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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Dupilumab Monotherapy in Patients ≥12 to <18 Years of Age, With Moderate-to-severe Atopic Dermatitis

    Summary
    EudraCT number
    2015-004458-16
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    05 Jun 2018

    Results information
    Results version number
    v1
    This version publication date
    19 Dec 2018
    First version publication date
    06 Feb 2019
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1526
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03054428
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, 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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001501-PIP01-13
    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
    10 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2018
    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 as a monotherapy in subjects ≥12 years to <18 years of age with moderate-to-severe atopic dermatitis (AD). The secondary objective of the study was to assess the safety of dupilumab as a monotherapy in subjects ≥12 years to <18 years of age 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 Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Mar 2017
    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
    United States: 220
    Country: Number of subjects enrolled
    Canada: 31
    Worldwide total number of subjects
    251
    EEA total number of subjects
    0
    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)
    251
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 50 sites in the United States and Canada between 21 March 2017 and 04 Jun 2018. A total of 295 subjects were screened in the study. The most common causes for screening failures were lack of adequate disease severity and lack of willingness to comply with study visits and procedures.

    Pre-assignment
    Screening details
    Out of 295 subjects, 251 were enrolled and randomized in an approximate 1:1:1 ratio to 1 of 3 treatment groups: Dupilumab once every 2 weeks (Q2W), Dupilumab once every 4 weeks (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
    Placebo
    Arm description
    Subjects received placebo matching dupilumab once every 2 weeks (Q2W) (including doubling the amount of placebo on day 1 to match the loading dose). In order to maintain blinding for the study, subjects in the <60 kilogram (kg) weight stratum received, in a 1:1 ratio, either placebo matching 200 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose) or placebo matching 300 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the subjects randomized to the placebo group received placebo matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to match the loading dose).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    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 Q4W
    Arm description
    Subjects received once every 4 weeks (Q4W) subcutaneous (SC) injections of 300 milligrams (mg) dupilumab following a loading dose of 600 mg on day 1. In order to maintain blinding, all subjects received an injection once every 2 weeks (Q2W) from day 1 to week 14. Subjects received placebo 2 millilitre (mL) injection at the weeks dupilumab was not given.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    REGN668
    Pharmaceutical forms
    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 200 mg or 300 mg Q2W
    Arm description
    Subjects with baseline weight <60 kg received once every 2 weeks (Q2W) subcutaneous (SC) injections of 200 milligram (mg) dupilumab following a loading dose of 400 mg on day 1. Subjects with baseline weight ≥60 kg received Q2W SC injections of 300 mg dupilumab following a loading dose of 600 mg on day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    REGN668
    Pharmaceutical forms
    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 Q4W Dupilumab 200 mg or 300 mg Q2W
    Started
    85
    84
    82
    Completed Week 16
    80
    81
    79
    Completed
    2
    4
    3
    Not completed
    83
    80
    79
         Transitioned to R668-AD-1434 open-label study
    76
    76
    -
         Physician decision
    -
    1
    1
         Lack of efficacy
    3
    1
    -
         Discontinued for R668-AD-1434, but did not enroll
    1
    -
    -
         Transitioned to R668-AD-1434 (open-label)
    -
    -
    73
         Consent withdrawn by subject
    3
    2
    3
         Discontinued to enroll in R668-AD-1434
    -
    -
    1
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matching dupilumab once every 2 weeks (Q2W) (including doubling the amount of placebo on day 1 to match the loading dose). In order to maintain blinding for the study, subjects in the <60 kilogram (kg) weight stratum received, in a 1:1 ratio, either placebo matching 200 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose) or placebo matching 300 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the subjects randomized to the placebo group received placebo matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to match the loading dose).

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Subjects received once every 4 weeks (Q4W) subcutaneous (SC) injections of 300 milligrams (mg) dupilumab following a loading dose of 600 mg on day 1. In order to maintain blinding, all subjects received an injection once every 2 weeks (Q2W) from day 1 to week 14. Subjects received placebo 2 millilitre (mL) injection at the weeks dupilumab was not given.

    Reporting group title
    Dupilumab 200 mg or 300 mg Q2W
    Reporting group description
    Subjects with baseline weight <60 kg received once every 2 weeks (Q2W) subcutaneous (SC) injections of 200 milligram (mg) dupilumab following a loading dose of 400 mg on day 1. Subjects with baseline weight ≥60 kg received Q2W SC injections of 300 mg dupilumab following a loading dose of 600 mg on day 1.

    Reporting group values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W Total
    Number of subjects
    85 84 82 251
    Age categorical
    Units: Subjects
        ≥12-<15
    41 45 43 129
        ≥15-<18
    44 39 39 122
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.5 ± 1.78 14.4 ± 1.59 14.5 ± 1.74 -
    Gender categorical
    Units: Subjects
        Female
    32 32 39 103
        Male
    53 52 43 148
    Race
    Units: Subjects
        White
    48 55 54 157
        Black or African American
    15 8 7 30
        Asian
    13 13 12 38
        Other
    6 8 7 21
        Not Reported/Missing
    3 0 2 5
    Ethnicity
    Units: Subjects
        NOT HISPANIC OR LATINO
    72 64 69 205
        HISPANIC OR LATINO
    13 20 13 46
    Investigator’s Global Assessment (IGA) Score
    IGA is an assessment scale used to determine severity of atopic dermatitis (AD) and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear).
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    3.5 ± 0.50 3.5 ± 0.50 3.5 ± 0.50 -
    Eczema Area and Severity Index (EASI) Score
    The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    35.5 ± 13.97 35.8 ± 14.82 35.3 ± 13.84 -
    Peak weekly averaged pruritus Numerical Rating Scale (NRS) Score
    Peak Pruritus NRS is an assessment tool used by subjects to report intensity of pruritus (itch) during a 24-hour recall period. Subjects were asked the following questions: For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable,’ how would you rate your itch at the worst moment during the previous 24 hours?” Baseline NRS was the prorated average of NRSs reported continuously for 7 days right before and on the baseline visit (ie, study day -6 to day 1).
    Units: Peak weekly average score
        arithmetic mean (standard deviation)
    7.7 ± 1.62 7.5 ± 1.84 7.5 ± 1.52 -
    Body Surface Area (BSA) of AD
    BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined.
    Units: Percentage of BSA
        arithmetic mean (standard deviation)
    56.4 ± 24.13 56.9 ± 23.51 56.0 ± 21.40 -
    Scoring Atopic Dermatitis (SCORAD) Score
    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).
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    70.4 ± 13.25 69.8 ± 14.12 70.6 ± 13.89 -
    Children’s Dermatology Life Quality Index (CDLQI) Total Score
    The CDLQI is a 10-item questionnaire used to measure how much a subject’s skin problem had affected the subject's quality of life (QOL) over a recall period of the past week. The questionnaire consists of 10 items. For each item the scale is rated as follows: 0 = Not at all = Not relevant 1 = Only a little 2 = Quite a lot 3 = Very much = yes = prevent school
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    13.1 ± 6.72 14.8 ± 7.38 13.0 ± 6.21 -
    Patient Oriented Eczema Measure (POEM)
    The POEM is a 7-item questionnaire used to assess disease symptoms in children and adults with atopic eczema. Subjects respond to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on symptom frequency during the past week (i.e., 0 = ‘no days’, 1 = ‘1 to 2 days’, 2 = ‘3 to 4= ‘every day’). The total score is the sum of the 7 items which is ranged from 0 to 28; a high score is indicative of a poor QOL.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    21.1 ± 5.38 21.1 ± 5.47 21.0 ± 5.01 -
    Total Hospital Anxiety and Depression Scale (HADS)
    The HADS is an instrument for screening anxiety and depression. The 14 items on the questionnaire, assessing how the subject was feeling in the past week, include 7 items related to anxiety and 7 items related to depression. A subject could score between 0 and 21 for each subscale (anxiety and depression). A high score is indicative of a poor state. Scores of 11 or more on either subscale are considered to be a 'definite case' of psychological morbidity, while scores of 8 to 10 represents 'probable case’ and 0 to 7 'not a case.'
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    11.6 ± 7.76 13.3 ± 8.17 12.6 ± 8.04 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo matching dupilumab once every 2 weeks (Q2W) (including doubling the amount of placebo on day 1 to match the loading dose). In order to maintain blinding for the study, subjects in the <60 kilogram (kg) weight stratum received, in a 1:1 ratio, either placebo matching 200 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose) or placebo matching 300 milligram (mg) dupilumab (including doubling the amount of placebo on day 1 to match the loading dose). In the ≥60 kg weight stratum, the subjects randomized to the placebo group received placebo matching 300 mg dupilumab (including doubling the amount of placebo on day 1 to match the loading dose).

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Subjects received once every 4 weeks (Q4W) subcutaneous (SC) injections of 300 milligrams (mg) dupilumab following a loading dose of 600 mg on day 1. In order to maintain blinding, all subjects received an injection once every 2 weeks (Q2W) from day 1 to week 14. Subjects received placebo 2 millilitre (mL) injection at the weeks dupilumab was not given.

    Reporting group title
    Dupilumab 200 mg or 300 mg Q2W
    Reporting group description
    Subjects with baseline weight <60 kg received once every 2 weeks (Q2W) subcutaneous (SC) injections of 200 milligram (mg) dupilumab following a loading dose of 400 mg on day 1. Subjects with baseline weight ≥60 kg received Q2W SC injections of 300 mg dupilumab following a loading dose of 600 mg on day 1.

    Primary: Percentage of Subjects with Investigator’s Global Assessment (IGA) 0 or 1 (and Reduction from Baseline of ≥2 Points) at Week 16

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    End point title
    Percentage of Subjects with Investigator’s Global Assessment (IGA) 0 or 1 (and Reduction from Baseline of ≥2 Points) at Week 16
    End point description
    IGA is an assessment scale used to determine severity of atopic dermatitis (AD) and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). Subjects with IGA "0" or "1" and a reduction from baseline of ≥2 points at Week 16 were reported. Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder. Subject considered non-responder after rescue treatment use – Full analysis set (FAS). FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percentage of subjects
        number (not applicable)
    2.4
    17.9
    24.4
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Analysis was performed using Cochran-Mantel-Haenszel (CMH) test stratified by baseline disease severity (IGA=3 vs IGA=4) and baseline weight group (less than [<] 60 kilogram [kg] vs greater than or equal to [≥] 60 kg).
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.2
         upper limit
    31.87
    Notes
    [1] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Analysis was performed using CMH test stratified by baseline disease severity (IGA=3 vs IGA=4) and baseline weight group (<60 kg vs >= 60 kg).
    Comparison groups
    Placebo v Dupilumab 300 mg Q4W
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    15.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.7
         upper limit
    24.31
    Notes
    [2] - Threshold for significance at 0.05 level.

    Primary: Percentage of Subjects with Eczema Area and Severity Index (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 (EASI)-75 (≥75% Improvement from Baseline) at Week 16
    End point description
    The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI­-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline to Week 16. Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder. Subject considered nonresponder after rescue treatment use – Full analysis set (FAS). FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percentage of Subjects
        number (not applicable)
    8.2
    38.1
    41.5
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Analysis was performed using CMH test stratified by baseline disease severity (IGA=3 vs IGA=4) and baseline weight group (< 60 kg vs >= 60 kg).
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    33.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    21.07
         upper limit
    45.39
    Notes
    [3] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Analysis was performed using CMH test stratified by baseline disease severity (IGA=3 vs IGA=4) and baseline weight group (< 60 kg vs >=60 kg).
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    29.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.94
         upper limit
    41.78
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Percent Change from Baseline in EASI Score at Week 16

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    End point title
    Percent Change from Baseline in EASI Score at Week 16
    End point description
    The EASI score was used to measure the severity and extent of AD and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. [Multiple imputation (MI) Method with Data Set to Missing after Rescue Treatment Use – Full analysis set (FAS). FAS included all randomized subjects. Values after first rescue treatment use were set to missing and subjects with missing EASI score at Week 16 were considered as non-¬responders.]
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percent change
        least squares mean (standard error)
    -23.6 ± 5.49
    -64.8 ± 4.51
    -65.9 ± 3.99
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. The confidence interval (CI) with p-value is based on treatment difference (Dupilumab group vs. Placebo) of the LS mean percent change using analysis of covariance (ANCOVA) model with baseline measurement as covariate and the treatment, randomization strata (baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg]) as fixed factors.
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    ANCOVA
    Parameter type
    Least Square (LS) Mean difference
    Point estimate
    -42.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -55.6
         upper limit
    -29.04
    Notes
    [5] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. The confidence interval (CI) with p-value is based on treatment difference (Dupilumab group vs. Placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata (baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg]) as fixed factors.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -41.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.44
         upper limit
    -28.02
    Notes
    [6] - Threshold for significance at 0.05 level.

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

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    End point title
    Percent Change From Baseline in Weekly Average of Daily Peak Pruritus Numerical Rating Scale (NRS) Score at Week 16
    End point description
    revise to weekly average post-baseline [MI Method with Data Set to Missing after Rescue Treatment Use – FAS. 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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: percent change
        least squares mean (standard error)
    -19.0 ± 4.09
    -45.5 ± 3.54
    -47.9 ± 3.43
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. The confidence interval (CI) with p-value is based on treatment difference (Dupilumab group vs. Placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata (baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg]) as fixed factors.
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.54
         upper limit
    -18.38
    Notes
    [7] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. The confidence interval (CI) with p-value is based on treatment difference (Dupilumab group vs. Placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata (baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg]) as fixed factors.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -26.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.45
         upper limit
    15.63
    Notes
    [8] - Threshold for significance at 0.05 level.

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

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    End point title
    Percentage of Subjects with Improvement (Reduction ≥3 Points) of Weekly Average of Daily Peak Pruritus 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]). Subjects achieving a reduction of ≥4 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 Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    83
    82
    Units: percentage of subjects
        number (not applicable)
    9.4
    38.6
    48.8
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Difference is Dupilumab minus Placebo. C.I. = Confidence interval calculated using normal approximation. P-values were derived by CMH test stratified by baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg].
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    percentage difference
    Point estimate
    39.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    26.9
         upper limit
    51.84
    Notes
    [9] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Difference is Dupilumab minus Placebo. C.I. = Confidence interval calculated using normal approximation. P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg].
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    29.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.97
         upper limit
    41.32
    Notes
    [10] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects with Improvement (Reduction) of Weekly Average of Daily Peak Pruritus NRS ≥4 Points From Baseline to Week 16

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    End point title
    Percentage of Subjects with Improvement (Reduction) of Weekly Average of Daily Peak Pruritus NRS ≥4 Points From Baseline to Week 16
    End point description
    revise [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 ≥ 4.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    84
    83
    82
    Units: Percentage of subjects
        number (not applicable)
    4.8
    26.5
    36.6
    Statistical analysis title
    Dupilumab 200 mg or 300 mg Q2W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Difference is Dupilumab minus Placebo. C.I. = Confidence interval calculated using normal approximation. P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg].
    Comparison groups
    Dupilumab 200 mg or 300 mg Q2W v Placebo
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    31.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.45
         upper limit
    43.2
    Notes
    [11] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error. Difference is Dupilumab minus Placebo. C.I. = Confidence interval calculated using normal approximation. P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by baseline disease severity [IGA=3 vs IGA=4] and baseline weight group [<60 kg vs ≥60 kg].
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    21.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.21
         upper limit
    32.28
    Notes
    [12] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects with EASI-50 at Week 16

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    End point title
    Percentage of Subjects with EASI-50 at Week 16
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-50 responders were the subjects who achieved >=50% overall improvement in EASI score at Week 16. Values after first rescue treatment used were set to missing. Subjects with missing value at week 16 were considered as a non-responder. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: percentage of subjects
        number (not applicable)
    12.9
    54.8
    61.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With EASI-90 at Week 16

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    End point title
    Percentage of Subjects With EASI-90 at Week 16
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-90 responders were the subjects who achieved >=90% overall improvement in EASI score at Week 16. Values after first rescue treatment used were set to missing. Subjects with missing value at week 16 were considered as a non-responder. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: percentage of subjects
        number (not applicable)
    2.4
    19.0
    23.2
    No statistical analyses for this end point

    Secondary: Time to Onset of Effect on Pruritus as Measured by Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >=3 From Baseline

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    End point title
    Time to Onset of Effect on Pruritus as Measured by Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >=3 From Baseline
    End point description
    It was measured by percentage of subjects with improvement of weekly average of daily peak pruritus numerical rating scale (NRS) score increased by 3 or more points from baseline. Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). FAS included all randomized subjects. Here, number of subjects analyzed=subjects with available data for specified endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    83
    82
    Units: weeks
        arithmetic mean (standard deviation)
    11.4 ± 5.63
    8.4 ± 5.92
    7.7 ± 5.57
    No statistical analyses for this end point

    Secondary: Time to Onset of Effect on Pruritus as Measured by Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >=4 From Baseline

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    End point title
    Time to Onset of Effect on Pruritus as Measured by Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >=4 From Baseline
    End point description
    It was measured by percentage of subjects with improvement of weekly average of daily peak pruritus numerical rating scale (NRS) score increased by 4 or more points from baseline. Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). FAS included all randomized subjects. Here, number of subjects analyzed=subjects with available data for specified endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    84
    83
    82
    Units: weeks
        arithmetic mean (standard deviation)
    12.8 ± 4.90
    9.9 ± 5.87
    10.6 ± 5.50
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Body Surface Area (BSA) at week 16

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    End point title
    Change From Baseline in Percent Body Surface Area (BSA) at week 16
    End point description
    BSA affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: percentage of body surface area
        least squares mean (standard error)
    -11.66 ± 2.720
    -33.41 ± 2.330
    -30.11 ± 2.337
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Scoring Atopic Dermatitis (SCORAD) Score at Week 16

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    End point title
    Percent Change From Baseline in Scoring Atopic Dermatitis (SCORAD) Score at 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). FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percent change
        least squares mean (standard error)
    -17.6 ± 3.76
    -47.5 ± 3.21
    -51.6 ± 3.23
    No statistical analyses for this end point

    Secondary: Change From Baseline in Children’s Dermatology Life Quality Index (CDLQI) Total Score at Week 16

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    End point title
    Change From Baseline in Children’s Dermatology Life Quality Index (CDLQI) Total Score at Week 16
    End point description
    The CDLQI is a 10-item questionnaire used to measure how much a subject’s skin problem had affected the subject's quality of life (QOL) over a recall period of the past week. The questionnaire consists of 10 items. For each item the scale is rated as follows: 0 = Not at all = Not relevant, 1 = Only a little, 2 = Quite a lot, 3 = Very much = yes = prevent school. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Scores on a scale
        least squares mean (standard error)
    -5.1 ± 0.62
    -8.8 ± 0.53
    -8.5 ± 0.50
    No statistical analyses for this end point

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

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    End point title
    Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16
    End point description
    The POEM is a 7-item questionnaire used to assess disease symptoms in children and adults with atopic eczema. Subjects respond to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on symptom frequency during the past week (i.e., 0 = ‘no days’, 1 = ‘1 to 2 days’, 2 = ‘3 to 4= ‘every day’). The total score is the sum of the 7 items which is ranged from 0 to 28; a high score is indicative of a poor quality of life (QOL). FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Scores on a scale
        least squares mean (standard error)
    -3.8 ± 0.96
    -9.5 ± 0.86
    -10.1 ± 0.76
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 16

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    End point title
    Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 16
    End point description
    revise
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Scores on a scale
        least squares mean (standard error)
    -1.54 ± 0.303
    -3.44 ± 0.260
    -3.70 ± 0.250
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 4

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    End point title
    Percent Change From Baseline in Weekly Average of Daily Peak Pruritus NRS at Week 4
    End point description
    Pruritus NRS scale 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]). FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percent change
        least squares mean (standard error)
    -12.5 ± 3.06
    -33.1 ± 3.05
    -34.7 ± 2.99
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) at Week 16

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    End point title
    Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) at Week 16
    End point description
    The HADS is an instrument for screening anxiety and depression. The 14 items on the questionnaire, assessing how the subject was feeling in the past week, include 7 items related to anxiety and 7 items related to depression. A subject could score between 0 and 21 for each sub-scale (anxiety and depression). A high score is indicative of a poor state. Scores of 11 or more on either sub-scale are considered to be a 'definite case' of psychological morbidity, while scores of 8 to 10 represents 'probable case’ and 0 to 7 'not a case.' FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Scores on a scale
        least squares mean (standard error)
    -2.5 ± 0.80
    -5.2 ± 0.73
    -3.8 ± 0.68
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >= 4 From Baseline at Week 4

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    End point title
    Percentage of Subjects With Improvement of Weekly Average of Daily Peak Pruritus NRS >= 4 From Baseline at Week 4
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    84
    82
    Units: Percentage of Subjects
        number (not applicable)
    4.8
    20.5
    22.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Skin-infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Through Week 16

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    End point title
    Percentage of Subjects With Skin-infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) Through Week 16
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to the end of study [Week 16]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. FAS included all randomized subjects. Here, number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    83
    82
    Units: Percentage of subjects
        number (not applicable)
    18.8
    9.6
    9.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Serious TEAEs Through Week 16

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    End point title
    Percentage of Subjects With Serious TEAEs Through Week 16
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to the end of study [Week 28]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg Q2W
    Number of subjects analysed
    85
    83
    82
    Units: Percentage of subjects
        number (not applicable)
    1.2
    0
    0
    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 (Day 197) regardless of seriousness or relationship to investigational product (IP).
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs (TEAEs) that developed/worsened during ‘on treatment period’ (from 1st dose of IP up to Day 113). TEAEs were collected for the 16-week treatment & follow-up period up to 12 weeks. After completing the treatment period, all were offered an opportunity to enroll in open-label extension (OLE) study R668-AD-1434.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Dupilumab 300 mg Q4W

    Reporting group title
    Dupilumab 200 mg or 300 mg
    Reporting group description
    Dupilumab 200 mg or 300 mg

    Serious adverse events
    Placebo Dupilumab 300 mg Q4W Dupilumab 200 mg or 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 83 (0.00%)
    0 / 82 (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 Q4W Dupilumab 200 mg or 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 85 (47.06%)
    34 / 83 (40.96%)
    39 / 82 (47.56%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 85 (10.59%)
    4 / 83 (4.82%)
    9 / 82 (10.98%)
         occurrences all number
    14
    5
    11
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    21 / 85 (24.71%)
    16 / 83 (19.28%)
    15 / 82 (18.29%)
         occurrences all number
    29
    27
    21
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 83 (0.00%)
    5 / 82 (6.10%)
         occurrences all number
    4
    0
    6
    Nasopharyngitis
         subjects affected / exposed
    4 / 85 (4.71%)
    10 / 83 (12.05%)
    5 / 82 (6.10%)
         occurrences all number
    5
    16
    8
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 85 (0.00%)
    5 / 83 (6.02%)
    2 / 82 (2.44%)
         occurrences all number
    0
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 85 (17.65%)
    7 / 83 (8.43%)
    10 / 82 (12.20%)
         occurrences all number
    23
    9
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2015
    Following changes were made: - Added a 200 mg Q2W regimen (with a loading dose of 400 mg on day 1) to the Q2W treatment group. Subjects below 60 kg received 200 mg Q2W, while subjects >=60 kg received 300 mg Q2W (with a loading dose of 600 mg on day 1). This weight-adjusted dosing better fulfilled the conventional therapeutic objective to utilize the minimum effective dose. - Changed duration of treatment period from 12 weeks to 16 weeks. - Revised inclusion and exclusion criteria. - Added a clarifying note that subjects who had a positive drug test due to a prescription drug being used for medical reasons, would still be eligible for enrollment into the study. - Removed the endpoint hierarchy under Multiplicity Considerations; details were specified in the SAP. - Removed the endpoint hierarchy under Multiplicity Considerations; details were specified in the SAP. - Updated all endpoints previously being assessed at 12 weeks to be assessed at 16 weeks (to align with increase in duration of treatment period from 12 weeks to 16 weeks). - Revised the number of imputations used to generate a complete data set for missing data from the FAS from 50 times to multiple times. - Corrected the IND number. - Added that “Regulatory approvals were also obtained where required by local legislation.” - Updated the Introduction to include more current information about completed and ongoing trials in the dupilumab program. - Revised the Biomarker Procedures section to align with the new procedures for collection, use, and storage of biomarker serum and plasma samples and DNA/RNA samples for the optional genomics sub-study. - Revised the definition of concomitant medications and procedures. - Deleted the section on Cytochrome P450. - Clarified the definition of the ADA analysis set. - Included that ADA positive samples would be further characterized for the presence of neutralizing antibody response.
    05 Jul 2017
    - Added an exclusion criterion. - Corrected the expellable volume for 200 mg to 1.14 mL instead of 1.0 mL. - Clarified the text indicating where moisturizers should be applied by the deletion of the following text in the third sentence “on the area(s) of nonlesional skin designated for such assessments". - Added the medication crisaborole to the list of prohibited agents because it is a treatment for atopic dermatitis and would interfere with the efficacy evaluation. - Added crisaborole to the list of prohibited medications to prevent any confounding of efficacy assessment for the study drug. - Added the medication crisaborole to the list of prohibited agents because it is a treatment for atopic dermatitis and would interfere with the efficacy evaluation. - Added crisaborole to the list of prohibited medications to prevent any confounding of efficacy assessment for the study drug. -Removed hematology and chemistry assessments at week 2 and week 12. - Removed the Pain Assessment with VAS from phone visit 16 for accuracy. - Added the IGA scale to the protocol. - The scale was already included in the efficacy procedures and in the Study Manual and was added to Appendix 2 for further clarification. - As per FDA request, provided further details on the methodology for multiple imputation of the continuous endpoints and deleted text related to missing data from the FAS. - For continuous endpoints, added that the MI with ANCOVA model would be used “as the primary analysis method.”
    23 Feb 2018
    - Key secondary endpoints were added. - Revision was made in Inclusion Criterion. - The biomarker sample type was changed from “serum/plasma” to “serum” based on clarification letter previously sent to investigators, regulatory authorities, ethic committees and independent review boards.

    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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