderate to severe atopic dermatitis who successfully completed treatment in the study M16-046.
    Protection of trial subjects
    The investigator or his/her representative will explain the nature of the study to the subject and answer all questions regarding this study. Prior to any study-related procedures being performed on the subject or any medications being discontinued by the subject in order to participate in this study, the informed consent statement will be reviewed, signed, and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements. A copy of the signed informed consent will be given to the subject and the original will be placed in the subject's medical record.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Malaysia: 20
    Country: Number of subjects enrolled
    New Zealand: 26
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 94
    Country: Number of subjects enrolled
    Croatia: 5
    Country: Number of subjects enrolled
    Czechia: 16
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Canada: 67
    Country: Number of subjects enrolled
    Israel: 7
    Worldwide total number of subjects
    475
    EEA total number of subjects
    198
    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)
    456
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 475 participants were enrolled at 114 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 US).

    Pre-assignment
    Screening details
    		 Participants originally randomized to upa or dupi in Parent Study M16-046 and continued in this study. The ITT Population consists of all enrolled participants who received at least 1 dose of study drug in the study and is used for all efficacy analyses. The Safety Population is the same as the ITT Population and is used for all safety analyses.

    Period 1
    Period 1 title
    Overall Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DUPI 300mg to UPA 30mg
    Arm description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received dupilumab (DUPI) in Parent Study M16-046 are included in the DUPI 300 mg Q2W/UPA 30 mg QD (DUPI/UPA) group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    upadacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received dupilumab (DUPI) in Parent Study M16-046 are included in the DUPI 300 mg Q2W/UPA 30 mg QD (DUPI/UPA) group.

    Arm title
    		 UPA 30mg to UPA 30mg
    Arm description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received upadacitinib (UPA) in Parent Study M16-046 are included in the UPA 30 mg QD/UPA 30 mg QD (UPA/UPA) group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    upadacitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received upadacitinib (UPA) in Parent Study M16-046 are included in the UPA 30 mg QD/UPA 30 mg QD (UPA/UPA) group.

    Number of subjects in period 1
    		DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg
    Started
    239
    236
    Completed
    214
    197
    Not completed
    25
    39
         Consent withdrawn by subject
    9
    10
         Adverse event, non-fatal
    4
    11
         Not specified
    5
    4
         Lost to follow-up
    5
    4
         Lack of efficacy
    2
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DUPI 300mg to UPA 30mg
    Reporting group description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received dupilumab (DUPI) in Parent Study M16-046 are included in the DUPI 300 mg Q2W/UPA 30 mg QD (DUPI/UPA) group.

    Reporting group title
    UPA 30mg to UPA 30mg
    Reporting group description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received upadacitinib (UPA) in Parent Study M16-046 are included in the UPA 30 mg QD/UPA 30 mg QD (UPA/UPA) group.

    Reporting group values
    		 DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg Total
    Number of subjects
    		 239 236 475
    Age categorical
    Units: Subjects
        < 40 years
    		 167 156 323
        ≥ 40 to < 65 years
    		 66 70 136
        ≥ 65 years
    		 6 10 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.3 ( 12.90 ) 36.1 ( 14.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 100 104 204
        Male
    		 139 132 271
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 17 16 33
        Not Hispanic or Latino
    		 222 220 442
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 49 46 95
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        Black or African American
    		 11 14 25
        White
    		 172 170 342
        More than one race
    		 5 3 8
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    DUPI 300mg to UPA 30mg
    Reporting group description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received dupilumab (DUPI) in Parent Study M16-046 are included in the DUPI 300 mg Q2W/UPA 30 mg QD (DUPI/UPA) group.

    Reporting group title
    UPA 30mg to UPA 30mg
    Reporting group description
    		 All participants in this study received upadacitinib 30 mg once a day (QD). Participants were grouped by previous treatment in Parent Study M16-046. Participants who received upadacitinib (UPA) in Parent Study M16-046 are included in the UPA 30 mg QD/UPA 30 mg QD (UPA/UPA) group.

    Primary: Number of Participants With Treatment-Emergent Adverse Events

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events [1]
    End point description
    Treatment-emergent adverse events (TEAEs) are defined as any adverse events that begin or worsen in severity after initiation of upadacitinib during Lead-In Study M16-046 for the UPA/UPA arm or this Study M19-850 DUPI/UPA arm through 30 days following the last dose of upadacitinib.
    End point type
    Primary
    End point timeframe
    UPA/UPA arm: BL visit in Lead-In M16-046 to last dose in Long-Term Extension M19-850 (median time on follow-up is 536 days); DUPI/UPA arm: BL visit in Long-Term Extension M19-850 to last dose plus a 30-day follow-up (median time on follow-up is 399 days).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There will be no statistical testing for all of the efficacy and safety endpoints.
    End point values
    		 DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg
    Number of subjects analysed
    239
    236
    Units: count of participants
    number (not applicable)
        Any TEAE
    205
    223
        TESAE
    14
    17
        AE leading to discontinuation of study drug
    12
    18
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment-Emergent Adverse Events of Special Interest (AESI)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events of Special Interest (AESI) [2]
    End point description
    Treatment-emergent adverse events were monitored throughout the study to identify any adverse events of special interest that may indicate a trend or risk to participants. AESIs are defined as any adverse events that begin or worsen in severity after initiation of upadacitinib during Study M16-046 for the UPA/UPA arm or Study M19-850 for the DUPI/UPA arm through 30 days following the last dose of upadacitinib. MACE defined as cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. VTE include deep vein thrombosis (DVT) and pulmonary embolism (PE)(fatal and non-fatal).
    End point type
    Primary
    End point timeframe
    UPA/UPA arm: BL visit in Lead-In M16-046 to last dose in Long-Term Extension M19-850 (median time on follow-up is 536 days); DUPI/UPA arm: BL visit in Long-Term Extension M19-850 to last dose plus a 30-day follow-up (median time on follow-up is 399 days).
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There will be no statistical testing for all of the efficacy and safety endpoints.
    End point values
    		 DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg
    Number of subjects analysed
    239
    236
    Units: Count of participants
    number (not applicable)
        Serious infections
    7
    8
        Opportunistic infection excluding TB & Herpes
    6
    4
        Malignancy
    1
    0
        Non-melanoma skin cancer (NMSC)
    0
    0
        Malignancy excluding NMSC
    1
    0
        Lymphoma
    0
    0
        Hepatic disorder
    19
    15
        Adjudicated gastrointestinal perforations
    0
    0
        Anemia
    7
    8
        Neutropenia
    10
    8
        Lymphopenia
    4
    5
        Herpes zoster
    26
    25
        Creatine phosphokinase (CPK) elevation
    31
    44
        Renal dysfunction
    0
    0
        Active tuberculosis
    0
    1
        Adjudicated MACE
    0
    0
        Adjudicated VTE
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants With Potentially Clinically Important (PCI) Laboratory Values as Assessed by the Investigator

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    End point title
    		 Percentage of Participants With Potentially Clinically Important (PCI) Laboratory Values as Assessed by the Investigator [3]
    End point description
    Clinical laboratory test values are considered PCI if they meet either the lower-limit or higher-limit PCI criteria defined in the categories below. Percentage of participants with PCI laboratory values are summarized for hematology and chemistry. The Number Analyzed is defined as the number of participants with at least one post-baseline value for the specific criteria. Post-baseline grade must also be more extreme (worse) than the baseline grade in order to be included in the count. If a participant does not have a baseline value then the participant would be counted in the numerator if the participant had at least one post-baseline. xULN = Times upper limit of the normal range. Amino = Aminotransferase
    End point type
    Primary
    End point timeframe
    From Baseline to 30 days following last dose of study drug (Week 52)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There will be no statistical testing for all of the efficacy and safety endpoints.
    End point values
    		 DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg
    Number of subjects analysed
    239 [4]
    236
    Units: Percentage of participants
    number (not applicable)
        Hemoglobin (G/L): Grade 3 (<80)
    0
    0.8
        Hemoglobin (G/L): Grade 3 or above
    0
    0.8
        Platelets (10^9/L): Grade 3 (25-<50)
    0
    0.4
        Platelets (10^9/L): Grade 4 (<25)
    0
    0
        Platelets (10^9/L): Grade 3 or above
    0
    0.4
        Leukocytes (10^9/L): Grade 3 (1.0-<2.0)
    0
    1.3
        Leukocytes (10^9/L): Grade 4 (<1.0)
    0
    0
        Leukocytes (10^9/L): Grade 3 or above
    0
    1.3
        Neutrophils (10^9/L): Grade 3 (0.5-<1.0)
    2.5
    3.4
        Neutrophils (10^9/L): Grade 4 (<0.5)
    0.4
    0.4
        Neutrophils (10^9/L): Grade 3 or above
    2.9
    3.8
        Lymphocytes (10^9/L): Grade 3 (0.2-<0.5)
    0.8
    3.4
        Lymphocytes (10^9/L): Grade 4 (<0.2)
    0
    0
        Lymphocytes (10^9/L): Grade 3 or above
    0.8
    3.4
        Alanine Amino (U/L): Grade 3 (>5.0-20.0xULN)
    0.4
    0.4
        Alanine Amino (U/L): Grade 4 (>20.0 xULN)
    0
    0
        Alanine Amino (U/L): Grade 3 or above
    0.4
    0.4
        Aspartate Amino (U/L): Grade 3 (>5.0-20.0xULN)
    0
    1.3
        Aspartate Amino (U/L): Grade 4 (>20.0 xULN)
    0
    0
        Aspartate Amino (U/L): Grade 3 or above
    0
    1.3
        Alkaline Phosphatase (U/L):Grade 3(>5.0-20.0 xULN)
    0
    0
        Alkaline Phosphatase (U/L): Grade 4 (>20.0 xULN)
    0
    0
        Alkaline Phosphatase (U/L): Grade 3 or above
    0
    0
        Creatine Kinase (U/ L): Grade 3 (>5.0-10.0xULN)
    4.2
    8.1
        Creatine Kinase (U/L): Grade 4 (>10.0 xULN)
    3.8
    5.1
        Creatine Kinase (U/L): Grade 3 or above
    8.0
    13.1
        Creatinine (UMOL/L): (>3.0-6.0 xULN OR >3.0xBL)
    0
    0.8
        Creatinine (UMOL/L): Grade 4 (>6.0 xULN)
    0
    0.4
        Creatinine (UMOL/L): Grade 3 or above
    0
    1.3
        Phosphate (MMOL/L): Grade 3 (0.3-<0.6)
    1.7
    1.3
        Phosphate (MMOL/L): Grade 4 (<0.3)
    0
    0
        Phosphate (MMOL/L): Grade 3 or above
    1.7
    1.3
        Calcium Hyper (MMOL/L): Grade 3 (>3.1-3.4)
    0
    0.4
        Calcium Hyper (MMOL/L): Grade 4 (>3.4)
    0
    0
        Calcium Hyper (MMOL/L): Grade 3 or above
    0
    0.4
        Calcium Hypo (MMOL/L): Grade 3 (1.5-<1.75)
    0
    0
        Calcium Hypo (MMOL/L): Grade 4 (<1.5)
    0
    0.4
        Calcium Hypo (MMOL/L): Grade 3 or above
    0
    0.4
        Sodium Hyper (MMOL/L): Grade 3 (>155-160)
    0.5
    0
        Sodium Hyper (MMOL/L): Grade 4 (>160)
    0
    0
        Sodium Hyper (MMOL/L): Grade 3 or above
    0.5
    0
        Sodium Hypo (MMOL/L): Grade 3 (120-<130)
    0
    0.4
        Sodium Hypo (MMOL/L): Grade 4 (<120)
    0
    0
        Sodium Hypo (MMOL/L): Grade 3 or above
    0
    0.4
        Potassium Hyper (MMOL/L): Grade 3 (>6.0-7.0)
    0
    0
        Potassium Hyper (MMOL/L): Grade 4 (>7.0)
    0
    0
        Potassium Hyper (MMOL/L): Grade 3 or above
    0
    0
        Potassium Hypo (MMOL/L): Grade 3 (2.5-<3.0)
    0
    0
        Potassium Hypo (MMOL/L): Grade 4 (<2.5)
    0
    0
        Potassium Hypo (MMOL/L): Grade 3 or above
    0
    0
        Glucose Hyper (MMOL/L): Grade 3 (>13.9-27.8)
    1.3
    0.4
        Glucose Hyper (MMOL/L): Grade 4 (>27.8)
    0
    0
        Glucose Hyper (MMOL/L): Grade 3 or above
    1.3
    0.4
        Glucose Hypo (MMOL/L): Grade 3 (1.7-<2.2)
    0
    0
        Glucose Hypo (MMOL/L): Grade 4 (<1.7)
    0
    0
        Glucose Hypo (MMOL/L): Grade 3 or above
    0
    0
        Albumin (G/L): Grade 3(<20)
    0
    0
        Albumin (G/L): Grade 3 or above
    0
    0
        Cholesterol (MMOL/L): Grade 3 (10.34<-12.92)
    1.3
    0
        Cholesterol (MMOL/L): Grade 4 (>12.92)
    0
    0
        Cholesterol (MMOL/L): Grade 3 or above
    1.3
    0
        Triglycerides (MMOL/L): Grade 3 (>5.7-11.4)
    3.4
    5.1
        Triglycerides (MMOL/L): Grade 4 (>11.4)
    0
    0
        Triglycerides (MMOL/L): Grade 3 or above
    3.4
    5.1
    Notes
    [4] - N=238 for all except Sodium Hyper/Hypo & Potassium Hyper/Hypo are N=212.
    No statistical analyses for this end point

    Primary: Percentage of Participants With Potentially Clinically Important (PCI) Vital Sign Measurements and Physical Examination Findings as Assessed by the Investigator

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    End point title
    		 Percentage of Participants With Potentially Clinically Important (PCI) Vital Sign Measurements and Physical Examination Findings as Assessed by the Investigator [5]
    End point description
    PCI post-baseline vital sign values are summarized for categories: systolic and diastolic blood pressures [sitting], pulse rate [sitting], and weight. Only those categories where at least 1 person had a non-PCI value at Baseline and met the PCI criterion at least once during post-baseline are reported. The Number Analyzed is defined as the number of participants with at least one post-baseline value for the specific criteria. Post-baseline grade must also be more extreme (worse) than the baseline grade in order to be included in the count. If a participant does not have a baseline value then the participant would be counted in the numerator if the participant had at least one post-baseline. BP = Blood Pressure
    End point type
    Primary
    End point timeframe
    From Baseline to 30 days following last dose of study drug (Week 52)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There will be no statistical testing for all of the efficacy and safety endpoints.
    End point values
    		 DUPI 300mg to UPA 30mg UPA 30mg to UPA 30mg
    Number of subjects analysed
    239 [6]
    236
    Units: Percentage of participants
    number (not applicable)
        Sitting Systolic BP (MMHG): ≤90 & ≥20 Decrease
    0.4
    0.8
        Sitting Systolic BP (MMHG): ≥160 & ≥20 Increase
    2.5
    5.5
        Sitting Diastolic BP (MMHG): ≤50 & ≥10 Decrease
    0.4
    1.3
        Sitting Diastolic BP (MMHG): ≥100 & ≥10 Increase
    2.1
    9.3
        Sitting Pulse Rate (BEATS/MIN): ≤50 & ≥15 Decrease
    1.7
    4.7
        Sitting Pulse Rate (BEATS/MIN):≥120 & ≥15 Increase
    0
    2.1
        Weight (KG): >7% Decrease
    5.5
    7.6
        Weight (KG): >7% Increase
    22.5
    39.0
    Notes
    [6] - N=238 for all except Weight is N=236.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and adverse event tables include treatment-emergent events reported from the time of informed consent to end of study in M19-850 (52 weeks of treatment plus a 30 day follow-up after last dose).
    Adverse event reporting additional description
    The median time on follow-up was 398 & 399 days for UPA/UPA & DUPI/UPA, respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    UPA 30mg to UPA 30mg
    Reporting group description
    		 -

    Reporting group title
    DUPI 300mg to UPA 30mg
    Reporting group description
    		 -

    Reporting group title
    Total
    Reporting group description
    		 -

    Serious adverse events
    		 UPA 30mg to UPA 30mg DUPI 300mg to UPA 30mg Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 236 (5.51%)
    14 / 239 (5.86%)
    27 / 475 (5.68%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    1
    0
    1
    Investigations
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    PROSTATE CANCER
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UTERINE LEIOMYOMA
         subjects affected / exposed
    0 / 236 (0.00%)
    2 / 239 (0.84%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FOOT FRACTURE
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    ESSENTIAL HYPERTENSION
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    FOOD ALLERGY
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    PANCREATITIS
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    ADNEXAL TORSION
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIOSIS
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS ATOPIC
         subjects affected / exposed
    1 / 236 (0.42%)
    1 / 239 (0.42%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BULLOUS IMPETIGO
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BONE TUBERCULOSIS
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    APPENDICITIS
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABSCESS JAW
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICHONDRITIS
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ECZEMA HERPETICUM
         subjects affected / exposed
    1 / 236 (0.42%)
    2 / 239 (0.84%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    3 / 236 (1.27%)
    0 / 239 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PILONIDAL DISEASE
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY SYNCYTIAL VIRUS INFECTION
         subjects affected / exposed
    0 / 236 (0.00%)
    1 / 239 (0.42%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 236 (0.42%)
    0 / 239 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 UPA 30mg to UPA 30mg DUPI 300mg to UPA 30mg Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    154 / 236 (65.25%)
    149 / 239 (62.34%)
    303 / 475 (63.79%)
    Investigations
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    35 / 236 (14.83%)
    31 / 239 (12.97%)
    66 / 475 (13.89%)
         occurrences all number
    47
    42
    89
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    14 / 236 (5.93%)
    4 / 239 (1.67%)
    18 / 475 (3.79%)
         occurrences all number
    14
    4
    18
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    15 / 236 (6.36%)
    14 / 239 (5.86%)
    29 / 475 (6.11%)
         occurrences all number
    22
    16
    38
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    54 / 236 (22.88%)
    49 / 239 (20.50%)
    103 / 475 (21.68%)
         occurrences all number
    65
    53
    118
    DERMATITIS ATOPIC
         subjects affected / exposed
    45 / 236 (19.07%)
    30 / 239 (12.55%)
    75 / 475 (15.79%)
         occurrences all number
    61
    48
    109
    ECZEMA
         subjects affected / exposed
    14 / 236 (5.93%)
    13 / 239 (5.44%)
    27 / 475 (5.68%)
         occurrences all number
    32
    17
    49
    Infections and infestations
    COVID-19
         subjects affected / exposed
    31 / 236 (13.14%)
    32 / 239 (13.39%)
    63 / 475 (13.26%)
         occurrences all number
    34
    34
    68
    HERPES SIMPLEX
         subjects affected / exposed
    12 / 236 (5.08%)
    8 / 239 (3.35%)
    20 / 475 (4.21%)
         occurrences all number
    13
    10
    23
    HERPES ZOSTER
         subjects affected / exposed
    19 / 236 (8.05%)
    25 / 239 (10.46%)
    44 / 475 (9.26%)
         occurrences all number
    20
    25
    45
    NASOPHARYNGITIS
         subjects affected / exposed
    15 / 236 (6.36%)
    26 / 239 (10.88%)
    41 / 475 (8.63%)
         occurrences all number
    23
    35
    58
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    12 / 236 (5.08%)
    14 / 239 (5.86%)
    26 / 475 (5.47%)
         occurrences all number
    13
    24
    37
    Metabolism and nutrition disorders
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    13 / 236 (5.51%)
    1 / 239 (0.42%)
    14 / 475 (2.95%)
         occurrences all number
    14
    1
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2019
    Version 2: Changes included clarifying that the safety endpoints were the primary endpoints for the study, further clarifying adverse reaction and SAE definitions, and clarifying management of study drug and subject treatment for herpes zoster or serious reactivated infection of any herpes virus.
    28 Jan 2020
    Version 3: Updated the number of sites and subjects to expand to all countries participating in Study M16-046. Other changes included updating benefits and risks to subjects to reflect updated safety language across the upadacitinib program, updating language for prohibited use of vaccines and strong CYP3A inhibitors or inducers, adding discontinuation criterion around confirmed thrombosis diagnosis and adding safety precautions around risk of thromboembolic events, clarifying language for AESIs, and updating toxicity management language to match updated Investigator's Brochure.
    06 Mar 2020
    Version 4: Clarified biomarker sample collection, updated study drug discontinuation criteria for subjects with worsening EASI score, added eczema herpeticum electronic case report form, and clarified the activity schedule to allow flexibility in return visits.
    07 Jan 2021
    Version 5: Incorporated necessary protocol modifications due to the COVID-19 pandemic, added an interim analysis, incorporated additional description about management of gastrointestinal perforation and serious herpes zoster, and provided clarification about the timing of efficacy assessments.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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