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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study to Demonstrate the Efficacy and Long-Term Safety of Dupilumab in Adult Patients With Moderate-to-Severe Atopic Dermatitis

    Summary
    EudraCT number
    2013-003254-24
    Trial protocol
    DE   CZ   IT   HU   NL   LV   BE   PL   ES   RO   FR  
    Global end of trial date
    19 Oct 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Dec 2019
    First version publication date
    24 Aug 2017
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Minor corrections

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1224
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02260986
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States,
    Public contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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
    Interim
    Date of interim/final analysis
    27 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate the efficacy of Dupilumab administered concomitantly with topical corticosteroid (TCS) through Week 16 in adult subjects with moderate-to-severe atopic dermatitis (AD) compared to placebo administered concomitantly with TCS.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    All subjects were required to apply moisturizers (emollients) at least twice daily for at least 7 consecutive days immediately before randomization and to continue throughout the study. Starting on Day 1/baseline, all subjects were required to initiate treatment with a TCS using a standardized regimen. The type and amount of topical products (TCS and topical calcineurin inhibitors [TCI]) used during the study were recorded. It was recommended that subjects use triamcinolone acetonide 0.1% cream or fluocinolone acetonide 0.025% ointment for medium potency, and hydrocortisone 1% cream for low potency.
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    United States: 139
    Country: Number of subjects enrolled
    Australia: 41
    Country: Number of subjects enrolled
    Canada: 115
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 117
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Poland: 144
    Country: Number of subjects enrolled
    Romania: 4
    Worldwide total number of subjects
    740
    EEA total number of subjects
    297
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    713
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 14 countries between 16 Sep 2014 and 19 Oct 2016. A total of 957 subjects were screened in the study.

    Pre-assignment
    Screening details
    Out of 957 subjects, 740 subjects were randomized and treated in the study. Subjects were randomized in 3:1:3 ratio to receive Dupilumab 300 mg once weekly (qw) or Dupilumab 300 mg every 2 weeks (q2w) or placebo (for Dupilumab) qw.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo qw
    Arm description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

    Arm title
    Dupilumab 300 mg q2w
    Arm description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, subjects received placebo.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab 300 mg q2w
    Investigational medicinal product code
    REGN668; SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

    Arm title
    Dupilumab 300 mg qw
    Arm description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab 300 mg qw
    Investigational medicinal product code
    REGN668; SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection among the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms.

    Number of subjects in period 1
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Started
    315
    106
    319
    Completed
    225
    93
    278
    Not completed
    90
    13
    41
         Protocol deviation
    14
    5
    16
         Car accident
    -
    -
    1
         Adverse event
    24
    -
    11
         Lack of efficacy
    27
    3
    -
         Pregnancy
    2
    -
    -
         Incorrect randomization
    -
    1
    -
         Consent withdrawn by subject
    17
    4
    9
         Lack of investigation product supply
    2
    -
    1
         Lost to follow-up
    4
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo qw
    Reporting group description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, subjects received placebo.

    Reporting group title
    Dupilumab 300 mg qw
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51.

    Reporting group values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw Total
    Number of subjects
    315 106 319 740
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.6 ± 13.01 39.6 ± 13.98 36.9 ± 13.67 -
    Gender categorical
    Units: Subjects
        Female
    122 44 128 294
        Male
    193 62 191 446
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    10 2 5 17
        Not Hispanic or Latino
    299 103 309 711
        Unknown or Not Reported
    6 1 5 12
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    83 29 89 201
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    19 2 13 34
        White
    208 74 208 490
        More than one race
    0 0 0 0
        Unknown or Not Reported
    5 1 9 15
    Eczema Area and Severity Index (EASI) Score
    The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD.
    Units: units on scale
        arithmetic mean (standard deviation)
    32.6 ± 12.93 33.6 ± 13.3 32.1 ± 12.76 -
    Investigator Global Assessment (IGA) Score
    IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear).
    Units: units on scale
        arithmetic mean (standard deviation)
    3.5 ± 0.5 3.5 ± 0.5 3.5 ± 0.5 -
    Weekly Peak Averaged Pruritus Numeric Rating Scale (NRS)
    Pruritus NRS was an assessment tool that was used to report the intensity of subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at worst moment during previous 24 hours (for maximum itch intensity on a scale of 0–10 [0=no itch;10=worst itch imaginable]).
    Units: units on scale
        arithmetic mean (standard deviation)
    7.3 ± 1.84 7.4 ± 1.66 7.1 ± 1.9 -
    Body Surface Area (BSA) Involvement with Atopic Dermatitis (AD)
    BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined.
    Units: percentage of BSA
        arithmetic mean (standard deviation)
    56.9 ± 21.69 59.5 ± 20.84 54.1 ± 21.76 -
    SCORing Atopic Dermatitis (SCORAD) Score
    SCORAD was a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23–31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). Data for SCORAD score was reported for a total of 734 subjects (Placebo qw: 313; Dupilumab 300 mg q2w: 105 and Dupilumab 300 mg qw: 316).
    Units: units on a scale
        arithmetic mean (standard deviation)
    66 ± 13.53 69.3 ± 15.24 65.9 ± 13.63 -
    Dermatology Life Quality Index (DLQI) Total Score
    DLQI was a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL.
    Units: units on scale
        arithmetic mean (standard deviation)
    14.7 ± 7.37 14.5 ± 7.31 14.4 ± 7.17 -
    Patient Oriented Eczema Measure (POEM)
    The POEM was a 7-item questionnaire that assessed disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). Data for POEM score was reported for a total of 739 subjects (Placebo qw: 314; Dupilumab 300 mg q2w: 106 and Dupilumab 300 mg qw: 319).
    Units: units on a scale
        arithmetic mean (standard deviation)
    20 ± 5.99 20.3 ± 5.68 20.1 ± 6.05 -
    Global Individual Signs Score (GISS)
    Individual components of the AD lesions (erythema, infiltration/papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0 = none, 1 = mild, 2 = moderate and 3 = severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease).
    Units: units on scale
        arithmetic mean (standard deviation)
    8.7 ± 1.84 8.9 ± 2.04 8.9 ± 1.8 -
    Total Hospital Anxiety Depression Scale (HADS)
    The HADS is a fourteen item scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.
    Units: units on scale
        arithmetic mean (standard deviation)
    12.6 ± 8.06 12.9 ± 7.73 12.8 ± 8.01 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo qw
    Reporting group description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, subjects received placebo.

    Reporting group title
    Dupilumab 300 mg qw
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51.

    Subject analysis set title
    Placebo qw
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.

    Subject analysis set title
    Dupilumab 300 mg q2w
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, subjects received placebo. Four subjects received fewer injections of Dupilumab 300 mg in Dupilumab 300 qw arm, were analyzed in Dupilumab 300 mg q2w arm.

    Subject analysis set title
    Dupilumab 300 mg qw
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51. Four subjects received fewer injections of Dupilumab 300 mg in Dupilumab 300 qw arm, were analyzed in Dupilumab 300 mg q2w arm.

    Primary: Percentage of Subjects With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16

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    End point title
    Percentage of Subjects With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 16
    End point description
    The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline to Week 16. All efficacy analyses were performed on the Full Analysis Set (FAS), which included all randomized subjects. Efficacy analyses were based on the treatment allocated by interactive voice response system/ interactive web response system (IVRS/IWRS) at randomization (as randomized).
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percentage of subjects
        number (not applicable)
    23.2
    68.9
    63.9
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    45.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.72
         upper limit
    55.66
    Notes
    [1] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    40.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    33.74
         upper limit
    47.81
    Notes
    [2] - Threshold for significance at 0.025 level.

    Primary: Percentage of Subjects With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 16

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    End point title
    Percentage of Subjects With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 16
    End point description
    IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Subjects with IGA score “0” or “1” and a reduction from baseline of ≥2 points at Week 16 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). (Co-primary efficacy endpoints are for the European Union [EU], EU reference market countries, and Japan only).
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percentage of subjects
        number (not applicable)
    12.4
    38.7
    39.2
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    26.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.34
         upper limit
    36.26
    Notes
    [3] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    26.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.33
         upper limit
    33.28
    Notes
    [4] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    299
    102
    295
    Units: percentage of subjects
        number (not applicable)
    19.7
    58.8
    50.8
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level for both comparisons.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    39.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.53
         upper limit
    49.65
    Notes
    [5] - Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing peak NRS at Week 16 were considered as non-responders.
    [6] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level for both comparisons.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    31.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    23.84
         upper limit
    38.39
    Notes
    [7] - Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing peak NRS at Week 16 were considered as non-responders.
    [8] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥3.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    306
    105
    309
    Units: percentage of subjects
        number (not applicable)
    27.8
    65.7
    62.5
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing peak NRS at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    37.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.56
         upper limit
    48.31
    Notes
    [9] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing peak NRS at Week 16 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    34.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.31
         upper limit
    42.05
    Notes
    [10] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 52

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    End point title
    Percentage of Subjects With Investigator’s Global Assessment (IGA) Score of “0” or “1” and Reduction From Baseline of ≥2 Points at Week 52
    End point description
    IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Subjects with IGA score of “0” or “1” and a reduction from baseline of ≥2 points at Week 52 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: percentage of subjects
        number (not applicable)
    12.5
    36
    40
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    23.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.72
         upper limit
    34.19
    Notes
    [11] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    27.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.42
         upper limit
    34.58
    Notes
    [12] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 52

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    End point title
    Percentage of Subjects With Eczema Area and Severity Index-75 (EASI-75) (≥75% Improvement From Baseline) at Week 52
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline to Week 52. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: percentage of subjects
        number (not applicable)
    21.6
    65.2
    64.1
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    43.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    32.5
         upper limit
    54.65
    Notes
    [13] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    42.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    34.91
         upper limit
    50.06
    Notes
    [14] - Threshold for significance at 0.025 level.

    Secondary: Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16

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    End point title
    Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percent change
        least squares mean (standard error)
    -30.3 ± 2.36
    -56.6 ± 3.95
    -57.1 ± 2.11
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -26.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.04
         upper limit
    -17.43
    Notes
    [15] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    634
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -26.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.83
         upper limit
    -20.73
    Notes
    [16] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 52 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    249
    86
    249
    Units: percentage of subjects
        number (not applicable)
    12.9
    51.2
    39
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    38.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    26.96
         upper limit
    49.66
    Notes
    [17] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    498
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    26.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.76
         upper limit
    33.45
    Notes
    [18] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥3 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 52
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 52 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥3.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    256
    88
    261
    Units: percentage of subjects
        number (not applicable)
    15.6
    55.7
    42.9
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    40.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.76
         upper limit
    51.35
    Notes
    [19] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 52 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    27.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.81
         upper limit
    34.76
    Notes
    [20] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 24

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 24
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 24 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    299
    102
    295
    Units: percentage of subjects
        number (not applicable)
    16.1
    53.9
    43.7
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 24 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    37.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.34
         upper limit
    48.4
    Notes
    [21] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 24 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    27.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.65
         upper limit
    34.7
    Notes
    [22] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 4

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 4
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 4 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    299
    102
    295
    Units: percentage of subjects
        number (not applicable)
    16.4
    37.3
    27.1
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 4 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    20.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.59
         upper limit
    31.15
    Notes
    [23] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 4 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021 [24]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    10.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.15
         upper limit
    17.31
    Notes
    [24] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 2

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 2
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 2 were reported. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with baseline peak pruritus NRS score ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    299
    102
    295
    Units: percentage of subjects
        number (not applicable)
    8
    17.6
    13.6
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 2 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0062 [25]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    9.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.61
         upper limit
    17.63
    Notes
    [25] - Threshold for significance at 0.025 level.
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity (IGA baseline values: IGA=3 vs IGA=4). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 2 were considered as non-responders.
    Comparison groups
    Dupilumab 300 mg qw v Placebo qw
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0344 [26]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    10.51
    Notes
    [26] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16

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    End point title
    Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 16
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: units on a scale
        least squares mean (standard error)
    -2.36 ± 0.138
    -4.17 ± 0.207
    -4.27 ± 0.126
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.297
         upper limit
    -1.322
    Notes
    [27] - Threshold for significance at 0.025 level.

    Secondary: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 16

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    End point title
    Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 16
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percent change
        least squares mean (standard error)
    -48.4 ± 3.82
    -80.5 ± 6.34
    -81.5 ± 5.78
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -32.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.37
         upper limit
    -17.82
    Notes
    [28] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Percent Body Surface Area (BSA) Affected by AD to Week 16

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    End point title
    Change From Baseline in Percent Body Surface Area (BSA) Affected by AD to Week 16
    End point description
    BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percentage of BSA
        least squares mean (standard error)
    -22.01 ± 1.158
    -40.39 ± 1.844
    -39.58 ± 1.065
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [29]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -18.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.583
         upper limit
    -14.187
    Notes
    [29] - Threshold for significance at 0.025 level.

    Secondary: Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 16

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    End point title
    Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 16
    End point description
    SCORAD was a clinical tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23–31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) were assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: percent change
        least squares mean (standard error)
    -36.2 ± 1.66
    -63.9 ± 2.52
    -65.9 ± 1.49
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -27.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.46
         upper limit
    -21.9
    Notes
    [30] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 16

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    End point title
    Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 16
    End point description
    The DLQI was a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: units on a scale
        least squares mean (standard error)
    -5.8 ± 0.34
    -10 ± 0.5
    -10.7 ± 0.31
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [31]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.31
         upper limit
    -3.02
    Notes
    [31] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 16

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    End point title
    Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 16
    End point description
    The POEM was a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: units on a scale
        least squares mean (standard error)
    -5.3 ± 0.41
    -12.7 ± 0.64
    -12.9 ± 0.37
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.85
         upper limit
    -5.93
    Notes
    [32] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 16

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    End point title
    Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 16
    End point description
    HADS was a fourteen-item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire is scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: units on a scale
        least squares mean (standard error)
    -4 ± 0.37
    -4.9 ± 0.58
    -5.4 ± 0.35
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with baseline measurements as covariate and the treatment, region and baseline IGA strata as fixed factors.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo qw
    Number of subjects included in analysis
    421
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1596 [33]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.27
         upper limit
    0.37
    Notes
    [33] - Threshold for significance at 0.025 level.

    Secondary: Percent Change From Baseline in Total Global Individual Signs Score (GISS) to Week 16

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    End point title
    Percent Change From Baseline in Total Global Individual Signs Score (GISS) to Week 16
    End point description
    Individual components of the AD lesions (erythema, infiltration/ papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0= none, 1= mild, 2= moderate and 3= severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: Percent Change
        least squares mean (standard error)
    -33.3 ± 1.89
    -55.4 ± 2.69
    -59.3 ± 1.64
    No statistical analyses for this end point

    Secondary: Proportion of Topical Atopic Dermatitis Medication-Free Days Through Week 52

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    End point title
    Proportion of Topical Atopic Dermatitis Medication-Free Days Through Week 52
    End point description
    Proportion of topical AD medication-free days through Week 52 was calculated as the number of days that a subject used neither topical corticosteroid (TCS)/ topical calcineurin inhibitors (TCI) nor system rescue therapy divided by the study days of each period. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline Up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: days
        arithmetic mean (standard deviation)
    10.5 ± 23.68
    16.6 ± 30.08
    22.5 ± 33.69
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 2

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    End point title
    Percent Change From Baseline in Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score to Week 2
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    106
    319
    Units: Percent Change
        least squares mean (standard error)
    -19.7 ± 1.58
    -27.3 ± 2.67
    -25.7 ± 1.57
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 52

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    End point title
    Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score to Week 52
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: Percent Change
        least squares mean (standard error)
    -60.9 ± 4.29
    -84.9 ± 6.73
    -87.8 ± 6.19
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Body Surface Area (BSA) Affected by AD to Week 52

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    End point title
    Change From Baseline in Percent Body Surface Area (BSA) Affected by AD to Week 52
    End point description
    BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: Percentage of BSA
        least squares mean (standard error)
    -29.41 ± 1.443
    -43.75 ± 1.874
    -43.67 ± 1.143
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 52

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    End point title
    Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Score to Week 52
    End point description
    SCORAD was a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23–31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) were assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: Percent Change
        least squares mean (standard error)
    -47.3 ± 2.18
    -69.7 ± 3.06
    -70.4 ± 1.72
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Global Individual Signs Score (GISS) to Week 52

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    End point title
    Percent Change From Baseline in Global Individual Signs Score (GISS) to Week 52
    End point description
    Individual components of the AD lesions (erythema, infiltration/ papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0= none, 1= mild, 2= moderate and 3= severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: Percent Change
        least squares mean (standard error)
    -40.8 ± 2.72
    -62.8 ± 3.35
    -64.4 ± 2.13
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 52

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    End point title
    Change From Baseline in Dermatology Life Quality Index (DLQI) to Week 52
    End point description
    The DLQI was a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: units on a scale
        least squares mean (standard error)
    -7.2 ± 0.4
    -11.4 ± 0.57
    -11.1 ± 0.36
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 52

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    End point title
    Change From Baseline in Patient Oriented Eczema Measure (POEM) to Week 52
    End point description
    The POEM was a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: units on a scale
        least squares mean (standard error)
    -7 ± 0.57
    -14.2 ± 0.78
    -13.2 ± 0.45
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 52

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    End point title
    Change From Baseline in Hospital Anxiety Depression Scale (HADS) to Week 52
    End point description
    HADS was a fourteen-item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire is scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    264
    89
    270
    Units: units on a scale
        least squares mean (standard error)
    -3.8 ± 0.47
    -5.5 ± 0.71
    -5.9 ± 0.42
    No statistical analyses for this end point

    Secondary: Number of Flares Through Week 52

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    End point title
    Number of Flares Through Week 52
    End point description
    AD flares were defined as worsening of the disease that required escalation/intensification of AD treatment. Number of flares occurred in the subjects from first dose through Week 52 were reported. All safety analysis were performed on safety analysis set (SAF) that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: flares
        number (not applicable)
    216
    20
    51
    No statistical analyses for this end point

    Secondary: Number of Serious Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation through Week 52

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    End point title
    Number of Serious Treatment Emergent Adverse Events (TEAEs) Leading to Study Drug Discontinuation through Week 52
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of casual relationship with this treatment. A Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs. All safety analysis were performed on SAF that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: events
        number (not applicable)
    28
    2
    10
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Skin Infection TEAEs (excluding Herpetic Infections) from Baseline through Week 52

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    End point title
    Percentage of Subjects With Skin Infection TEAEs (excluding Herpetic Infections) from Baseline through Week 52
    End point description
    Any untoward medical occurrence in subjects who received IMP was considered an AE without regard to possibility of casual relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during "on-treatment period" (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included subjects with both serious and non-serious AEs. Skin infection TEAEs were identified based on blinded adjudication of all reported TEAEs under the 2 primary System Organ Classes (SOC): SOC = “Infection and Infestations” or SOC = “Skin and Subcutaneous Tissue Disorders”. Blinded adjudication was performed and finalized by the study medical monitor before database lock. All safety analysis were performed on SAF that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: percentage of subjects
        number (not applicable)
    17.8
    10.9
    8.3
    No statistical analyses for this end point

    Secondary: Number of Skin Infection TEAEs (excluding Herpetic Infections) from Baseline through Week 52

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    End point title
    Number of Skin Infection TEAEs (excluding Herpetic Infections) from Baseline through Week 52
    End point description
    Any untoward medical occurrence in subjects who received IMP was considered an AE without regard to possibility of casual relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during "on-treatment period" (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included subjects with both serious and non-serious AEs. Skin infection TEAEs were identified based on blinded adjudication of all reported TEAEs under the 2 primary System Organ Classes (SOC): SOC = “Infection and Infestations” or SOC = “Skin and Subcutaneous Tissue Disorders”. Blinded adjudication was performed and finalized by the study medical monitor before database lock. All safety analysis were performed on SAF that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: events
        number (not applicable)
    80
    15
    29
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Skin Infection TEAEs (excluding Herpetic Infections) Requiring Systemic Treatment from Baseline through Week 52

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    End point title
    Percentage of Subjects With Skin Infection TEAEs (excluding Herpetic Infections) Requiring Systemic Treatment from Baseline through Week 52
    End point description
    Any untoward medical occurrence in subjects who received IMP was considered an AE without regard to possibility of casual relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during "on-treatment period" (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included subjects with both serious and non-serious AEs. Skin infection TEAEs were identified based on blinded adjudication of all reported TEAEs under the 2 primary System Organ Classes (SOC): SOC = “Infection and Infestations” or SOC = “Skin and Subcutaneous Tissue Disorders”. Blinded adjudication was performed and finalized by the study medical monitor before database lock. All safety analysis were performed on SAF that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: percentage of subjects
        number (not applicable)
    9.5
    5.5
    3.8
    No statistical analyses for this end point

    Secondary: Number of Skin Infection TEAEs (excluding Herpetic Infections) Requiring Systemic Treatment from Baseline through Week 52

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    End point title
    Number of Skin Infection TEAEs (excluding Herpetic Infections) Requiring Systemic Treatment from Baseline through Week 52
    End point description
    Any untoward medical occurrence in subjects who received IMP was considered an AE without regard to possibility of casual relationship with this treatment. TEAEs were defined as AEs that developed or worsened or became serious during "on-treatment period" (time from the first dose of study drug up to end of treatment at Week 52). Any TEAE included subjects with both serious and non-serious AEs. Skin infection TEAEs were identified based on blinded adjudication of all reported TEAEs under the 2 primary System Organ Classes (SOC): SOC = “Infection and Infestations” or SOC = “Skin and Subcutaneous Tissue Disorders”. Blinded adjudication was performed and finalized by the study medical monitor before database lock. All safety analysis were performed on SAF that included all randomized subjects who received any study drug, and were analyzed as-treated.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    315
    110
    315
    Units: events
        number (not applicable)
    44
    7
    13
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score to Week 16

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    End point title
    Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score to Week 16
    End point description
    ACQ-5 questionnaire was a validated questionnaire comprising of 5 questions for asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath, and wheeze. Subjects were asked to rate their asthma symptoms during the previous week on a 7-point scale as 0=no impairment, 6=maximum impairment. ACQ-5 score is the mean of the 5 questions and range between 0 (totally controlled) and 6 (severely uncontrolled) (a higher score indicated lower asthma control). All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). Here, number of subjects analyzed = subjects with ACQ-5 value at baseline. The ACQ-5 questionnaire was administered only to the subjects with a medical history of asthma.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    154
    48
    145
    Units: units on a scale
        least squares mean (standard error)
    -0.12 ± 0.082
    -0.19 ± 0.113
    -0.36 ± 0.068
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Sinonasal Outcome Test (SNOT-22) Score to Week 16

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    End point title
    Change From Baseline in Sinonasal Outcome Test (SNOT-22) Score to Week 16
    End point description
    The SNOT 22 was a validated measure of health related quality of life in sinonasal disease. It is a 22 item questionnaire with each item assigned a score ranging from 0-5. The total score may range from 0 (no disease) -110 (worst disease) (lower scores represent better health related quality of life. All efficacy analyses were performed on the FAS, which included all randomized subjects. Efficacy analyses were based on the treatment allocated by the IVRS/IWRS at randomization (as randomized). The SNOT-22 was administered only to subjects with chronic inflammatory conditions of the nasal mucosa and/or paranasal sinuses.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo qw Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    99
    45
    99
    Units: units on a scale
        least squares mean (standard error)
    -4.77 ± 1.903
    -6.38 ± 2.445
    -10.39 ± 1.63
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time-frame was 'On treatment (Week 52) period' defined time from administration of first dose of study drug to study completion date of Week 52 visit (365 days starting from first dose of study drug if the date of Week 52 visit was unavailable).
    Adverse event reporting additional description
    All Adverse Events were collected from signature of informed consent form up to study completion date of the Week 52 visit regardless of seriousness or relationship to investigational product. Reported AEs and deaths are treatment-emergent that is AEs developed/worsened and deaths that occurred during 'On treatment (Week 52) period'.SAF population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by placebo (for Dupilumab) alternating with a single 300 mg injection of Dupilumab q2w from Week 1 to Week 51. During weeks in which Dupilumab was not administered, subjects received placebo. Four subjects received fewer injections of Dupilumab 300 mg in Dupilumab 300 qw arm, were analyzed in Dupilumab 300 mg q2w arm.

    Reporting group title
    Placebo qw
    Reporting group description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection qw from Week 1 to Week 51.

    Reporting group title
    Dupilumab 300 mg qw
    Reporting group description
    Two subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection of Dupilumab qw from Week 1 to Week 51. Four subjects received fewer injections of Dupilumab 300 mg in Dupilumab 300 qw arm, were analyzed in Dupilumab 300 mg q2w arm.

    Serious adverse events
    Dupilumab 300 mg q2w Placebo qw Dupilumab 300 mg qw
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 110 (3.64%)
    20 / 315 (6.35%)
    12 / 315 (3.81%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Penile squamous cell carcinoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Soft tissue inflammation
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 315 (0.00%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 315 (0.00%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystoid macular oedema
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 315 (0.32%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pseudarthrosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 110 (0.00%)
    0 / 315 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema herpeticum
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 315 (0.32%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 315 (0.00%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dupilumab 300 mg q2w Placebo qw Dupilumab 300 mg qw
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 110 (67.27%)
    216 / 315 (68.57%)
    228 / 315 (72.38%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    5 / 110 (4.55%)
    19 / 315 (6.03%)
    7 / 315 (2.22%)
         occurrences all number
    5
    23
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 110 (4.55%)
    19 / 315 (6.03%)
    24 / 315 (7.62%)
         occurrences all number
    5
    30
    48
    Eye disorders
    Blepharitis
         subjects affected / exposed
    6 / 110 (5.45%)
    3 / 315 (0.95%)
    11 / 315 (3.49%)
         occurrences all number
    7
    3
    14
    Conjunctivitis allergic
         subjects affected / exposed
    13 / 110 (11.82%)
    19 / 315 (6.03%)
    54 / 315 (17.14%)
         occurrences all number
    20
    22
    74
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    16 / 110 (14.55%)
    24 / 315 (7.62%)
    60 / 315 (19.05%)
         occurrences all number
    34
    102
    224
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    40 / 110 (36.36%)
    161 / 315 (51.11%)
    91 / 315 (28.89%)
         occurrences all number
    52
    278
    133
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 110 (3.64%)
    17 / 315 (5.40%)
    9 / 315 (2.86%)
         occurrences all number
    4
    25
    13
    Nasopharyngitis
         subjects affected / exposed
    26 / 110 (23.64%)
    62 / 315 (19.68%)
    63 / 315 (20.00%)
         occurrences all number
    40
    89
    88
    Oral herpes
         subjects affected / exposed
    4 / 110 (3.64%)
    10 / 315 (3.17%)
    17 / 315 (5.40%)
         occurrences all number
    9
    15
    31
    Sinusitis
         subjects affected / exposed
    2 / 110 (1.82%)
    9 / 315 (2.86%)
    18 / 315 (5.71%)
         occurrences all number
    2
    11
    20
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 110 (10.00%)
    34 / 315 (10.79%)
    46 / 315 (14.60%)
         occurrences all number
    21
    52
    78
    Urinary tract infection
         subjects affected / exposed
    2 / 110 (1.82%)
    14 / 315 (4.44%)
    16 / 315 (5.08%)
         occurrences all number
    3
    16
    22

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2014
    Modification of study design: Dupilumab to be administered concomitantly with TCS; Incorporated the doses selected for phase 3 studies based on results of an interim analysis of a phase 2b dose-ranging study. The doses selected were 300 mg qw and 300 mg q2w; Increased the number of subjects to 700 and randomized in a 3:1:3 ratio to Dupilumab 300 mg qw, Dupilumab 300 mg q2w and matching placebo; Changed time of the assessment of the efficacy endpoints to week 16 from week 12; Clarified that different health authorities requested different primary endpoints although the study was to be conducted the same in all countries; Modified secondary endpoints and added exploratory endpoints. Modified Inclusion/Exclusion Criteria; Expanded section on prohibited medications; Modified section on study drug continuation rules; Modified assessments (Added Patient Global Assessment of Treatment; added Atopic keratoconjunctivitis [AKC], ACQ-5 and SNOT-22; added a second question for subject assessment of pruritus; added Hemoglobin A1c [HbA1c] to study assessments; changed frequency and timing of some assessments).
    22 Oct 2014
    Incorporated changes concerning the concomitant use of dupilumab and systemic corticosteroids that had already been made in the US-specific protocol (for global [R668-AD-1224.01] and UK-specific [R668-AD-1224.01GB] protocols only); Added positive HBcAb as an exclusion; Updated prohibited medications; Removed “treatment with a live (attenuated) vaccine” from the list of events that would lead to temporary discontinuation of study drug; Added “rescue treatment prior to week 2” to the list of events that would lead to permanent discontinuation of study drug; Modified the AKC assessment schedule; Added % BSA to the assessments to be completed prior to escalation of TCS treatment; Specified that fasting was recommended prior to obtaining laboratory samples; Clarified the description of IGA; Clarified subject population for SNOT-22 assessment; -Included an assessment of vital signs at visit 3; Changed reporting time for AEs leading to study withdrawal; Clarified reporting requirements for pregnancy or a complication of pregnancy in a female partner of a male subject; Modified statistics section for greater clarity and to expand on MMRM; Updated the cut-off date for earlier studies.
    24 Feb 2015
    Added text to indicate that for background treatment with moisturizers (emollients), to allow adequate assessment of skin dryness, moisturizers should not be applied on the area(s) of non-lesional skin designated for such assessments for at least 8 hours before each clinic visit; Changed the terminology of “European Medicines Agency (EMA) reference market” to “European Union (EU) reference market”, and “reference market submissions” to “reference market countries”; Made revisions to indicate that Japan had been added to the countries that would use the co-primary endpoints; Separated the secondary endpoints into 2 parts: Key Secondary Endpoints and Other Secondary Endpoints; Moved some of the secondary endpoint to the “key secondary endpoints” section; Added some endpoints in the “other secondary endpoints” section; Moved the following endpoint to the end of “other secondary endpoints”: “incidence of skin-infection TEAEs requiring systemic treatment from baseline through Week 56; Revised the definition for the FAS and added per protocol set (PPS) for efficacy analysis; Added description of methods for missing data imputation and data analysis for continuous secondary endpoints to be used in US and US reference market countries; Added an inclusion criterion requiring a subject to have a baseline Pruritus NRS average score for maximum itch intensity ≥3 to be eligible to enroll in the study; Changed one of recommended super high potency TCS from “betamethasone dipropionate 0.05% cream” to “betamethasone dipropionate 0.05% optimized ointment” to be consistent with the study reference manual, and made revision to clarify that the standardized low or median potency TCS daily regimen was once daily; Added a statement in the “Rescue Medications” section for clarity and to be consistent with the section of Reasons for Permanent Discontinuation of study drug; Clarified that ECGs should be performed before blood was drawn during visits requiring blood draws.
    02 Oct 2015
    Removed the requirement that no subjects would receive study drug from both vials and prefilled syringes; Indicated that the primary analysis, which would include the Week 16 primary and key secondary endpoints for all randomized subjects, would also contain Week 52 efficacy endpoints, which at a minimum would include all subjects randomized by 27 April 2015 and whose pertinent data (i.e. data required for Week 52 analyses) had been collected and validated; Modified and reorder key secondary efficacy endpoints, other secondary endpoints, and exploratory endpoints to match the SAP; Modified the statement regarding subjects with anti-drug antibody (ADA) titer of ≥240 at their last study visit returning to the clinic for additional samples.

    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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