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    Clinical Trial Results:
    A Phase 3 Confirmatory Study Investigating the Efficacy and Safety of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis

    Summary
    EudraCT number
    2014-001198-15
    Trial protocol
    EE   DE   ES   FI   DK   BG  
    Global end of trial date
    11 Feb 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Feb 2020
    First version publication date
    08 Mar 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1334
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02277743
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: SOLO 1
    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
    Final
    Date of interim/final analysis
    15 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 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 monotherapy compared to placebo treatment in adult subjects with moderate-to-severe atopic dermatitis (AD).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Oct 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
    Japan: 106
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    United States: 238
    Country: Number of subjects enrolled
    Canada: 48
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Estonia: 54
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 124
    Worldwide total number of subjects
    671
    EEA total number of subjects
    265
    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)
    639
    From 65 to 84 years
    31
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 10 countries between 28 Oct 2014 and 12 Feb 2016. A total of 917 subjects were screened in the study.

    Pre-assignment
    Screening details
    Out of 917 subjects, 671 were randomized and 669 were treated in the study. Subjects were randomized in 1:1:1 ratio to receive dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w) or placebo 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
    Assessor, Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection once weekly (qw) from Week 1 to Week 15.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Dupilumab)
    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 a placebo alternating with single 300 mg injection of Dupilumab qw from Week 1 to Week 15.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    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 15.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    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 Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Started
    224
    224
    223
    Treated
    223
    223
    223
    Completed
    184
    208
    197
    Not completed
    40
    16
    26
         Protocol deviation
    1
    1
    1
         Other than specified
    18
    5
    16
         Adverse event
    10
    6
    6
         Lack of efficacy
    11
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection once weekly (qw) from Week 1 to Week 15.

    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 a placebo alternating with single 300 mg injection of Dupilumab qw from Week 1 to Week 15.

    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 15.

    Reporting group values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw Total
    Number of subjects
    224 224 223 671
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.5 ± 13.91 39.8 ± 14.68 39.3 ± 14.39 -
    Gender categorical
    Units: Subjects
        Female
    106 94 81 281
        Male
    118 130 142 390
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    212 215 212 639
        Hispanic or Latino
    11 6 8 25
        Not reported or missing
    1 3 3 7
    Race
    Units: Subjects
        White
    146 155 149 450
        Black or African American
    16 10 20 46
        Asian
    56 54 51 161
        Unknown or Not Reported
    6 5 3 14
        American Indian or Alaska Native
    0 0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        More than one race
    0 0 0 0
    Region
    Units: Subjects
        North and South America
    95 95 96 286
        Asia Pacific
    40 42 38 120
        Eastern Europe
    23 22 24 69
        Western Europe
    66 65 65 196
    Eczema Area and Severity Index (EASI) Score
    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 to 72 points, with the higher scores reflecting the worse severity of AD. Data for EASI score was reported for 670 subjects (n=223, 224 and 223). Number of participants analyzed = participants with available data for the baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    34.5 ± 14.47 33 ± 13.57 33.2 ± 13.98 -
    Investigator’s Global Assessment (IGA) Score
    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). Data for IGA score was reported for 670 subjects (n=223, 224 and 223).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3.5 ± 0.5 3.5 ± 0.5 3.5 ± 0.5 -
    Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS)
    Pruritus NRS scale is a tool used to report the intensity of subject’s pruritus (itch), both maximum and average intensity, during a 24-hr recall period. Subjects were asked the following: how would a subject rate his itch at the worst moment during the previous 24 hrs (for maximum itch intensity on a scale of 0–10 [0=no itch; 10=worst itch imaginable]). Weekly average obtained in the 7-day period prior to baseline visit. Data for pruritus NRS score was reported for 669 subjects (n=224, 224 & 221). Number of subjects analyzed = subjects with available data for the baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    7.4 ± 1.77 7.2 ± 1.89 7.2 ± 2.06 -
    Body Surface Area (BSA) Involvement with Atopic Dermatitis
    Body surface area 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. Data for Body surface area was reported for 670 subjects (n=223, 224 and 223). Number of participants analyzed = participants with available data for the baseline parameter.
    Units: Percentage of body surface area
        arithmetic mean (standard deviation)
    57.5 ± 23.38 54.7 ± 23.19 56.1 ± 22.96 -
    SCORing Atopic Dermatitis (SCORAD) Score
    SCORAD is a tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis ("Severity scoring of atopic dermatitis: SCORAD index. 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 669 subjects (n=223, 223 & 223). Number of subjects analyzed = subjects with available data for baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    68.3 ± 13.96 66.9 ± 13.97 67.5 ± 13.61 -
    Dermatology Life Quality Index (DLQI) Score
    The DLQI is 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. Data for DLQI score was reported for 670 subjects (n=223, 224 and 223).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    14.8 ± 7.23 13.9 ± 7.37 14.1 ± 7.51 -
    Patient Oriented Eczema Measure (POEM)
    The POEM is 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]). Data for POEM score was reported for 670 subjects (n=223, 224 and 223).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    20.3 ± 5.9 19.8 ± 6.37 20.4 ± 6.25 -
    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. Data for GISS was reported for 670 subjects (n=223, 224 and 223). Number of participants analyzed = participants with available data for the baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    9 ± 1.85 8.9 ± 1.81 8.9 ± 1.74 -
    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. Data for HADS score was reported for 615 subjects (n=204, 207 and 204).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    12.6 ± 8.33 12.2 ± 7.26 12.6 ± 7.95 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection once weekly (qw) from Week 1 to Week 15.

    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 a placebo alternating with single 300 mg injection of Dupilumab qw from Week 1 to Week 15.

    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 15.

    Subject analysis set title
    Placebo
    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 15. One subject randomized to placebo but received Dupilumab, analyzed in Dupilumab 300 mg q2w arm.

    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 alternating with single 300 mg injection of Dupilumab qw from Week 1 to Week 15. One subject randomized to placebo and 5 subjects randomized to Dupilumab 300 mg qw arm, received Dupilumab 300 mg q2w and 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 15. Five subjects randomized to Dupilumab qw arm, 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 to 72 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. Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 16 were considered as non-­responders. Full analysis set (FAS) included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    224
    224
    223
    Units: Percentage of subjects
        number (not applicable)
    14.7
    51.3
    52.5
    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.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    36.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.58
         upper limit
    44.63
    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.
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    37.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    29.7
         upper limit
    45.77
    Notes
    [2] - Threshold for significance at 0.025 level.  

    Primary: Percentage of Subjects with Investigator’s Global Assessment (IGA) Score of “0” or “1” (clear or almost clear) 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” (clear or almost clear) and Reduction from Baseline of ≥2 Points at Week 16
    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 "0" or "1" and a reduction from baseline of ≥2 points at Week 16 were reported. Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 16 were counted as non-responders. Analysis was performed on FAS population.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    224
    224
    223
    Units: Percentage of Subjects
        number (not applicable)
    10.3
    37.9
    37.2
    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.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    27.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.18
         upper limit
    35.17
    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.
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.47
         upper limit
    34.44
    Notes
    [4] -  Threshold for significance at 0.025 level. 

    Secondary: Percentage of Subjects with Improvement (Reduction ≥4 Points) of 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 Pruritus Numerical Rating Scale (NRS) Score from Baseline to Week 16
    End point description
    Pruritus NRS scale is a tool used to report the intensity of subject’s pruritus (itch), both maximum and average intensity, during a 24-hr recall period. Subjects were asked the following: how would a subject rate his itch at the worst moment during the previous 24 hrs (for maximum itch intensity on a scale of 0–10 [0=no itch; 10=worst itch imaginable]). Weekly average obtained in the 7-day period prior to baseline visit. Data for pruritus NRS score was reported for 669 subjects (n=224, 224 & 221). Number of subjects analyzed = subjects with available data for the baseline parameter.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    212
    213
    201
    Units: Percentage of subjects
        number (not applicable)
    12.3
    40.8
    40.3
    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 the previous endpoint was statistically significant at 0.025 level.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    28.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.64
         upper limit
    36.52
    Notes
    [5] - 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.
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.94
         upper limit
    36.13
    Notes
    [6] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with Improvement (Reduction ≥3 Points) of Pruritus NRS Score from Baseline to Week 16

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    End point title
    Percentage of Subjects with Improvement (Reduction ≥3 Points) of Pruritus NRS Score from Baseline to Week 16
    End point description
    Subjects achieving a reduction of ≥3 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 16 were counted as non-responders. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with baseline peak pruritus NRS ≥3.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    221
    220
    211
    Units: Percentage of subjects
        number (not applicable)
    17.2
    46.8
    51.7
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    29.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.36
         upper limit
    37.88
    Notes
    [7] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    34.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    26.08
         upper limit
    42.84
    Notes
    [8] - Threshold for significance at 0.025 level.

    Secondary: Percent Change from Baseline in Peak Daily Pruritus NRS Score to Week 16

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    End point title
    Percent Change from Baseline in Peak Daily Pruritus NRS Score to Week 16
    End point description
    Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    96
    169
    162
    Units: Percent change
        arithmetic mean (standard deviation)
    -26.8 ± 28.38
    -51.1 ± 28.81
    -49 ± 33.45
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -24.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -32.26
         upper limit
    -17.52
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -22.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -30.33
         upper limit
    -15.33
    Notes
    [10] - Threshold for significance at 0.025 level.  

    Secondary: Percentage of Subjects with Improvement (Reduction ≥4 Points) of Pruritus NRS Score from Baseline to Week 4

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    End point title
    Percentage of Subjects with Improvement (Reduction ≥4 Points) of Pruritus NRS Score from Baseline to Week 4
    End point description
    Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 4 were reported. Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 4 were counted as non-responders. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with baseline peak pruritus NRS ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 4
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    212
    213
    201
    Units: Percentage of subjects
        number (not applicable)
    6.1
    16
    23.4
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    9.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.95
         upper limit
    15.71
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    17.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.57
         upper limit
    23.93
    Notes
    [12] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with Improvement (Reduction ≥4 Points) of Pruritus NRS Score from Baseline to Week 2

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    End point title
    Percentage of Subjects with Improvement (Reduction ≥4 Points) of Pruritus NRS Score from Baseline to Week 2
    End point description
    Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 2 were reported. Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 2 were counted as non-responders. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with baseline pruritus NRS ≥4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    212
    213
    201
    Units: Percentage of subjects
        number (not applicable)
    3.3
    9.4
    9.5
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0097 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    6.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.49
         upper limit
    10.68
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0094 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    6.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.45
         upper limit
    10.86
    Notes
    [14] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in Peak Daily Pruritus NRS Score to Week 16

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    End point title
    Change From Baseline in Peak Daily Pruritus NRS Score to Week 16
    End point description
    Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    96
    169
    162
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.13 ± 2.044
    -3.78 ± 2.325
    -3.72 ± 2.186
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.236
         upper limit
    -1.26
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.189
         upper limit
    -1.186
    Notes
    [16] - Threshold for significance at 0.025 level.

    Secondary: Percent Change From Baseline in EASI Score to Week 16

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    End point title
    Percent Change From Baseline in EASI Score to Week 16
    End point description
    Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    97
    173
    162
    Units: Percent change
        arithmetic mean (standard deviation)
    -39.5 ± 33.66
    -73.9 ± 26.28
    -73.8 ± 26.41
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -34.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.35
         upper limit
    -26.88
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -34.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.17
         upper limit
    -26.56
    Notes
    [18] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with Eczema Area and Severity Index­-50 (EASI­-50) (≥50% Improvement from Baseline) at Week 16

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    End point title
    Percentage of Subjects with Eczema Area and Severity Index­-50 (EASI­-50) (≥50% Improvement from Baseline) at Week 16
    End point description
    EASI-50 responders were the subjects who achieved ≥50% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment were set to missing and subjects with missing EASI-­50 scores at Week 16 were counted as non-responders. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    224
    224
    223
    Units: Percentage of subjects
        number (not applicable)
    24.6
    68.8
    61
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    44.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.91
         upper limit
    52.48
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    36.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.9
         upper limit
    44.96
    Notes
    [20] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with Eczema Area and Severity Index­-90 (EASI­-90) (≥90% Improvement from Baseline) at Week 16

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    End point title
    Percentage of Subjects with Eczema Area and Severity Index­-90 (EASI­-90) (≥90% Improvement from Baseline) at Week 16
    End point description
    EASI-90 responders were the subjects who achieved ≥90% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment were set to missing and subjects with missing EASI-90 scores at Week 16 were counted as non-responders. Analysis was performed on FAS population.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    224
    224
    223
    Units: Percentage of subjects
        number (not applicable)
    7.6
    35.7
    33.2
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    28.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.96
         upper limit
    35.29
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentage
    Point estimate
    25.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.51
         upper limit
    32.68
    Notes
    [22] - Threshold for significance at 0.025 level.

    Secondary: Change from Baseline in Percent Body Surface Area (BSA) to Week 16

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    End point title
    Change from Baseline in Percent Body Surface Area (BSA) to Week 16
    End point description
    Body surface area 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. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    97
    173
    162
    Units: Percentage of body surface area
        arithmetic mean (standard deviation)
    -17.2 ± 17.381
    -33.72 ± 19.619
    -35.42 ± 19.926
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -17.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.487
         upper limit
    -13.353
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -18.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.125
         upper limit
    -14.65
    Notes
    [24] - 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 is a tool for assessing the severity of atopic dermatitis developed by the European Task Force on Atopic Dermatitis ("Severity scoring of atopic dermatitis: SCORAD index. 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 669 subjects (n=223, 223 & 223). Number of subjects analyzed = subjects with available data for baseline parameter.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    97
    172
    161
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -28.9 ± 24.25
    -57.2 ± 24.03
    -56.7 ± 24.27
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [25]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -28.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.79
         upper limit
    -21.54
    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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.09
         upper limit
    -20.87
    Notes
    [26] - 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 is 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. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    97
    173
    162
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -5.6 ± 5.86
    -9 ± 6.61
    -8.8 ± 6.79
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.16
         upper limit
    -2.8
    Notes
    [27] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.87
         upper limit
    -2.49
    Notes
    [28] - 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 is 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]). Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    96
    173
    162
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -5.3 ± 6.24
    -11.5 ± 7.07
    -11.3 ± 6.36
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [29]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.02
         upper limit
    -5.01
    Notes
    [29] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -5.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.44
         upper limit
    -4.32
    Notes
    [30] - 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
    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. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    82
    159
    146
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -2.7 ± 4.4
    -4.8 ± 5.5
    -4.9 ± 5.36
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [31]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.44
         upper limit
    -0.95
    Notes
    [31] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [32]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.46
         upper limit
    -1.03
    Notes
    [32] - Threshold for significance at 0.025 level.

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

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    End point title
    Percent Change From Baseline in 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. Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    97
    173
    162
    Units: Percent Change
        arithmetic mean (standard deviation)
    -26.2 ± 25.7
    -52.5 ± 27.33
    -51.1 ± 26.58
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [33]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.04
         upper limit
    -18.91
    Notes
    [33] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [34]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -25.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.06
         upper limit
    -18.12
    Notes
    [34] - Threshold for significance at 0.025 level.

    Secondary: Percent Change from Baseline in Peak Daily Pruritus NRS Score to Week 2

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    End point title
    Percent Change from Baseline in Peak Daily Pruritus NRS Score to Week 2
    End point description
    Analysis was performed on FAS population. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 2
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    194
    214
    212
    Units: Percent Change
        arithmetic mean (standard deviation)
    -4.2 ± 22.77
    -20.4 ± 21.4
    -18.9 ± 28.4
    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).
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [35]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -16.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.08
         upper limit
    -11.9
    Notes
    [35] - 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).
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [36]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -15.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.62
         upper limit
    -10.5
    Notes
    [36] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with Skin Infection Treatment Emergent Adverse Events (TEAEs) Requiring Systemic Treatment from Baseline through Week 16

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    End point title
    Percentage of Subjects with Skin Infection Treatment Emergent Adverse Events (TEAEs) Requiring Systemic Treatment from Baseline through Week 16
    End point description
    Analysis was performed on safety analysis set (SAF) which included all randomized subjects who received any study drug, and was analyzed as treated. Statistical significance in the hierarchical testing of secondary hypotheses was broken at this endpoint. Therefore, subsequent secondary efficacy endpoints were not tested for statistical significance.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    222
    229
    218
    Units: Percentage of Subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Emergent Serious Adverse Events (TESAEs) from Baseline through Week 16

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    End point title
    Percentage of Subjects with Treatment Emergent Serious Adverse Events (TESAEs) from Baseline through Week 16
    End point description
    Analysis was performed on safety analysis set (SAF) which included all randomized subjects who received any study drug, and was analyzed as treated. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    222
    229
    218
    Units: Percentage of Subjects
        number (not applicable)
    5
    3.1
    0.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Emergent Adverse Events (TEAEs) Leading to Treatment Discontinuation from Baseline through Week 16

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    End point title
    Percentage of Subjects with Treatment Emergent Adverse Events (TEAEs) Leading to Treatment Discontinuation from Baseline through Week 16
    End point description
    Analysis was performed on safety analysis set (SAF) which included all randomized subjects who received any study drug, and was analyzed as treated. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    Placebo Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Number of subjects analysed
    222
    229
    218
    Units: Percentage of Subjects
        number (not applicable)
    0.9
    1.7
    1.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Week 28) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that developed/worsened during the ‘on-treatment period’ (including the 16 week treatment period).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects exposed to Placebo (for Dupilumab) for 16 weeks (mean exposure of 14 weeks).

    Reporting group title
    Dupilumab 300 mg qw
    Reporting group description
    Subjects exposed to Dupilumab 300 mg qw for 16 weeks (mean exposure of 15 weeks).

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Subjects exposed to Dupilumab 300 mg alternating with placebo qw for 16 weeks (mean exposure of 15 weeks).

    Serious adverse events
    Placebo Dupilumab 300 mg qw Dupilumab 300 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 222 (5.41%)
    2 / 218 (0.92%)
    7 / 229 (3.06%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Limb operation
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 218 (0.46%)
    0 / 229 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Suicidal ideation
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 218 (0.00%)
    0 / 229 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 218 (0.46%)
    0 / 229 (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
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    3 / 222 (1.35%)
    0 / 218 (0.00%)
    2 / 229 (0.87%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Infections and infestations
    Abscess sweat gland
         subjects affected / exposed
    0 / 222 (0.00%)
    0 / 218 (0.00%)
    1 / 229 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Kidney infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 218 (0.46%)
    0 / 229 (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
    Mastitis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 218 (0.00%)
    0 / 229 (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
    Placebo Dupilumab 300 mg qw Dupilumab 300 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 222 (43.69%)
    90 / 218 (41.28%)
    92 / 229 (40.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 222 (5.86%)
    11 / 218 (5.05%)
    21 / 229 (9.17%)
         occurrences all number
    16
    15
    33
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    3 / 222 (1.35%)
    8 / 218 (3.67%)
    12 / 229 (5.24%)
         occurrences all number
    3
    11
    13
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    13 / 222 (5.86%)
    41 / 218 (18.81%)
    19 / 229 (8.30%)
         occurrences all number
    18
    111
    63
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    66 / 222 (29.73%)
    21 / 218 (9.63%)
    35 / 229 (15.28%)
         occurrences all number
    77
    26
    44
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 222 (9.91%)
    26 / 218 (11.93%)
    27 / 229 (11.79%)
         occurrences all number
    30
    34
    32
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 222 (3.15%)
    12 / 218 (5.50%)
    7 / 229 (3.06%)
         occurrences all number
    7
    14
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2014
    -Clarified the required period for application of emollients prior to randomization was at least the 7 consecutive days immediately before randomization. -Added positive hepatitis B core antibody as an exclusion criterion in response to a health authority request. -Clarified the first step of rescue treatment should be limited to topical medications if possible. -Modified the list of medications leading to temporary or permanent discontinuation of study drug, and added possible resumption of study drug treatment after the medication leading to discontinuation was stopped. -Revised the list of prohibited medications, and the study periods in which they were prohibited. -Modified the frequency for subject self-assessment of pruritus. -Specified that fasting was recommended but not mandatory prior to collecting samples for laboratory testing. -Allowed retesting for bilirubin and creatine phosphokinase.
    04 Feb 2015
    -Clarified that emollients should not be applied to areas of non-lesional designated for assessment of skin dryness for at least 8 hours before each clinic visit. -Changed the terminology for the European reference market and indicated that Japan had been added to the countries that would use co-primary endpoint. -Reorganized the secondary endpoints into “Key” and “Other” categories. -Revised the definition of the Full Analysis Set, and added the Per Protocol Set. -Added description of methods for missing data imputation, and for 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 score ≥3 for weekly average of peak daily pruritus to be eligible to enroll in the study. -Clarified that non-invasive skin swabs were included in a sub-study that was conducted at selected sites. -Added a potential use for research samples: to study biomarkers that had predictive utility for response to dupilumab treatment. -Clarified that samples for exploratory biomarker testing had been banked. -Clarified the assessment of “Other” endpoints through week 16 that would include both absolute and percent changes. -For the primary efficacy analysis, added a sensitivity analysis using the Cochran-Mantel-Haenszel adjusted by randomization strata on observed values, regardless of rescue medication use or missing values.

    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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