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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study Investigating the Efficacy, Safety, Pharmacokinetic and Biomarker Profiles of Dupilumab (REGN668, SAR231893) Administered to Adult Patients with Moderate-to-Severe Atopic Dermatitis

    Summary
    EudraCT number
    2012-003651-11
    Trial protocol
    HU   CZ   DE   PL  
    Global end of trial date
    10 Sep 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Dec 2019
    First version publication date
    07 Aug 2016
    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-1021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01859988
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, 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
    09 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of multiple dupilumab dose-regimens, compared to placebo, in adult patients with moderate-to-severe 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
    Topical corticosteroids
    Evidence for comparator
    -
    Actual start date of recruitment
    15 May 2013
    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
    Poland: 35
    Country: Number of subjects enrolled
    Czech Republic: 18
    Country: Number of subjects enrolled
    Germany: 83
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    United States: 112
    Country: Number of subjects enrolled
    Canada: 54
    Country: Number of subjects enrolled
    Japan: 58
    Worldwide total number of subjects
    380
    EEA total number of subjects
    156
    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)
    372
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 95 study sites in 7 countries. A total of 452 subjects were screened between 15 May 2013 and 10 January 2014. 380 subjects were randomized and 379 were treated. 72 subjects were screen failures mainly due to exclusion and inclusion criteria not met.

    Pre-assignment
    Screening details
    Randomization was stratified by disease severity (moderate Investigator's global assessment [IGA] = 3 versus severe IGA = 4 atopic dermatitis and region (Japan versus rest of world). Assignment to arms was done centrally in 1:1:1:1:1:1 ratio for Dupilumab (300 mg qw; 300 mg q2w; 200 mg q2w; 300 mg q4w & 100 mg q4w) and Placebo.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    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 every week (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 (300 mg/2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    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 single injection of Placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab every 2 weeks (q2w) 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 (300 mg/2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    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 (2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    Arm title
    Dupilumab 200 mg q2w
    Arm description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single injection of Placebo (for Dupilumab) alternating with single 200 mg injection of Dupilumab q2w 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 (200 mg/2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    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 (2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    Arm title
    Dupilumab 300 mg q4w
    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 every 4 weeks (q4w) and Placebo (for Dupilumab) qw when Dupilumab not administered 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 (300 mg/2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    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 (2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    Arm title
    Dupilumab 100 mg q4w
    Arm description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 100 mg injection of Dupilumab q4w and Placebo (for Dupilumab) qw when Dupilumab not administered 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 (100 mg/2 ml & 200 mg/2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    Arm title
    Placebo
    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 15.
    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 (2 ml) in the different quadrants of the abdomen (avoiding navel and waist areas) and upper thighs.

    Number of subjects in period 1
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Started
    63
    64
    62
    65
    65
    61
    Treated
    63
    64
    61
    65
    65
    61
    Completed
    52
    52
    34
    55
    42
    42
    Not completed
    11
    12
    28
    10
    23
    19
         Other than specified
    -
    2
    11
    3
    5
    3
         Physician decision
    1
    3
    1
    3
    4
    1
         Protocol violation
    -
    -
    1
    -
    -
    -
         Adverse event
    2
    1
    3
    1
    2
    2
         Lack of efficacy
    1
    1
    5
    -
    7
    9
         Consent withdrawn by subject
    6
    3
    4
    3
    2
    2
         Lost to follow-up
    1
    2
    3
    -
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    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 every week (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 single injection of Placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab every 2 weeks (q2w) from Week 1 to Week 15.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single injection of Placebo (for Dupilumab) alternating with single 200 mg injection of Dupilumab q2w from Week 1 to Week 15.

    Reporting group title
    Dupilumab 300 mg q4w
    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 every 4 weeks (q4w) and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    Reporting group title
    Dupilumab 100 mg q4w
    Reporting group description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 100 mg injection of Dupilumab q4w and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    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 qw from Week 1 to Week 15.

    Reporting group values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo Total
    Number of subjects
    63 64 62 65 65 61 380
    Age categorical
    Units: Subjects
    Age continuous
    Data is reported for the 379 treated subjects included in the efficacy and safety analyses.
    Units: years
        arithmetic mean (standard deviation)
    36.2 ± 10.74 39.4 ± 12.06 35.8 ± 14.9 36.8 ± 10.77 36.6 ± 11.55 37.2 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    20 23 26 25 31 21 146
        Male
    43 41 36 40 34 40 234

    End points

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    End points reporting groups
    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 every week (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 single injection of Placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab every 2 weeks (q2w) from Week 1 to Week 15.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single injection of Placebo (for Dupilumab) alternating with single 200 mg injection of Dupilumab q2w from Week 1 to Week 15.

    Reporting group title
    Dupilumab 300 mg q4w
    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 every 4 weeks (q4w) and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    Reporting group title
    Dupilumab 100 mg q4w
    Reporting group description
    Two subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 100 mg injection of Dupilumab q4w and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    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 qw from Week 1 to Week 15.

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

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    End point title
    Percent Change in Eczema Area and Severity Index Score (EASI) From Baseline to 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. Analysis was performed on full analysis set (FAS) included all randomized subjects who received at least 1 dose of study drug. Here, number of subjects analyzed = subjects with EASI score assessment at specified time-points. Efficacy data was set to missing after use of rescue medication. Missing values imputed by last observation carried forward (LOCF). Here 'n' signifies number of subjects with available data for each specified category: (Score at) Baseline; (Score at) Week 16; (Percent) Change at Week 16
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    65
    65
    61
    Units: Percent change
    arithmetic mean (standard deviation)
        Baseline (n=63,64,61,65,65,61)
    30.1 ± 11.23
    33.8 ± 14.52
    32.9 ± 15.5
    29.4 ± 11.48
    32.2 ± 13.49
    32.9 ± 13.77
        Week 16 (n=61,63,60,65,64,61)
    7.2 ± 8.83
    10.7 ± 12.89
    10.9 ± 12.41
    9.8 ± 11.16
    17.4 ± 15.28
    25.6 ± 18.32
        Change at Week 16 (n=61,63,60,65,64,61)
    -75.5 ± 26.86
    -70.5 ± 35.09
    -67.4 ± 31.97
    -64.9 ± 37.21
    -46.7 ± 41.96
    -20.2 ± 46.15
    Statistical analysis title
    Dupilumab 300 mg qw vs Placebo
    Statistical analysis description
    LS mean and standrad error were obtained using analysis of covariance(ANCOVA) model with treatment and randomization strata(moderate vs severe;Japan vs rest of world) and relevant baseline values as covariates. Multiplicity was controlled using hierarchical testing procedure: highest dose vs. placebo was tested first.Comparison order was 300 mg qw, 300 mg q2w, 200 mg q2w, 300 mg q4w & 100 mg q4w, vs placebo respectively.Testing continues only if previous comparison was statistically significant.
    Comparison groups
    Dupilumab 300 mg qw v Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    ANCOVA
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -55.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -68.9
         upper limit
    -42.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.74
    Notes
    [1] - Threshold for significance at 0.05.
    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
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -50.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -63.3
         upper limit
    -37
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.67
    Notes
    [2] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 200 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 200 mg q2w v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -47.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -60.6
         upper limit
    -34.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.76
    Notes
    [3] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 300 mg q4w 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 q4w v Placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -45.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -58.5
         upper limit
    -32.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.66
    Notes
    [4] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 100 mg q4w vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Dupilumab 100 mg q4w v Placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -26.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.8
         upper limit
    -13.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.65
    Notes
    [5] - Threshold for significance at 0.05.

    Secondary: Percentage of Subjects Who Achieved Investigator's Global Assessment (IGA) Response at Week 16

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    End point title
    Percentage of Subjects Who Achieved Investigator's Global Assessment (IGA) Response 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). Values after first rescue medication were set to missing and subjects with missing IGA score at Week 16 were treated as a non-responders. Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    65
    65
    61
    Units: Percentage of subjects
        number (confidence interval 95%)
    33.3 (21.95 to 46.34)
    29.7 (18.91 to 42.42)
    27.9 (17.15 to 40.83)
    21.5 (12.31 to 33.49)
    12.3 (5.47 to 22.82)
    1.6 (0.04 to 8.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved IGA Score Reduction of ≥2 at Week 16

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    End point title
    Percentage of Subjects Who Achieved IGA Score Reduction of ≥2 at Week 16
    End point description
    Values after first rescue medication were set to missing and subjects with missing IGA score at Week 16 were treated as a non-responders. Analysis was done on FAS.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    65
    65
    61
    Units: Percentage of subjects
        number (confidence interval 95%)
    50.8 (37.89 to 63.62)
    46.9 (34.28 to 59.77)
    42.6 (30.04 to 55.94)
    35.4 (23.92 to 48.23)
    20 (11.1 to 31.77)
    9.8 (3.7 to 20.19)
    No statistical analyses for this end point

    Secondary: Percent Change in Peak Weekly Averaged Pruritus Numerical Rating Scores (NRS) From Baseline to Week 16

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    End point title
    Percent Change in Peak Weekly Averaged Pruritus Numerical Rating Scores (NRS) From Baseline to Week 16
    End point description
    Pruritus NRS is an assessment tool that is 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 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]). Analysis was performed on FAS. Here, number of subjects analyzed = subjects with pruritus NRS assessment at specified time-points. Efficacy data was set to missing after use of rescue medication. Missing values imputed by LOCF. Here 'n' signifies number of subjects with available data for specified category. (Score at) Baseline; (Score at) Week 16; (Percent) Change at Week 16
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    64
    65
    61
    Units: Percent change
    arithmetic mean (standard deviation)
        Baseline (n=62,63,59,63,64,58)
    6.54 ± 1.54
    6.74 ± 2.072
    6.98 ± 2.315
    6.84 ± 1.853
    6.71 ± 1.882
    6.34 ± 1.832
        Week 16 (n=63,64,61,64,65,61)
    3.07 ± 2.148
    3.64 ± 2.388
    4.21 ± 2.763
    3.99 ± 2.449
    5.26 ± 2.465
    6.05 ± 2.312
        Change at Week 16 (n=62,63,58,63,64,58)
    -52.85 ± 31.368
    -46.22 ± 31.964
    -40.6 ± 33.073
    -38.69 ± 38.366
    -21.47 ± 32.952
    -0.43 ± 38.423
    No statistical analyses for this end point

    Secondary: Absolute Change in Peak Weekly Averaged Pruritus NRS From Baseline to Week 16

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    End point title
    Absolute Change in Peak Weekly Averaged Pruritus NRS From Baseline to Week 16
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed = subjects with pruritus NRS assessment at specified time-points. Efficacy data was set to missing after use of rescue medication. Missing values imputed by LOCF. Here 'n' signifies number of subjects with available data for specified category. (Score at) Baseline; (Score at) Week 16; (Absolute) Change at Week 16
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    64
    65
    61
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=62,63,59,63,64,58)
    6.54 ± 1.54
    6.74 ± 2.072
    6.98 ± 2.315
    6.84 ± 1.853
    6.71 ± 1.882
    6.34 ± 1.832
        Week 16 (n=63,64,61,64,65,61)
    3.07 ± 2.148
    3.64 ± 2.388
    4.21 ± 2.763
    3.99 ± 2.449
    5.26 ± 2.465
    6.05 ± 2.312
        Change at Week 16 (n=62,63,59,63,64,58)
    -3.48 ± 2.32
    -3.16 ± 2.467
    -2.77 ± 2.595
    -2.79 ± 2.609
    -1.46 ± 2.038
    -0.27 ± 2.28
    No statistical analyses for this end point

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

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    End point title
    Absolute Change in EASI Score From Baseline to Week 16
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed = subjects with EASI score assessment at specified time-points. Efficacy data was set to missing after use of rescue medication. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    60
    65
    64
    61
    Units: Units on a scale
        least squares mean (standard error)
    -23.1 ± 1.7
    -21.1 ± 1.68
    -20.7 ± 1.71
    -20.4 ± 1.62
    -13.8 ± 1.64
    -5.8 ± 1.71
    No statistical analyses for this end point

    Secondary: Percent Change in SCORing Atopic Dermatitis (SCORAD) Scores from Baseline to Week 16

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    End point title
    Percent Change in SCORing Atopic Dermatitis (SCORAD) Scores from Baseline to Week 16
    End point description
    SCORAD is 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.) are assessed and scored. Total score ranges from 0 [absent disease] to 103 [severe disease]). Analysis was performed on FAS. Here, number of subjects analyzed = subjects with SCORAD score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    60
    65
    64
    60
    Units: Percent change
        least squares mean (standard deviation)
    -56.9 ± 4.12
    -51.2 ± 4.05
    -46 ± 4.12
    -48.8 ± 3.95
    -26.6 ± 3.98
    -13.8 ± 4.14
    No statistical analyses for this end point

    Secondary: Absolute Change in SCORAD Scores From Baseline to Week 16

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    End point title
    Absolute Change in SCORAD Scores From Baseline to Week 16
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed = subjects with SCORAD score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    60
    65
    64
    60
    Units: Units on a scale
        least squares mean (standard error)
    -38.2 ± 2.76
    -34.4 ± 2.71
    -30.9 ± 2.76
    -33.1 ± 2.64
    -18 ± 2.66
    -10.5 ± 2.77
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved 50%, 75% and 90% Reduction from Baseline in EASI Score (EASI-50, EASI-75 and EASI-90 Respectively) at Week 16

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    End point title
    Percentage of Subjects Who Achieved 50%, 75% and 90% Reduction from Baseline in EASI Score (EASI-50, EASI-75 and EASI-90 Respectively) at Week 16
    End point description
    Analysis was performed on FAS. Subjects with a missing EASI score at Week 16 were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    65
    65
    61
    Units: Percentage of participants
    number (confidence interval 95%)
        Reduction of 50%
    82.5 (70.9 to 90.95)
    78.1 (66.03 to 87.49)
    62.3 (48.96 to 74.39)
    70.8 (58.17 to 81.4)
    44.6 (32.27 to 57.47)
    29.5 (18.52 to 42.57)
        Reduction of 75%
    60.3 (47.2 to 72.43)
    53.1 (40.23 to 65.72)
    55.7 (42.45 to 68.45)
    49.2 (36.6 to 61.93)
    29.2 (18.6 to 41.83)
    11.5 (4.74 to 22.22)
        Reduction of 90%
    36.5 (24.73 to 49.6)
    29.7 (18.91 to 42.42)
    31.1 (19.9 to 44.29)
    29.3 (18.6 to 41.83)
    15.4 (7.63 to 26.48)
    3.3 (0.4 to 11.35)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved 50%, 75% and 90% Reduction From Baseline in SCORAD Score (SCORAD-50, SCORAD-75 and SCORAD-90 Respectively) at Week 16

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    End point title
    Percentage of Subjects Who Achieved 50%, 75% and 90% Reduction From Baseline in SCORAD Score (SCORAD-50, SCORAD-75 and SCORAD-90 Respectively) at Week 16
    End point description
    Analysis was performed on FAS. Subjects with a missing SCORAD score at Week 16 were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    63
    64
    61
    65
    65
    61
    Units: Percentage of participants
    number (confidence interval 95%)
        Reduction of 50%
    68.3 (55.3 to 79.4)
    59.4 (46.4 to 71.5)
    52.5 (39.3 to 65.4)
    55.4 (42.5 to 67.7)
    26.2 (16 to 38.5)
    19.7 (10.6 to 31.8)
        Reduction of 75%
    23.8 (14 to 36.2)
    25 (15 to 37.4)
    16.4 (8.2 to 28.1)
    21.5 (12.3 to 33.5)
    7.7 (2.5 to 17)
    3.3 (0.4 to 11.3)
        Reduction of 90%
    6.3 (1.8 to 15.5)
    6.3 (1.7 to 15.2)
    4.9 (1 to 13.7)
    3.1 (0.4 to 10.7)
    3.1 (0.4 to 10.7)
    0 (0 to 5.9)
    No statistical analyses for this end point

    Secondary: Percent Change in Patient Oriented Eczema Measure (POEM) Scores from Baseline to Week 16

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    End point title
    Percent Change in Patient Oriented Eczema Measure (POEM) Scores from Baseline to Week 16
    End point description
    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 to 28 (high score indicative of poor quality of life [QOL]). Analysis was performed on FAS. Here, number of subjects analyzed = subjects with POEM score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    59
    65
    64
    59
    Units: Percent change
        least squares mean (standard error)
    -57.3 ± 4.52
    -44 ± 4.44
    -49.2 ± 5.54
    -46.6 ± 4.33
    -14.2 ± 4.35
    0.2 ± 4.61
    No statistical analyses for this end point

    Secondary: Absolute Change in POEM Scores from Baseline to Week 16

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    End point title
    Absolute Change in POEM Scores from Baseline to Week 16
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed = subjects with POEM score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    59
    65
    64
    59
    Units: Units on a scale
        least squares mean (standard error)
    -12.1 ± 0.88
    -9.8 ± 0.87
    -10.4 ± 0.89
    -9.9 ± 0.85
    -3.3 ± 0.85
    -1.1 ± 0.9
    No statistical analyses for this end point

    Secondary: Changes in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations, and Lichenification) From Baseline to Week 16

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    End point title
    Changes in Global Individual Signs Score (GISS) Components (Erythema, Infiltration/Papulation, Excoriations, and Lichenification) From Baseline 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. Here, number of subjects analyzed = subjects with GISS score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    60
    65
    64
    61
    Units: Units on a scale
    least squares mean (standard error)
        Erythema
    -0.9 ± 0.1
    -0.9 ± 0.1
    -0.8 ± 0.1
    -0.8 ± 0.1
    -0.4 ± 0.1
    -0.2 ± 0.1
        Infiltration/papulation
    -1.2 ± 0.11
    -1.1 ± 0.11
    -1 ± 0.11
    -1.1 ± 0.1
    -0.6 ± 0.11
    -0.3 ± 0.11
        Excoriations
    -1.4 ± 0.11
    -1.4 ± 0.11
    -1.1 ± 0.11
    -1.3 ± 0.11
    -0.6 ± 0.11
    -0.4 ± 0.11
        Lichenification
    -1.1 ± 0.12
    -1.1 ± 0.11
    -1 ± 0.12
    -1.1 ± 0.11
    -0.7 ± 0.11
    -0.3 ± 0.12
    No statistical analyses for this end point

    Secondary: Changes in GISS Cumulative Score from Baseline to Week 16

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    End point title
    Changes in GISS Cumulative Score from Baseline to Week 16
    End point description
    Analysis was performed on FAS. Here, number of subjects analyzed = subjects with GISS score assessment at specified time-points. Missing values imputed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Dupilumab 300 mg qw Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 100 mg q4w Placebo
    Number of subjects analysed
    61
    63
    60
    65
    64
    61
    Units: Units on a scale
        least squares mean (standard error)
    -4.6 ± 0.38
    -4.5 ± 0.37
    -3.9 ± 0.38
    -4.3 ± 0.37
    -2.3 ± 0.37
    -1.2 ± 0.38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Baseline to Week 32) regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    TEAEs that developed during the treatment and follow-up period (time period from the administration of first dose of study drug to the EOS visit).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects who received 2 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.

    Reporting group title
    Dupilumab 100 mg q4w
    Reporting group description
    Subjects who received 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 100 mg injection of Dupilumab q4w and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    Reporting group title
    Dupilumab 300 mg q4w
    Reporting group description
    Subjects who received 2 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 q4w and Placebo (for Dupilumab) qw when Dupilumab not administered from Week 1 to Week 15.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    Subjects who received 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single injection of Placebo (for Dupilumab) alternating with single 200 mg injection of Dupilumab q2w from Week 1 to Week 15.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Subjects who received 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single injection of Placebo (for Dupilumab) alternating with single 300 mg injection of Dupilumab q2w from Week 1 to Week 15.

    Reporting group title
    Dupilumab 300 mg qw
    Reporting group description
    Subjects who received 2 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 qw from Week 1 to Week 15.

    Serious adverse events
    Placebo Dupilumab 100 mg q4w Dupilumab 300 mg q4w Dupilumab 200 mg q2w Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 61 (6.56%)
    5 / 65 (7.69%)
    3 / 65 (4.62%)
    1 / 61 (1.64%)
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    1 / 61 (1.64%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hip dysplasia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    1 / 61 (1.64%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    1 / 61 (1.64%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 65 (6.15%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Dupilumab 100 mg q4w Dupilumab 300 mg q4w Dupilumab 200 mg q2w Dupilumab 300 mg q2w Dupilumab 300 mg qw
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 61 (62.30%)
    38 / 65 (58.46%)
    39 / 65 (60.00%)
    34 / 61 (55.74%)
    34 / 64 (53.13%)
    35 / 63 (55.56%)
    Investigations
    Blood triglycerides increased
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    4 / 65 (6.15%)
    0 / 61 (0.00%)
    1 / 64 (1.56%)
    0 / 63 (0.00%)
         occurrences all number
    0
    0
    5
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    2 / 61 (3.28%)
    4 / 64 (6.25%)
    4 / 63 (6.35%)
         occurrences all number
    1
    0
    1
    2
    4
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 61 (3.28%)
    7 / 65 (10.77%)
    5 / 65 (7.69%)
    9 / 61 (14.75%)
    5 / 64 (7.81%)
    8 / 63 (12.70%)
         occurrences all number
    2
    18
    6
    24
    13
    40
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 65 (0.00%)
    1 / 65 (1.54%)
    0 / 61 (0.00%)
    1 / 64 (1.56%)
    4 / 63 (6.35%)
         occurrences all number
    0
    0
    1
    0
    1
    5
    Conjunctivitis allergic
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 65 (1.54%)
    3 / 65 (4.62%)
    6 / 61 (9.84%)
    2 / 64 (3.13%)
    3 / 63 (4.76%)
         occurrences all number
    2
    1
    3
    9
    4
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 65 (0.00%)
    4 / 65 (6.15%)
    1 / 61 (1.64%)
    1 / 64 (1.56%)
    2 / 63 (3.17%)
         occurrences all number
    3
    0
    4
    1
    1
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 65 (6.15%)
    0 / 65 (0.00%)
    0 / 61 (0.00%)
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    1
    4
    0
    0
    2
    1
    Vomiting
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 65 (0.00%)
    0 / 65 (0.00%)
    4 / 61 (6.56%)
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    3
    0
    0
    7
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    10 / 61 (16.39%)
    11 / 65 (16.92%)
    10 / 65 (15.38%)
    8 / 61 (13.11%)
    13 / 64 (20.31%)
    8 / 63 (12.70%)
         occurrences all number
    12
    13
    12
    10
    19
    9
    Urticaria
         subjects affected / exposed
    0 / 61 (0.00%)
    4 / 65 (6.15%)
    0 / 65 (0.00%)
    1 / 61 (1.64%)
    0 / 64 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    5
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 65 (1.54%)
    1 / 65 (1.54%)
    4 / 61 (6.56%)
    4 / 64 (6.25%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    1
    5
    4
    1
    Back pain
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 65 (4.62%)
    2 / 65 (3.08%)
    0 / 61 (0.00%)
    2 / 64 (3.13%)
    2 / 63 (3.17%)
         occurrences all number
    5
    3
    5
    0
    3
    16
    Infections and infestations
    Herpes simplex
         subjects affected / exposed
    0 / 61 (0.00%)
    5 / 65 (7.69%)
    1 / 65 (1.54%)
    3 / 61 (4.92%)
    2 / 64 (3.13%)
    1 / 63 (1.59%)
         occurrences all number
    0
    7
    1
    4
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    16 / 61 (26.23%)
    20 / 65 (30.77%)
    21 / 65 (32.31%)
    16 / 61 (26.23%)
    16 / 64 (25.00%)
    16 / 63 (25.40%)
         occurrences all number
    23
    29
    29
    25
    18
    23
    Oral herpes
         subjects affected / exposed
    0 / 61 (0.00%)
    5 / 65 (7.69%)
    3 / 65 (4.62%)
    2 / 61 (3.28%)
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    0
    8
    4
    4
    5
    0
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 61 (18.03%)
    5 / 65 (7.69%)
    5 / 65 (7.69%)
    2 / 61 (3.28%)
    6 / 64 (9.38%)
    5 / 63 (7.94%)
         occurrences all number
    11
    7
    6
    2
    8
    7
    Urinary tract infection
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 65 (3.08%)
    3 / 65 (4.62%)
    6 / 61 (9.84%)
    3 / 64 (4.69%)
    0 / 63 (0.00%)
         occurrences all number
    2
    2
    3
    7
    5
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2013
    It included the following changes: -The enrollment period for subjects at clinical sites in Japan was changed; - Exclusion criteria was clarified to define the potential subject population; - The prohibited medications and procedures section was reorganized and the text was clarified; - The timing of the primary analysis was changed.
    27 Jun 2013
    - The length of screening period was increased to 28 days; - Added a section for study committees; - Modified the time points for some of the assessments: photographs, periostin, and serum pregnancy test; - Specified that photographs were taken only at selected sites; - The inclusion/exclusion criteria was clarified to further define the subject population; - Permitted/prohibited medications text was modified to improve clarity regarding the use of prescription moisturizers or moisturizers containing additives; - Expanded description of skin barrier function tests; - Reporting period for any pregnancy was redefined occurring in a female subject of female partner of a male subject during the study; - PK variables were modified; - Modifications to statistical plan.
    03 Dec 2013
    - Added a provision for an interim analysis; - Added description and criteria for subjects to undergo reduced follow-up duration and transition into an open-label extension study; - The definition of FAS was revised.

    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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