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    Clinical Trial Results:
    A phase 3 study investigating the efficacy, safety, and tolerability of Dupilumab administered to adult patients with severe atopic dermatitis who are not adequately controlled with or are intolerant to oral cyclosporine A, or when this treatment is not medically advisable

    Summary
    EudraCT number
    2015-002653-35
    Trial protocol
    DE   PL   BE   GB   NL   SK   AT   IE   ES  
    Global end of trial date
    29 Mar 2017

    Results information
    Results version number
    v3(current)
    This version publication date
    04 Sep 2020
    First version publication date
    06 Feb 2019
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1424
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02755649
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States,
    Public contact
    Clinical Trial Administrator, Regeneron Pharmaceuticals, Inc.,, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Administrator, 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
    25 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 2 dose regimens of dupilumab compared to placebo, administered with concomitant topical corticosteroids (TCS), in adult subjects with severe AD who are not adequately controlled with, or are intolerant to, oral CSA, or when this treatment is currently not medically advisable.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jan 2016
    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
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 107
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Germany: 142
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    325
    EEA total number of subjects
    309
    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)
    316
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 73 sites in Europe. A total of 390 subjects were screened between 28 Jan 2016 and 14 Sep 2016. Of those, 325 subjects were enrolled into the study and randomized. Sixty subjects were considered screen failures, mostly due to unmet eligibility criteria.

    Pre-assignment
    Screening details
    After providing informed consent, subjects were assessed for study eligibility. Screening assessments were performed between day -28 & day -15, prior to randomization. Subjects who met eligibility criteria at baseline (day 1) were randomized in a 1:1:1 ratio to receive dupilumab (weekly[QW] or every 2 weeks[Q2W]) or placebo.

    Period 1
    Period 1 title
    Started (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo QW + TCS
    Arm description
    Subjects received one subcutaneous (SC) injection of matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (Matched to Dupilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of placebo matching to dupilumab QW following a loading dose on Day 1 from Week 1 to Week 15.

    Investigational medicinal product name
    Topical corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects received topical corticosteroids (TCS) using a standardized regimen through the end of the treatment period (Week 16).

    Arm title
    Dupilumab 300 mg Q2W + TCS
    Arm description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, subjects received matching placebo. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab 300 mg
    Investigational medicinal product code
    REGN668
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received one SC injection of Dupilumab every 2 weeks (Q2W) (following two SC injections on day 1) from Week 1 to Week 15.

    Investigational medicinal product name
    Topical corticosteroids (TCS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects received treatment with topical corticosteroids (TCS) using a standardized regimen through the end of the treatment period (Week 16).

    Arm title
    Dupilumab 300 mg QW + TCS
    Arm description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).
    Arm type
    Experimental

    Investigational medicinal product name
    Topical corticosteroids (TCS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects received treatment with topical corticosteroids (TCS) using a standardized regimen through the end of the treatment period (Week 16).

    Investigational medicinal product name
    Dupilumab 300 mg
    Investigational medicinal product code
    REGN668
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received one SC injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15.

    Number of subjects in period 1
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Started
    108
    107
    110
    Completed (Week 16 - Treatment Period)
    107
    106
    109
    Completed
    7
    8
    8
    Not completed
    101
    99
    102
         Rolled over into OLE study
    99
    98
    100
         Physician decision
    -
    -
    2
         Currently undecided
    1
    -
    -
         Did not complete follow-up visits
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg Q2W + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, subjects received matching placebo. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS Total
    Number of subjects
    108 107 110 325
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.9 ± 13.35 37.5 ± 12.89 38.7 ± 13.21 -
    Gender categorical
    Units: Subjects
        Female
    40 42 44 126
        Male
    68 65 66 199
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    3 1 5 9
        Not Hispanic or Latino
    101 99 101 301
        Unknown or Not Reported
    4 7 4 15
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    2 2 2 6
        Native Hawaiian or Other pacific Islander
    0 0 0 0
        Black or African American
    0 0 2 2
        White
    104 104 105 313
        More than one race
    2 0 1 3
        Unknown is Not Reported
    0 1 0 1
    Region of Enrollment
    Units: Subjects
        Austria
    2 2 3 7
        Belgium
    4 4 3 11
        Germany
    51 48 43 142
        Ireland
    0 1 1 2
        Netherlands
    4 6 6 16
        Poland
    33 39 35 107
        Russia
    7 0 9 16
        Slovakia
    1 2 1 4
        Spain
    2 1 0 3
        United Kingdom
    4 4 9 17
    Investigator's Global Assessment (IGA) score
    Units: Subjects
        IGA score = 3
    56 57 58 171
        IGA score = 4
    52 50 52 154
    Eczema Area and Severity Index (EASI) Score
    Units: units on a scale
        arithmetic mean (standard deviation)
    32.9 ± 10.80 33.3 ± 9.93 33.1 ± 11.02 -
    Peak weekly averaged pruritus Numerical Rating Scale (NRS) score
    Units: subjects
        arithmetic mean (standard deviation)
    6.4 ± 2.23 6.6 ± 2.10 6.2 ± 2.01 -
    Body Surface Area (BSA) involvement of atopic dermatitis
    Units: units on a scale
        arithmetic mean (standard deviation)
    55.0 ± 20.51 56.1 ± 17.83 56.0 ± 19.26 -
    SCORing Atopic Dermatitis (SCORAD) score
    Units: units on a scale
        arithmetic mean (standard deviation)
    67.0 ± 12.20 68.6 ± 11.91 66.0 ± 12.70 -
    Global Individual Signs Score (GISS)
    Units: Units on a scale
        arithmetic mean (standard deviation)
    9.4 ± 1.63 9.3 ± 1.64 9.1 ± 1.63 -
    Dermatology Life Quality Index (DLQI) Total Score
    Units: units on a scale
        arithmetic mean (standard deviation)
    13.2 ± 7.60 14.5 ± 7.63 13.8 ± 8.03 -
    Patient Oriented Eczema Measure (POEM)
    Units: units on a scale
        arithmetic mean (standard deviation)
    19.1 ± 5.99 19.3 ± 6.21 18.6 ± 6.97 -
    Total Hospital Anxiety Depression Scale (HADS)
    Units: units on a scale
        arithmetic mean (standard deviation)
    13.0 ± 7.85 12.8 ± 8.01 13.3 ± 8.15 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg Q2W + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, subjects received matching placebo. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    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 is used to measure the severity and extent of atopic dermatitis (AD) and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline to Week 16. The analysis population for efficacy analyses is the Full Analysis Set (FAS) which included all randomized subjects. Efficacy analyses were based on the treatment allocated (as randomized).
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of Subjects
        number (not applicable)
    29.6
    62.6
    59.1
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across 2 dose regimens. Difference is Dupilumab minus placebo. Confidence Interval (CI) calculated using normal approximation. Subjects with missing values at Week 16 were categorized as non-responders at Week 16. Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated.
    Comparison groups
    Dupilumab 300 mg QW + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    29.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.87
         upper limit
    42.05
    Notes
    [1] - Threshold for significance at 0.05 level. P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by disease severity (IGA 3 vs IGA 4) and prior Cyclosporine A (CSA) use (Yes, No).
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across 2 dose regimens. Difference is Dupilumab minus placebo. Confidence Interval (CI) calculated using normal approximation. Subjects with missing values at Week 16 were categorized as non-responders at Week 16. Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated.
    Comparison groups
    Dupilumab 300 mg Q2W + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.41
         upper limit
    45.57
    Notes
    [2] - Threshold for significance at 0.05 level. P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by disease severity (IGA 3 vs IGA 4) and prior Cyclosporine A (CSA) use (Yes, No).

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

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    End point title
    Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score at Week 16
    End point description
    The EASI score is used to measure the severity and extent of atopic dermatitis (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. The analysis population for efficacy analyses is the FAS which included all randomized subjects. Efficacy analyses were based on the treatment allocated (as randomized). Here “number of subjects analyzed” = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    105
    Units: Percent change
        least squares mean (standard error)
    -46.6 ± 2.76
    -79.8 ± 2.59
    -78.2 ± 2.55
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    Hierarchical testing approach to control Type-1 error rate at 0.05 across 2 dose regimens.CI w/p-value is based on treatment difference(dupilumab vs placebo) of LS mean percent change using multiple imputation (MI) w/ANCOVA model w/baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    -31.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.85
         upper limit
    -24.3
    Notes
    [3] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -33.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.42
         upper limit
    -25.88
    Notes
    [4] - Threshold for significance at 0.05 level

    Secondary: Percentage of Subjects With Eczema Area and Severity Index (EASI) Score (≥75% Improvement From Baseline) at Week 16 for subjects With Prior CSA Use

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    End point title
    Percentage of Subjects With Eczema Area and Severity Index (EASI) Score (≥75% Improvement From Baseline) at Week 16 for subjects With Prior CSA Use
    End point description
    The EASI score is used to measure the severity and extent of atopic dermatitis (AD) and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the subjects who achieved ≥75% overall improvement in EASI score from baseline to Week 16. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    72
    69
    69
    Units: Percentage of subjects
        number (not applicable)
    26.4
    58.0
    56.5
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Dupilumab 300 mg QW + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    30.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.63
         upper limit
    45.64
    Notes
    [5] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Dupilumab 300 mg Q2W + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    31.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.11
         upper limit
    47.05
    Notes
    [6] - Threshold for significance at 0.05 level.

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

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    End point title
    Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) at Week 16
    End point description
    The Pruritus NRS is an assessment tool 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]). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    102
    103
    Units: Percent change
        least squares mean (standard error)
    -25.4 ± 3.39
    -53.9 ± 3.14
    -51.7 ± 3.09
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Dupilumab 300 mg QW + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    ANCOVA
    Parameter type
    LS mean difference
    Point estimate
    -26.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.07
         upper limit
    -17.41
    Notes
    [7] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Dupilumab 300 mg Q2W + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference]
    Point estimate
    -28.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.34
         upper limit
    -19.68
    Notes
    [8] - Threshold for significance at 0.05 level

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

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    End point title
    Percentage of Subjects With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus NRS From Baseline to Week 16
    End point description
    Pruritus NRS is an assessment tool used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Subjects achieving a reduction of ≥4 points from baseline in weekly average of peak daily pruritus NRS score at Week 16 were reported. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    91
    94
    94
    Units: Percentage of subjects
        number (not applicable)
    14.3
    45.7
    40.4
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Dupilumab 300 mg QW + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    26.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.89
         upper limit
    38.39
    Notes
    [9] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Dupilumab 300 mg Q2W + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    31.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.08
         upper limit
    43.83
    Notes
    [10] - Threshold for significance at 0.05 level.

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

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    End point title
    Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) at Week 2
    End point description
    Pruritus NRS is an assessment tool 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's 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]). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint. Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    105
    105
    110
    Units: Percent change
        least squares mean (standard error)
    -10.0 ± 2.24
    -17.2 ± 2.25
    -19.7 ± 2.21
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [11]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -9.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.8
         upper limit
    -3.66
    Notes
    [11] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Dupilumab 300 mg Q2W + TCS v Placebo QW + TCS
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0214 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.31
         upper limit
    -1.06
    Notes
    [12] - Threshold for significance at 0.05 level

    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
    The SCORAD is a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23–31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) are assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    104
    Units: Percent change
        least squares mean (standard error)
    -29.5 ± 2.55
    -62.4 ± 2.48
    -58.3 ± 2.45
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -28.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.56
         upper limit
    -21.93
    Notes
    [13] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -32.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.7
         upper limit
    -26.06
    Notes
    [14] - Threshold for significance at 0.05 level

    Secondary: Percentage of Subjects Achieving SCORAD 50 (≥50% Improvement From Baseline) at Week 16

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    End point title
    Percentage of Subjects Achieving SCORAD 50 (≥50% Improvement From Baseline) at Week 16
    End point description
    The SCORAD is a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). 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). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized).
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    25.9
    66.4
    55.5
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    29.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.1
         upper limit
    41.96
    Notes
    [15] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    40.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.24
         upper limit
    52.61
    Notes
    [16] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in Percent Body Surface Area (BSA) Involvement With Atopic Dermatitis (AD) at Week 16

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    End point title
    Change From Baseline in Percent Body Surface Area (BSA) Involvement With Atopic Dermatitis (AD) 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. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "number of subjects analyzed" = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    104
    Units: Percent BSA
        least squares mean (standard error)
    -19.57 ± 1.798
    -39.23 ± 1.715
    -37.52 ± 1.690
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment,randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors. Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -17.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.706
         upper limit
    -13.197
    Notes
    [17] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -19.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -24.431
         upper limit
    -14.895
    Notes
    [18] - Threshold for significance at 0.05 level

    Secondary: Percentage of Subjects With Investigator Global Assessment (IGA) 0 or 1 (on the 0 to 4 IGA Scale) and a Reduction From Baseline of ≥2 Points at Week 16

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    End point title
    Percentage of Subjects With Investigator Global Assessment (IGA) 0 or 1 (on the 0 to 4 IGA Scale) and a Reduction From Baseline of ≥2 Points at Week 16
    End point description
    IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5 point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Subjects with IGA score of "0" or "1" and a reduction from baseline of ≥2 points at Week 16 were reported. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized).
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    13.9
    40.2
    39.1
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    25.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.99
         upper limit
    36.41
    Notes
    [19] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    26.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.95
         upper limit
    37.65
    Notes
    [20] - Threshold for significance at 0.05 level

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

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    End point title
    Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 16
    End point description
    The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score is indicative of a poor QOL. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "number of subjects analyzed" = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    104
    Units: Units on a scale
        least squares mean (standard error)
    -4.5 ± 0.49
    -9.5 ± 0.46
    -8.8 ± 0.45
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.6
         upper limit
    -3.04
    Notes
    [21] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No])as fixed factors. Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.31
         upper limit
    -3.74
    Notes
    [22] - Threshold for significance at 0.05 level

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

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    End point title
    Change From Baseline in the Patient Oriented Eczema Measure (POEM) at Week 16
    End point description
    The POEM is a 7-item questionnaire that assesses disease symptoms (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "number of subjects analyzed" = subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    88
    103
    104
    Units: units on a scale
        least squares mean (standard error)
    -4.3 ± 0.62
    -11.9 ± 0.60
    -11.4 ± 0.59
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No])as fixed factors. Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.78
         upper limit
    -5.47
    Notes
    [23] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No])as fixed factors. Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.29
         upper limit
    -5.97
    Notes
    [24] - Threshold for significance at 0.05 level

    Secondary: Change From Baseline in Mean Weekly Dose of Topical Corticosteroid (TCS) Use During Treatment Period

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    End point title
    Change From Baseline in Mean Weekly Dose of Topical Corticosteroid (TCS) Use During Treatment Period
    End point description
    The type, amount, frequency, and potency of topical products used during the study were recorded at home by subjects in a medication diary. Subjects returned TCS tubes at each clinic visit up until week 16, and these tubes were weighed by the site staff to determine the actual amount of TCS used. During the 16-week placebo-controlled study treatment period, medium-potency TCS dosing frequency was symptom-based (IGA score) adjusted every 4 weeks per the protocol-specified tapering algorithm. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Grams
        least squares mean (standard error)
    25.1 ± 1.48
    15.0 ± 1.51
    17.5 ± 1.49
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [25]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -7.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.64
         upper limit
    -3.51
    Notes
    [25] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -10.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.15
         upper limit
    -5.95
    Notes
    [26] - Threshold for significance at 0.05 level

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

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    End point title
    Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) Score at Week 16
    End point description
    The HADS is a fourteen item scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    104
    Units: units on a scale
        least squares mean (standard error)
    -2.3 ± 0.56
    -6.1 ± 0.54
    -5.2 ± 0.53
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [27]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.41
         upper limit
    -1.43
    Notes
    [27] - Threshold for significance at 0.05 level
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.38
         upper limit
    -2.4
    Notes
    [28] - Threshold for significance at 0.05 level

    Secondary: Percent Change From Baseline in the Total Global Individual Signs Score (GISS) at Week 16 (Erythema, Infiltration/ Papulation, Excoriations, Lichenification)

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    End point title
    Percent Change From Baseline in the Total Global Individual Signs Score (GISS) at Week 16 (Erythema, Infiltration/ Papulation, Excoriations, Lichenification)
    End point description
    Individual components of the AD lesions (erythema, infiltration/ papulation, excoriations, and lichenification) were rated globally (each assessed for the whole body, not by anatomical region) on a 4-point scale (0= none, 1= mild, 2= moderate and 3= severe) using the EASI severity grading criteria. Total score ranges from 0 (absent disease) to 12 (severe disease). The analysis population for efficacy analyses is the FAS. Efficacy analyses were based on the treatment allocated (as randomized). Full Analysis Set (FAS) included all randomized. Here "Number of Subjects analyzed" = Subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    89
    103
    104
    Units: Percent change
        least squares mean (standard error)
    -29.0 ± 2.75
    -55.2 ± 2.66
    -53.3 ± 2.65
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab group vs. placebo)of LS mean percent change using MI with ANCOVA with baseline measurement as covariate & treatment,randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use[Yes,No])as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [29]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -24.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.63
         upper limit
    -16.88
    Notes
    [29] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error rate at 0.05 across 2 dose regimens.CI with p-value is based on treatment difference(dupilumab vs. placebo) of LS mean percent change using MI with ANCOVA model with baseline measurement as covariate & treatment, randomization strata(disease severity[IGA 3 vs IGA 4] & prior CSA use [Yes,No]) as fixed factors.Efficacy data from subjects who received rescue treatment were set to missing after timepoint of rescue & then imputed by MI.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -26.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.49
         upper limit
    -18.86
    Notes
    [30] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Treatment Period

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    End point title
    Percentage of Subjects With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Treatment Period
    End point description
    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 to the last study dose (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. Safety analysis set (SAF) included all randomized subjects who received any study drug; it was based on the treatment received (as treated).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    8.3
    1.9
    3.6
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1486
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    -4.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.97
         upper limit
    1.58
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0319
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    -6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.27
         upper limit
    -0.65

    Secondary: Percentage of Subjects Having at Least One Serious Treatment Emergent Adverse Event (TEAE) Through Treatment Period

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    End point title
    Percentage of Subjects Having at Least One Serious Treatment Emergent Adverse Event (TEAE) Through Treatment Period
    End point description
    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 to the last study dose (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. SAF included all randomized subjects who received any study drug; it was based on the treatment received (as treated).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    1.9
    1.9
    1.8
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9829
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    3.53
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    3.63

    Secondary: Percentage of Subjects Having at Least One Treatment-Emergent Adverse Event (TEAE) Leading to Treatment Discontinuation Through Treatment Period

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    End point title
    Percentage of Subjects Having at Least One Treatment-Emergent Adverse Event (TEAE) Leading to Treatment Discontinuation Through Treatment Period
    End point description
    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 to the last study dose (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. SAF included all randomized subjects who received any study drug; it was based on the treatment received (as treated).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    0.9
    0
    1.8
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5619
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.19
         upper limit
    3.97
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3241
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.73
         upper limit
    0.88

    Secondary: Percentage of Subjects With Treatment-Emergent Adverse Events Through Treatment Period

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    End point title
    Percentage of Subjects With Treatment-Emergent Adverse Events Through Treatment Period
    End point description
    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 to the last study dose (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. SAF included all randomized subjects who received any study drug; it was based on the treatment received (as treated).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Placebo QW + TCS Dupilumab 300 mg Q2W + TCS Dupilumab 300 mg QW + TCS
    Number of subjects analysed
    108
    107
    110
    Units: Percentage of subjects
        number (not applicable)
    69.4
    72.0
    69.1
    Statistical analysis title
    Dupilumab 300 mg QW + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg QW + TCS
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9518
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.6
         upper limit
    11.9
    Statistical analysis title
    Dupilumab 300 mg Q2W + TCS vs Placebo QW + TCS
    Statistical analysis description
    A hierarchical testing approach was used to control Type-1 error at 0.05 across the 2 dose regimens. Difference is dupilumab minus placebo. CI calculated using normal approximation. P-values were derived by CMH test stratified by disease severity (IGA 3 vs IGA 4) and prior CSA use (Yes,No). Subjects who used rescue treatment were categorized as non-responders from time rescue treatment was initiated. Subjects with missing values at Week 16 were categorized as non-responders at Week 16.
    Comparison groups
    Placebo QW + TCS v Dupilumab 300 mg Q2W + TCS
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6833
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    difference in percentages
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.64
         upper limit
    14.68

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of informed consent form up to end of study (EOS), Week 28, regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Pre-treatment AEs were AEs that developed/worsened in severity during pre-treatment period (from informed consent to first dose of study drug); All AEs collected during treatment and follow-up period were considered TEAEs. TEAEs were AEs that developed or worsened in severity compared to baseline during treatment and follow-up period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg QW + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Reporting group title
    Dupilumab 300 mg Q2W + TCS
    Reporting group description
    Subjects received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, subjects received matching placebo. All subjects were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, subjects could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Subjects who did not enter the OLE study were followed for up to an additional 12 weeks for safety ([Week 28, end of study (EOS) period]).

    Serious adverse events
    Placebo QW + TCS Dupilumab 300 mg QW + TCS Dupilumab 300 mg Q2W + TCS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 110 (2.73%)
    2 / 107 (1.87%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Emphysema
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 107 (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
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 107 (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
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo QW + TCS Dupilumab 300 mg QW + TCS Dupilumab 300 mg Q2W + TCS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 108 (41.67%)
    51 / 110 (46.36%)
    54 / 107 (50.47%)
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    1 / 108 (0.93%)
    4 / 110 (3.64%)
    7 / 107 (6.54%)
         occurrences all number
    2
    7
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 108 (9.26%)
    11 / 110 (10.00%)
    10 / 107 (9.35%)
         occurrences all number
    17
    13
    20
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    7 / 108 (6.48%)
    10 / 110 (9.09%)
    16 / 107 (14.95%)
         occurrences all number
    9
    11
    18
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    18 / 108 (16.67%)
    10 / 110 (9.09%)
    8 / 107 (7.48%)
         occurrences all number
    26
    15
    10
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    4 / 108 (3.70%)
    8 / 110 (7.27%)
    12 / 107 (11.21%)
         occurrences all number
    4
    8
    14
    Nasopharyngitis
         subjects affected / exposed
    18 / 108 (16.67%)
    18 / 110 (16.36%)
    22 / 107 (20.56%)
         occurrences all number
    26
    24
    29

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2016
    1. Extended the treatment period from 16 weeks to 24 weeks and add week 24 endpoints to meet the criteria for dupilumab to be considered for chronic use in the treatment of AD. 2. The introduction was modified to provide support for the safety of a 24-week treatment period. 3. As a result, endpoints for week 24 corresponding to those for week 16 have been added and the hierarchy modified accordingly. 4. As the treatment period is extended from 16 weeks to 24 weeks and there is a 1-step analysis after the last patient completes 16 weeks of treatment, planned interim analysis section has been modified to state that the results of the 1-step analysis will not be used to change the conduct and integrity of the study. 1-step analysis has also been modified to accommodate the extension of the treatment period and the addition of week 24 endpoints. 5. Removed the endpoint “Percent change from baseline to week 16 in the GISS”. 6. Exclusion criterion #4 was changed from “within 8 weeks prior to the screening visit” to “within 4 weeks of the baseline visit”. The original wording would have resulted in automatic exclusion of all patients on systemic treatments (which is common in a population with severe AD) who present for screening. The revised criterion is now also consistent with all other AD protocols. 7. The secondary endpoint “Topical treatment for AD – medication-free days” was added

    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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