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    Clinical Trial Results:
    Master protocol of three randomized, double-blind, placebo-controlled, multi-center, parallel-group studies of dupilumab in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine treatment in patients naïve to omalizumab and in patients who are intolerant or incomplete responders to omalizumab

    Summary
    EudraCT number
    		 2019-003775-19
    Trial protocol
    		 DE   FR   HU   GB   ES   Outside EU/EEA  
    Global end of trial date
    25 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 May 2025
    First version publication date
    09 May 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC16461
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04180488
    WHO universal trial number (UTN)
    		 U1111-1241-8208
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    82 Avenue Raspail, Gentilly, France, 94250
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    20 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of dupilumab in study participants with chronic spontaneous urticaria (CSU) who remain symptomatic despite the use of H1 antihistamine (Study A and Study C: omalizumab naïve; Study B: omalizumab intolerant or incomplete responders).
    Protection of trial subjects
    For pediatrics: The study was conducted by investigators experienced in the treatment of pediatric participants. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia might have been used to minimize distress and discomfort. For adults: Participants were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trial, participants were provided with individual participant cards indicating the nature of the trial the participant is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2019
    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
    Argentina: 41
    Country: Number of subjects enrolled
    Canada: 99
    Country: Number of subjects enrolled
    China: 44
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    397
    EEA total number of subjects
    76
    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)
    5
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    329
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study comprised of 3 randomized studies of similar design: 2 studies were conducted in participants who were omalizumab naïve (Study A [55 centers in 9 countries] and Study C [50 centers in 9 countries]) and 1 study was conducted in participants who were omalizumab intolerant or incomplete responders (Study B [61 centers in 11 countries]).

    Pre-assignment
    Screening details
    		 Total 138 participants in Study A, 108 participants in Study B and 151 participants in Study C were randomized in a 1:1 ratio to receive either weight-tiered dupilumab or matching placebo in respective studies. As pre-specified in the protocol and statistical analysis plan (SAP), the results are presented by study and treatment group/intervention.

    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
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Study A: Placebo
    Arm description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as subcutaneous (SC) injection including loading dose from Day 1 up to 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to dupilumab was administered from Day 1 up to 24 weeks.

    Arm title
    		 Study A: Dupilumab
    Arm description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 milligrams (mg) SC injection every 2 weeks (q2w) for adults and those adolescents who weighed >=60 kilograms (kg) at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection every 4 weeks (q4w) for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    REGN668, Dupixent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was administered for 24 weeks as specified in the protocol.

    Arm title
    		 Study B: Placebo
    Arm description
    		 Participants who were intolerant or incomplete responders to omalizumab received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to dupilumab was administered from Day 1 up to 24 weeks.

    Arm title
    		 Study B: Dupilumab
    Arm description
    		 Participants who were intolerant or incomplete responders to omalizumab received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents weighing >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1 or - 200 mg SC injection q2w for adolescents weighing <60 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    REGN668, Dupixent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was administered for 24 weeks as specified in the protocol.

    Arm title
    		 Study C: Placebo
    Arm description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to dupilumab was administered from Day 1 up to 24 weeks.

    Arm title
    		 Study C: Dupilumab
    Arm description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents who weighed >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection q4w for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    REGN668, Dupixent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was administered for 24 weeks as specified in the protocol.

    Number of subjects in period 1
    		Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Started
    68
    70
    54
    54
    77
    74
    Completed
    55
    63
    47
    49
    67
    66
    Not completed
    13
    7
    7
    5
    10
    8
         Consent withdrawn by subject
    8
    4
    5
    2
    8
    6
         Adverse event, non-fatal
    3
    2
    -
    -
    -
    -
         Not related to Coronavirus Disease-2019 (COVID-19)
    2
    1
    1
    3
    2
    2
         Poor compliance to protocol
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study A: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as subcutaneous (SC) injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study A: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 milligrams (mg) SC injection every 2 weeks (q2w) for adults and those adolescents who weighed >=60 kilograms (kg) at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection every 4 weeks (q4w) for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Reporting group title
    Study B: Placebo
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study B: Dupilumab
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents weighing >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1 or - 200 mg SC injection q2w for adolescents weighing <60 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1.

    Reporting group title
    Study C: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study C: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents who weighed >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection q4w for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Reporting group values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab Total
    Number of subjects
    		 68 70 54 54 77 74 397
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.9 ( 14.8 ) 40.7 ( 16.2 ) 46.8 ( 16.3 ) 48.6 ( 15.6 ) 44.0 ( 16.7 ) 45.6 ( 17.1 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 50 41 41 37 59 47 275
        Male
    		 18 29 13 17 18 27 122
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 0 0 1 2
        Asian
    		 16 19 11 6 29 33 114
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 1 0 0 1
        Black or African American
    		 2 1 2 3 2 0 10
        White
    		 48 47 41 43 38 32 249
        More than one race
    		 1 1 0 0 2 1 5
        Unknown or Not Reported
    		 1 1 0 1 6 7 16
    Weekly Urticaria Activity (UAS7) Score
    Once daily UAS is sum of daily hive severity score (HSS) and daily itch severity score (ISS) recorded in electronic (e)-diary. Daily HSS assesses number of wheals; range 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity; range 0 (none) to 3 (intense). Daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores=greater severity of urticaria symptoms. Baseline=sum of daily scores for the 7 days prior to the day of randomization.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 30.8 ( 8.2 ) 31.9 ( 7.2 ) 31.9 ( 8.1 ) 31.0 ( 7.9 ) 28.1 ( 7.9 ) 28.6 ( 7.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Study A: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as subcutaneous (SC) injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study A: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 milligrams (mg) SC injection every 2 weeks (q2w) for adults and those adolescents who weighed >=60 kilograms (kg) at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection every 4 weeks (q4w) for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Reporting group title
    Study B: Placebo
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study B: Dupilumab
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents weighing >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1 or - 200 mg SC injection q2w for adolescents weighing <60 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1.

    Reporting group title
    Study C: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study C: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents who weighed >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection q4w for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Primary: Change From Baseline in Weekly Urticaria Activity Score at Week 24

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    End point title
    		 Change From Baseline in Weekly Urticaria Activity Score at Week 24
    End point description
    UAS is a validated composite patient-reported outcome (PRO) measure for assessing CSU. The once daily UAS is the sum of the daily HSS and daily ISS recorded in e-diary. Daily HSS assesses number of wheals and range from 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity and range from 0 (none) to 3 (intense). The daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create the UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores indicate greater severity of urticaria symptoms. Least squares (LS) mean is presented. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization. The intent-to-treat (ITT) population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -12.00 ( 1.81 )
    -20.53 ( 1.76 )
    -8.54 ( 2.14 )
    -14.37 ( 2.16 )
    -11.21 ( 2.65 )
    -15.86 ( 2.66 )
    Statistical analysis title
    		 Change From Baseline in UAS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an analysis of covariance (ANCOVA) model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0003 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.16
         upper limit
    		 -3.9
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error.
    [2] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Change From Baseline in UAS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0226 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.65
         upper limit
    		 -0.65
    Notes
    [3] - A hierarchical testing procedure was used to control the overall type I error.
    [4] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Change From Baseline in UAS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study B: Placebo v Study B: Dupilumab
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.039 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.37
         upper limit
    		 -0.3
    Notes
    [5] - A hierarchical testing procedure was used to control the overall type I error.
    [6] - Threshold for significance at 2-sided 0.043 level.

    Secondary: Change From Baseline in Weekly Itch Severity Score at Week 24

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    End point title
    		 Change From Baseline in Weekly Itch Severity Score at Week 24
    End point description
    ISS was recorded in e-diary. The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. LS mean is presented. Baseline was defined as the sum of daily scores obtained for 7 days prior to randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -6.01 ( 0.94 )
    -10.24 ( 0.91 )
    -4.81 ( 1.08 )
    -7.68 ( 1.10 )
    -6.10 ( 1.40 )
    -8.64 ( 1.41 )
    Statistical analysis title
    		 Change From Baseline in ISS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0005 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.63
         upper limit
    		 -1.84
    Notes
    [7] - A hierarchical testing procedure was used to control the overall type I error.
    [8] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Change From Baseline in ISS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0184 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.65
         upper limit
    		 -0.43
    Notes
    [9] - A hierarchical testing procedure was used to control the overall type I error.
    [10] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Change From Baseline in ISS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study B: Placebo v Study B: Dupilumab
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0449 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.68
         upper limit
    		 -0.07
    Notes
    [11] - A hierarchical testing procedure was used to control the overall type I error.
    [12] - Threshold for significance at 2-sided 0.043 level.

    Secondary: Change From Baseline in Weekly Hives Severity Score at Week 24

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    End point title
    		 Change From Baseline in Weekly Hives Severity Score at Week 24
    End point description
    Daily HSS was recorded in e-diary. The HSS7 score is the sum of daily HSS ranging from 0 (none) to 3 (more than 50 hives) recorded by a participant at the same time of each day over 7 days with an overall scale of 0 (no hives) to 21 (severe hives). Higher scores indicate greater intensity of hives. LS mean is presented. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -5.90 ( 0.93 )
    -10.28 ( 0.91 )
    -3.63 ( 1.11 )
    -6.64 ( 1.11 )
    -5.11 ( 1.31 )
    -7.27 ( 1.32 )
    Statistical analysis title
    		 Change From Baseline in HSS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0003 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.78
         upper limit
    		 -1.98
    Notes
    [13] - A hierarchical testing procedure was used to control the overall type I error.
    [14] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Change From Baseline in HSS7 at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0316 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.15
         upper limit
    		 -0.19
    Notes
    [15] - A hierarchical testing procedure was used to control the overall type I error.
    [16] - Threshold for significance at 2- sided 0.05 level.

    Secondary: Percentage of Responders for Weekly Itch Severity Score Minimally Important Difference (MID) at Week 24

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    End point title
    		 Percentage of Responders for Weekly Itch Severity Score Minimally Important Difference (MID) at Week 24
    End point description
    The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. An ISS7 MID response was defined as >=5 points decrease from baseline after study intervention. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
        number (not applicable)
    42.6
    72.9
    38.9
    59.3
    51.9
    70.3
    Statistical analysis title
    		 Percentage of Responders for ISS7 MID at Week 24
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0109 [18]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.507
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.231
         upper limit
    		 5.107
    Notes
    [17] - A hierarchical testing procedure was used to control the overall type I error.
    [18] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 Percentage of Responders for ISS7 MID at Week 24
    Statistical analysis description
    Cochran-Mantel-Haenszel (CMH) test performed on association between responder status and intervention group, adjusted by baseline disease severity (UAS7<28,>=28), presence of angioedema at baseline and region.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0014 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.413
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.596
         upper limit
    		 7.299
    Notes
    [19] - A hierarchical testing procedure was used to control the overall type I error.
    [20] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Percentage of Participants With Weekly Urticaria Activity Score <=6 at Week 24

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    End point title
    		 Percentage of Participants With Weekly Urticaria Activity Score <=6 at Week 24
    End point description
    UAS is a validated composite PRO measure for assessing CSU activity. The once daily UAS is the sum of the daily HSS and daily ISS recorded in e-diary. Daily HSS assesses number of wheals and range from 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity and range from 0 (none) to 3 (intense). The daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create the UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores indicate greater severity of urticaria symptoms. In evaluating urticaria control using UAS7, an UAS7 score of <=6 indicated a well-controlled urticaria. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
        number (not applicable)
    23.5
    45.7
    18.5
    24.1
    23.4
    40.5
    Statistical analysis title
    		 Percentage of Participants With UAS7<=6 at Week 24
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0045 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.371
         upper limit
    		 7.176
    Notes
    [21] - A hierarchical testing procedure was used to control the overall type I error.
    [22] - Threshold for significance at 2- sided 0.05 level.
    Statistical analysis title
    		 Percentage of Participants With UAS7<=6 at Week 24
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.0075 [24]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.848
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.301
         upper limit
    		 6.234
    Notes
    [23] - A hierarchical testing procedure was used to control the overall type I error
    [24] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Percentage of Participants With Weekly Urticaria Activity Score =0 at Week 24

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    End point title
    		 Percentage of Participants With Weekly Urticaria Activity Score =0 at Week 24
    End point description
    UAS is a validated composite PRO measure for assessing CSU activity. The once daily UAS is the sum of the daily HSS and daily ISS recorded in e-diary. Daily HSS assesses number of wheals and range from 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity and range from 0 (none) to 3 (intense). The daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create the UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores indicate greater severity of urticaria symptoms. In evaluating urticaria control using UAS7, an UAS7 score of 0 indicated an absence of both itch and hives and a complete resolution of CSU symptoms. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
        number (not applicable)
    13.2
    31.4
    9.3
    13.0
    18.2
    29.7
    Statistical analysis title
    		 UAS7=0 at Week 24
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0187 [26]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.677
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.127
         upper limit
    		 6.359
    Notes
    [25] - A hierarchical testing procedure was used to control the overall type I error.
    [26] - Threshold for significance at 2-sided 0.05 level.
    Statistical analysis title
    		 UAS7=0 at Week 24
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.0199 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.908
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.173
         upper limit
    		 7.209
    Notes
    [27] - A hierarchical testing procedure was used to control the overall type I error.
    [28] - Threshold for significance at 2- sided 0.05 level.

    Secondary: Change From Baseline in Urticaria Control Test (UCT) at Week 24

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    End point title
    		 Change From Baseline in Urticaria Control Test (UCT) at Week 24
    End point description
    The UCT assessed urticaria control based on 4 items (severity of pruritus and wheals urticaria symptoms; frequency of treatment being not sufficient; quality-of-life [QoL] impairment; overall urticarial control). Each item was rated on a 5-point Likert-type scale from 0 (no control) to 4 (maximum control). The overall UCT score was the sum of all 4 individual item scores with a range of 0 (no disease control) to 16 (complete disease control). Higher scores indicated greater disease control. LS mean is presented. Baseline was defined as the last available value up to randomization date and prior to the first dose of study intervention. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    4.88 ( 0.61 )
    7.71 ( 0.59 )
    3.38 ( 0.74 )
    5.33 ( 0.77 )
    4.16 ( 0.94 )
    5.09 ( 0.95 )
    Statistical analysis title
    		 Change From Baseline in UCT at Week 24
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study C: Placebo v Study C: Dupilumab
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.194 [30]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 2.34
    Notes
    [29] - A hierarchical testing procedure was used to control the overall type I error.
    [30] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Change From Baseline in Weekly Itch Severity Score at Week 12

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    End point title
    		 Change From Baseline in Weekly Itch Severity Score at Week 12
    End point description
    ISS was recorded in e-diary. The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. LS mean is presented. Baseline was defined as the sum of daily scores obtained for 7 days prior to randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -6.01 ( 0.85 )
    -8.37 ( 0.84 )
    -4.52 ( 0.95 )
    -7.37 ( 0.97 )
    -5.31 ( 1.32 )
    -7.15 ( 1.32 )
    Statistical analysis title
    		 Change From Baseline in ISS7 at Week 12
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.0377 [32]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 -0.13
    Notes
    [31] - A hierarchical testing procedure was used to control the overall type I error.
    [32] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Change From Baseline in Weekly Urticaria Activity Score at Week 12

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    End point title
    		 Change From Baseline in Weekly Urticaria Activity Score at Week 12
    End point description
    UAS is a validated composite PRO measure for assessing CSU activity. The once daily UAS is the sum of the daily HSS and daily ISS recorded in e-diary. Daily HSS assesses number of wheals and range from 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity and range from 0 (none) to 3 (intense). The daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create the UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores indicate greater severity of urticaria symptoms. LS mean is presented. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -11.79 ( 1.64 )
    -16.81 ( 1.62 )
    -8.22 ( 1.91 )
    -13.33 ( 1.94 )
    -9.51 ( 2.54 )
    -12.87 ( 2.54 )
    Statistical analysis title
    		 Change From Baseline in UAS7 at Week 12
    Statistical analysis description
    Analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, presence of angioedema at baseline, and regions as covariates.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.0223 [34]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.32
         upper limit
    		 -0.72
    Notes
    [33] - A hierarchical testing procedure was used to control the overall type I error.
    [34] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Percentage of Participants With Weekly Urticaria Activity Score <=6 and =0 at Week 12

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    End point title
    		 Percentage of Participants With Weekly Urticaria Activity Score <=6 and =0 at Week 12
    End point description
    UAS is a validated composite PRO measure for assessing CSU activity. The once daily UAS is the sum of the daily HSS and daily ISS recorded in e-diary. Daily HSS assesses number of wheals and range from 0 (none) to 3 (more than 50 hives) whereas daily ISS assesses itch intensity and range from 0 (none) to 3 (intense). The daily UAS scores range from 0 to 6 point/day. Once daily UAS scores are summed over 7-day period to create the UAS7 with an overall scale of 0 (no urticaria) to 42 (severe urticaria). Higher scores indicate greater severity of urticaria symptoms. In evaluating urticaria control using UAS7, an UAS7 score of <=6 indicated a well-controlled urticaria and an UAS7 score of 0 indicated an absence of both itch and hives and a complete resolution of CSU symptoms. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
    number (not applicable)
        UAS7 <=6
    17.6
    34.3
    9.3
    24.1
    16.9
    31.1
        UAS7=0
    8.8
    15.7
    1.9
    13.0
    11.7
    17.6
    Statistical analysis title
    		 UAS7 <=6 at Week 12
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.0215 [36]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.645
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.154
         upper limit
    		 6.061
    Notes
    [35] - A hierarchical testing procedure was used to control the overall type I error.
    [36] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Percentage of Responders for Weekly Itch Severity Score Minimally Important Difference at Week 12

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    End point title
    		 Percentage of Responders for Weekly Itch Severity Score Minimally Important Difference at Week 12
    End point description
    The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. An ISS7 MID response was defined as >=5 points decrease from baseline after study intervention. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
        number (not applicable)
    52.9
    70.0
    46.3
    64.8
    51.9
    58.1
    Statistical analysis title
    		 MID at Week 12
    Statistical analysis description
    CMH test was performed on the association between the responder status and intervention group, adjusted by baseline disease severity (UAS7 <28, >=28), presence of angioedema at baseline, and region.
    Comparison groups
    Study A: Placebo v Study A: Dupilumab
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.0971 [38]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.872
    Confidence interval
         level
    		 85%
         sides
    2-sided
         lower limit
    		 0.893
         upper limit
    		 3.923
    Notes
    [37] - A hierarchical testing procedure was used to control the overall type I error.
    [38] - Threshold for significance at 2-sided 0.05 level.

    Secondary: Change From Baseline in Weekly Hives Severity Score at Week 12

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    End point title
    		 Change From Baseline in Weekly Hives Severity Score at Week 12
    End point description
    Daily HSS was recorded in e-diary. The HSS7 score is the sum of daily HSS ranging from 0 (none) to 3 (more than 50 hives) recorded by a participant at the same time of each day over 7 days with an overall scale of 0 (no hives) to 21 (severe hives). Higher scores indicate greater intensity of hives. LS mean is presented. Baseline was defined as the sum of the daily scores for the 7 days prior to the day of randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    -5.69 ( 0.83 )
    -8.39 ( 0.83 )
    -3.71 ( 1.01 )
    -5.97 ( 1.02 )
    -4.22 ( 1.28 )
    -5.75 ( 1.28 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urticaria Control Test at Week 12

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    End point title
    		 Change From Baseline in Urticaria Control Test at Week 12
    End point description
    The UCT assessed urticaria control based on 4 items (severity of pruritus and wheals urticaria symptoms; frequency of treatment being not sufficient; QoL impairment; overall urticarial control). Each item was rated on a 5-point Likert-type scale from 0 (no control) to 4 (maximum control). The overall UCT score was the sum of all 4 individual item scores with a range of 0 (no disease control) to 16 (complete disease control). Higher scores indicated greater disease control. LS mean is presented. Baseline was defined as the last available value up to randomization date and prior to the first dose of study intervention. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: score on a scale
        least squares mean (standard error)
    4.62 ( 0.57 )
    6.48 ( 0.57 )
    3.11 ( 0.65 )
    5.48 ( 0.67 )
    3.26 ( 0.88 )
    4.61 ( 0.89 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Itch Severity Score at Weeks 4, 8, 16 and 20

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    End point title
    		 Change From Baseline in Weekly Itch Severity Score at Weeks 4, 8, 16 and 20
    End point description
    ISS was recorded in e-diary. The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. Mean is presented. Baseline was defined as the sum of daily scores obtained for 7 days prior to randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization. Only those participants with data collected at specified timepoints are reported. Here, n=participants analyzed for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 4, 8, 16 and 20
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    65
    70
    54
    54
    72
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=65,70,54,54,72,69)
    -3.30 ( 6.54 )
    -4.96 ( 5.49 )
    -4.12 ( 6.28 )
    -5.51 ( 5.64 )
    -3.78 ( 4.73 )
    -5.26 ( 5.16 )
        Week 8 (n=62,68,50,52,70,69)
    -4.98 ( 7.49 )
    -6.99 ( 6.78 )
    -4.27 ( 5.92 )
    -7.25 ( 6.29 )
    -4.92 ( 5.67 )
    -7.83 ( 6.02 )
        Week 16 (n=58,66,50,51,68,70)
    -5.61 ( 7.45 )
    -9.43 ( 6.86 )
    -4.52 ( 6.68 )
    -8.05 ( 7.43 )
    -6.22 ( 5.78 )
    -8.24 ( 7.37 )
        Week 20 (n=57,64,49,50,67,66)
    -6.40 ( 7.82 )
    -10.04 ( 7.22 )
    -5.35 ( 7.17 )
    -7.54 ( 7.94 )
    -6.64 ( 6.43 )
    -9.27 ( 6.58 )
    No statistical analyses for this end point

    Secondary: Time to First Weekly Itch Severity Score Minimally Important Difference Response During the 24-Week Treatment Period

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    End point title
    		 Time to First Weekly Itch Severity Score Minimally Important Difference Response During the 24-Week Treatment Period
    End point description
    The ISS represents severity of itch on a scale ranging from 0 (none) to 3 (intense). The ISS7 score was the sum of daily ISS scores recorded by a participant at the same time each day over 7 days with an overall scale of 0 (no impact) to 21 (severe impact). Higher scores indicated greater intensity of itch. The MID for ISS7 was a change of 5.0 points. Time to first ISS7 MID response (ISS7 >=5) was defined as time to reduction from baseline of 5 points or more. Kaplan-Meier estimate is presented. Baseline was defined as the sum of daily scores obtained for 7 days prior to randomization. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: weeks
        median (confidence interval 95%)
    4.0 (2.0 to 8.0)
    3.0 (2.0 to 5.0)
    4.0 (2.0 to 7.0)
    3.0 (2.0 to 4.0)
    5.0 (3.0 to 7.0)
    3.5 (3.0 to 5.0)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Angioedema Activity Score Over 7 Days (AAS7) at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Angioedema Activity Score Over 7 Days (AAS7) at Weeks 12 and 24
    End point description
    AAS is a diary in which participants document on daily basis presence or absence of angioedema during past 24 hours. If angioedema is present, participants answer 5 additional questions about time of day swelling episode occurred and severity and impact on daily functioning and appearance this swelling episode has had. Each AAS item is scored between 0 (minimum) and 3 (maximum). Daily AASs range from (no episodes) to 15 (severe episodes) points.AAS7 score is sum of daily AAS scores reported by participant at same time of each day over 7 days, with range of 0 (no angioedema episodes) to 105 (highest angioedema severity). Higher scores indicate greater angioedema activity. Mean is presented. Baseline: sum of the daily scores for the 7 days prior to the day of randomization. Analysis was performed on ITT population. Only those participants with angioedema at baseline and with data collected at specified timepoints are reported. Here, n=participants analyzed for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    31
    27
    32
    20
    21
    12
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 12 (n=31,27,32,19,18,11)
    -23.46 ( 21.76 )
    -19.14 ( 18.89 )
    -16.74 ( 21.74 )
    -19.41 ( 34.44 )
    -32.14 ( 32.15 )
    -34.33 ( 36.19 )
        Week 24 (n=29,26,28,20,21,12)
    -23.56 ( 23.04 )
    -18.76 ( 22.85 )
    -15.83 ( 25.73 )
    -13.95 ( 37.22 )
    -31.00 ( 36.38 )
    -36.28 ( 27.61 )
    No statistical analyses for this end point

    Secondary: Percentage of Well-controlled Participants (Urticaria Control Test >=12) at Weeks 12 and 24

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    End point title
    		 Percentage of Well-controlled Participants (Urticaria Control Test >=12) at Weeks 12 and 24
    End point description
    The UCT assessed urticaria control based on 4 items (severity of pruritus and wheals urticaria symptoms; frequency of treatment being not sufficient; QoL impairment; overall urticarial control). Each item was rated on a 5-point Likert-type scale from 0 (no control) to 4 (maximum control). The overall UCT score was the sum of all 4 individual item scores with a range of 0 (no disease control) to 16 (complete disease control). Higher scores indicated greater disease control. An UCT score of >=12 (out of maximum 16) indicated a well-controlled urticaria disease status. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
    number (not applicable)
        Week 12
    27.9
    44.3
    18.5
    51.9
    22.1
    37.8
        Week 24
    30.9
    48.6
    20.4
    44.4
    39.0
    50.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-related Quality-of-life as Measured by Children’s Dermatology Life Quality Index (CDLQI) in Participants >=6 to <16 Years old at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Health-related Quality-of-life as Measured by Children’s Dermatology Life Quality Index (CDLQI) in Participants >=6 to <16 Years old at Weeks 12 and 24
    End point description
    CDLQI measures impact of skin disease on children’s HRQoL;contains 10 questions(symptoms feelings associated with disease,impact of disease on leisure,school or holidays,personal relationships,sleep&side effects of treatment for skin disease);recall period of 7 days.9 of 10 questions scored on 4-point Likert scale from 0(not at all/question unanswered) to 3(very much).Question 7 has additional possible response(prevented school) and assigned score of 3(0 [not at all] to 3[definitely]).Total CDLQI score=sum of score of each question ranging 0 (no impact) to 30 (severe impact). Higher score=greater impact on child’s HRQoL.Mean is presented.Baseline:last available value up to randomization date and prior to first dose of study intervention.ITT population. Only those participants >=6 and <16 years with data collected at specified timepoints are reported. n=participants analyzed for specified category.99999=number analyzed was 0; 9999=standard deviation not calculated for 1 participant.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    1
    2
    0 [39]
    1
    5
    2
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 12 (n=1,2,0,1,5,2)
    -5.00 ( 9999 )
    -8.00 ( 5.66 )
    ( )
    -7 ( 9999 )
    -4.60 ( 10.04 )
    -9.00 ( 2.83 )
        Week 24 (0,2,0,1,5,2)
    99999 ( 99999 )
    -12.50 ( 12.02 )
    ( )
    -7 ( 9999 )
    -5.60 ( 7.83 )
    -4.50 ( 7.78 )
    Notes
    [39] - No participants were analyzed.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-related Quality-of-life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) in Participants >=16 Years old at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Health-related Quality-of-life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) in Participants >=16 Years old at Weeks 12 and 24
    End point description
    DLQI assesses impact of skin disease on participants’ HRQoL over previous week;contains 10 questions related to symptoms,leisure activities,work/school or holiday time,personal relationships including intimate,side effects of treatment,and emotional reactions to having a skin disease.Questions (except question 7) scored on 4-point Likert scale: 0(not at all),1(a little),2(a lot),3(very much).Question 7 about work/studying asked whether work/study was prevented;then (if “No”) to what degree the skin condition has been a problem at work/study;item again rated on 3-point Likert scale:0(not at all) to 3(a lot).Total DLQI=summing score of each question;ranged from 0 (no impact) to 30 (severe impact).Higher scores indicated poor HRQoL.Baseline:last available value up to randomization date and prior to first dose of study intervention.ITT population. Only those participants >=16 years with data collected at specified timepoints are reported. n=participants analyzed for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    65
    65
    51
    47
    67
    70
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 12 (n=65,65,51,47,67,70)
    -7.55 ( 7.47 )
    -8.55 ( 6.27 )
    -4.53 ( 6.28 )
    -6.77 ( 6.92 )
    -5.01 ( 6.25 )
    -6.61 ( 7.04 )
        Week 24 (n=61,64,49,45,63,67)
    -7.56 ( 8.13 )
    -9.50 ( 5.92 )
    -4.96 ( 6.87 )
    -6.91 ( 7.51 )
    -6.81 ( 6.54 )
    -8.09 ( 7.66 )
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) of Chronic Spontaneous Urticaria at Weeks 12 and 24

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    End point title
    		 Patient Global Impression of Change (PGIC) of Chronic Spontaneous Urticaria at Weeks 12 and 24
    End point description
    The PGIC is a 1-item questionnaire that asks the participant to provide the overall self-assessment of change in their CSU on a 7-point scale compared to just before participant started taking the study intervention. Response choices are: 0 (very much better), 1 (moderately better), 2 (a little better), 3 (no change), 4 (a little worse), 5 (moderately worse), 6 (very much worse). Higher score indicate worsening. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization. Only those participants with data collected at Weeks 12 and 24 are reported. Here, n=participants analyzed for specified category.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    66
    69
    54
    52
    73
    73
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 12 (n=66,69,54,52,73,73)
    1.68 ( 1.43 )
    1.10 ( 1.24 )
    2.06 ( 1.29 )
    1.62 ( 1.46 )
    1.59 ( 1.23 )
    1.27 ( 1.44 )
        Week 24 (n=61,68,50,50,68,70)
    1.70 ( 1.50 )
    1.04 ( 1.51 )
    1.90 ( 1.64 )
    1.44 ( 1.55 )
    1.18 ( 1.36 )
    1.01 ( 1.48 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Global Impression of Severity (PGIS) of Chronic Spontaneous Urticaria at Weeks 12 and 24

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    End point title
    		 Change From Baseline in Patient Global Impression of Severity (PGIS) of Chronic Spontaneous Urticaria at Weeks 12 and 24
    End point description
    The PGIS is a 1-item questionnaire that asks participants to provide the overall self-assessment of their disease severity on a 4-point scale for the past week. Response choices are: 1 (none), 2 (mild), 3 (moderate), 4 (severe). Higher score indicate more severity. Baseline was defined as the last available value up to randomization date and prior to the first dose of study intervention. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization. Only those participants with data collected at specified timepoints are reported. Here, n=participants analyzed for a specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 12 and 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    66
    69
    54
    52
    73
    73
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 12 (n=66,69,54,52,73,73)
    -0.89 ( 0.98 )
    -1.23 ( 0.93 )
    -0.46 ( 0.93 )
    -1.15 ( 1.04 )
    -0.82 ( 0.98 )
    -0.95 ( 0.97 )
        Week 24 (n=61,68,50,50,68,70)
    -0.97 ( 1.18 )
    -1.44 ( 0.92 )
    -0.54 ( 1.16 )
    -0.96 ( 1.05 )
    -1.03 ( 1.09 )
    -1.33 ( 1.05 )
    No statistical analyses for this end point

    Secondary: Time to First Oral Corticosteroid (OCS) use for Chronic Spontaneous Urticaria During the 24-week Treatment Period

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    End point title
    		 Time to First Oral Corticosteroid (OCS) use for Chronic Spontaneous Urticaria During the 24-week Treatment Period
    End point description
    Participants receiving OCS as rescue medications for CSU were recorded by the Investigator in e-case report form (eCRF) during the 24-week treatment period. Kaplan-Meier estimate for time to first OCS use is presented. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: weeks
        median (confidence interval 95%)
    0.110 (0.048 to 0.200)
    0.087 (0.035 to 0.168)
    0.158 (0.074 to 0.271)
    0.116 (0.047 to 0.220)
    0.067 (0.025 to 0.138)
    0.014 (0.001 to 0.068)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Receiving Oral Corticosteroid for Chronic Spontaneous Urticaria During the 24-week Treatment Period

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    End point title
    		 Percentage of Participants Receiving Oral Corticosteroid for Chronic Spontaneous Urticaria During the 24-week Treatment Period
    End point description
    Percentage of participants receiving OCS as rescue medications for CSU were recorded by the Investigator in eCRF during the 24-week treatment period. The ITT population included all randomized participants analyzed according to the intervention group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: percentage of participants
        number (not applicable)
    10.3
    8.6
    14.8
    11.1
    6.5
    1.4
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were defined as AEs that developed, worsened or became serious during the TE period. The safety population included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. As pre-specified in the protocol and SAP, the results are presented by study and treatment group/intervention.
    End point type
    Secondary
    End point timeframe
    From first dose of study intervention (Day 1) up to end of follow-up, approximately 36 weeks each for Study A, B and C
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    68
    70
    54
    54
    77
    74
    Units: participants
        TEAEs
    40
    38
    29
    33
    41
    40
        TESAEs
    5
    2
    2
    3
    1
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Anti-drug Antibodies (ADA) Against Dupilumab

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    End point title
    		 Number of Participants With Treatment-emergent Anti-drug Antibodies (ADA) Against Dupilumab
    End point description
    Blood samples were collected at specified timepoints and ADA samples were assayed using validated methods. Treatment-emergent ADA response was defined as a positive response in the ADA assay post first dose when baseline results were negative or missing. Number of participants with treatment-emergent ADA response is presented. The ADA population included all participants in the safety population who had at least 1 non-missing ADA result after first dose of the study intervention.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Study A: Placebo Study A: Dupilumab Study B: Placebo Study B: Dupilumab Study C: Placebo Study C: Dupilumab
    Number of subjects analysed
    66
    69
    53
    52
    75
    72
    Units: participants
    1
    9
    2
    10
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study intervention (Day 1) up to end of follow-up, approximately 36 weeks each for Study A, B and C
    Adverse event reporting additional description
    Analysis was performed on the safety population. As pre-specified in the protocol and SAP, the results are presented by study and treatment group/intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Study A: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study C: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents who weighed >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection q4w for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Reporting group title
    Study B: Dupilumab
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents weighing >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1 or - 200 mg SC injection q2w for adolescents weighing <60 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1.

    Reporting group title
    Study C: Placebo
    Reporting group description
    		 Participants who were omalizumab naïve received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Reporting group title
    Study A: Dupilumab
    Reporting group description
    		 Participants who were omalizumab naïve received dupilumab for 24 weeks as follows: - 300 mg SC injection q2w for adults and those adolescents who weighed >=60 kg at screening starting from Week 2 following a loading dose of 600 mg (2×300 mg injections) on Day 1, - 200 mg SC injection q2w for adolescents who weighed <60 kg and children (>=6 to <12 years of age) who weighed >=30 kg at screening starting from Week 2 following a loading dose of 400 mg (2×200 mg injections) on Day 1 and - 300 mg SC injection q4w for children (>=6 to <12 years of age) who weighed <30 kg and >=15 kg at screening starting from Week 4 following a loading dose of 600 mg (2×300 mg injections) on Day 1.

    Reporting group title
    Study B: Placebo
    Reporting group description
    		 Participants who were intolerant or incomplete responders to omalizumab received placebo matched to dupilumab as SC injection including loading dose from Day 1 up to 24 weeks.

    Serious adverse events
    		 Study A: Placebo Study C: Dupilumab Study B: Dupilumab Study C: Placebo Study A: Dupilumab Study B: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 68 (7.35%)
    5 / 74 (6.76%)
    3 / 54 (5.56%)
    1 / 77 (1.30%)
    2 / 70 (2.86%)
    2 / 54 (3.70%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal Adenocarcinoma
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    1 / 54 (1.85%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    1 / 77 (1.30%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Hepatic Steatosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis Atopic
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Spontaneous Urticaria
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    1 / 54 (1.85%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic Angioedema
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    1 / 54 (1.85%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    1 / 70 (1.43%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    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
    Osteoarthritis
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 74 (1.35%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 74 (0.00%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Study A: Placebo Study C: Dupilumab Study B: Dupilumab Study C: Placebo Study A: Dupilumab Study B: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 68 (27.94%)
    20 / 74 (27.03%)
    17 / 54 (31.48%)
    15 / 77 (19.48%)
    12 / 70 (17.14%)
    15 / 54 (27.78%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 68 (0.00%)
    5 / 74 (6.76%)
    3 / 54 (5.56%)
    2 / 77 (2.60%)
    1 / 70 (1.43%)
    2 / 54 (3.70%)
         occurrences all number
    0
    5
    3
    2
    1
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 74 (0.00%)
    3 / 54 (5.56%)
    0 / 77 (0.00%)
    0 / 70 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    4 / 68 (5.88%)
    4 / 74 (5.41%)
    0 / 54 (0.00%)
    0 / 77 (0.00%)
    3 / 70 (4.29%)
    3 / 54 (5.56%)
         occurrences all number
    9
    10
    0
    0
    13
    4
    Injection Site Reaction
         subjects affected / exposed
    2 / 68 (2.94%)
    3 / 74 (4.05%)
    1 / 54 (1.85%)
    1 / 77 (1.30%)
    4 / 70 (5.71%)
    1 / 54 (1.85%)
         occurrences all number
    10
    8
    1
    1
    9
    2
    Skin and subcutaneous tissue disorders
    Chronic Spontaneous Urticaria
         subjects affected / exposed
    6 / 68 (8.82%)
    2 / 74 (2.70%)
    6 / 54 (11.11%)
    3 / 77 (3.90%)
    3 / 70 (4.29%)
    3 / 54 (5.56%)
         occurrences all number
    6
    2
    8
    4
    4
    4
    Angioedema
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 74 (4.05%)
    2 / 54 (3.70%)
    1 / 77 (1.30%)
    1 / 70 (1.43%)
    0 / 54 (0.00%)
         occurrences all number
    4
    3
    2
    1
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 74 (5.41%)
    1 / 54 (1.85%)
    6 / 77 (7.79%)
    1 / 70 (1.43%)
    4 / 54 (7.41%)
         occurrences all number
    3
    4
    1
    6
    1
    5
    Covid-19
         subjects affected / exposed
    2 / 68 (2.94%)
    6 / 74 (8.11%)
    5 / 54 (9.26%)
    4 / 77 (5.19%)
    1 / 70 (1.43%)
    4 / 54 (7.41%)
         occurrences all number
    2
    6
    5
    4
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Apr 2020
    The primary purpose of this amendment was to increase the sample size of Study A (omalizumab naïve population) based on recommendation from Food and Drug Administration to power the studies using conservative assumptions with regards to intervention effect and variability and to include children aged >=6 to <12 years (for Study A only), and to switch the primary and the key secondary endpoints to establish UAS7 as the primary endpoint for European Union (EU) and EU reference countries based on recommendations from European Medicines Agency.
    29 Apr 2021
    The primary purpose of this amendment was to plan for an interim analysis for Study B when 80 randomized participants would have completed their 24-week intervention period.
    17 Mar 2022
    The primary purpose of this amendment was to conduct a Study C with a study population and design similar to the completed Study A to meet Health Authority requirements to provide data from 2 adequate and well-controlled clinical trials to support filing of a marketing application. In addition, key Study A results and information on the Study B prespecified interim analysis outcome were added to this amended protocol.

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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