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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Investigating the Efficacy and Safety of Multiple Dupilumab Dose Regimens Administered as Monotherapy for Maintaining Treatment Response in Patients With Atopic Dermatitis

    Summary
    EudraCT number
    2014-003384-38
    Trial protocol
    LT   EE   DE   FI   SE   GB   DK   ES   BG   PL   IT  
    Global end of trial date
    17 Oct 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Mar 2020
    First version publication date
    06 Feb 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1415
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02395133
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Investigational New Drug: IND 107969
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd., Tarrytown, United States,
    Public contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials information, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the ability of different Dupilumab dose regimens, administered as monotherapy, to maintain the treatment response achieved after 16 weeks of initial treatment with Dupilumab monotherapy compared to placebo.
    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
    24 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 153
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Singapore: 6
    Worldwide total number of subjects
    422
    EEA total number of subjects
    172
    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)
    397
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 15 countries between 25 March 2015 and 18 October 2016. A total of 422 subjects were randomized in the study.

    Pre-assignment
    Screening details
    Out of the 475 enrolled subjects, 422 were randomized and 420 received either placebo or Dupilumab. Subjects were randomized in 2:1:1:1 ratio to receive Dupilumab 300 milligram (mg) once weekly/twice weekly (QW/Q2W), Dupilumab 300 mg four times a week (Q4W), Dupilumab 300 mg eight times a week (Q8W) and Placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo QW
    Arm description
    Subcutaneous injection of Placebo (for Dupilumab) was administered weekly (QW) from Week 1 (Day 1) to Week 36.
    Arm type
    Placebo

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

    Arm title
    Dupilumab 300 mg Q8W
    Arm description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every eight week (Q8W) from Week 1 to Week 36.
    Arm type
    Experimental

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

    Arm title
    Dupilumab 300 mg Q4W
    Arm description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every four week (Q4W) from Week 1 to Week 36.
    Arm type
    Experimental

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

    Arm title
    Dupilumab 300 mg Q2W/QW
    Arm description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every week (QW) or twice a week (Q2W) from Week 1 to Week 36.
    Arm type
    Experimental

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

    Number of subjects in period 1
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Started
    83
    84
    86
    169
    Completed
    69
    75
    76
    155
    Not completed
    14
    9
    10
    14
         Protocol deviation
    1
    1
    -
    3
         Other than specified
    5
    2
    2
    4
         Adverse event
    4
    1
    3
    -
         Lack of efficacy
    1
    -
    1
    1
         Pregnancy
    -
    -
    3
    -
         Consent withdrawn with no reason given
    1
    3
    -
    2
         Consent withdrawn with personal reason
    -
    1
    -
    3
         Lost to follow-up
    -
    1
    1
    -
         Sponsor decision
    2
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo QW
    Reporting group description
    Subcutaneous injection of Placebo (for Dupilumab) was administered weekly (QW) from Week 1 (Day 1) to Week 36.

    Reporting group title
    Dupilumab 300 mg Q8W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every eight week (Q8W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every four week (Q4W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q2W/QW
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every week (QW) or twice a week (Q2W) from Week 1 to Week 36.

    Reporting group values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW Total
    Number of subjects
    83 84 86 169 422
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.1 ± 13.64 37.3 ± 13.98 38.5 ± 16.76 38.5 ± 13.94 -
    Gender categorical
    Units: Subjects
        Female
    32 33 43 87 195
        Male
    51 51 43 82 227
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 3 1 10 16
        Not Hispanic or Latino
    75 81 85 155 396
        Unknown or Not Reported
    6 0 0 4 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0
        Asian
    17 18 16 31 82
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    7 8 4 7 26
        White
    54 56 64 124 298
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    5 2 2 7 16
    Region of Enrollment
    Units: Subjects
        North America
    38 39 38 77 192
        Japan
    12 11 12 23 58
        Europe
    33 34 36 69 172
    Eczema Area and Severity Index (EASI) score
    The EASI score was 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 range from 0 (minimum) to 72 (maximum) points,with the higher scores reflecting the worse severity of AD.
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.5 ± 2.31 2.3 ± 2.33 2.8 ± 3.31 2.6 ± 2.92 -
    Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS)
    Pruritus NRS scale is an assessment tool that is used to report the intensity of subjects'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]).
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.8 ± 2.11 2.7 ± 2.27 3.1 ± 2.16 2.8 ± 1.92 -
    Body Surface Area (BSA) Involvement with AD
    Body surface area affected by AD was assessed for each section of the body (the possible highest score for each region was: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]). It was reported as a percentage of all major body sections combined.
    Units: percentage of body surface area
        arithmetic mean (standard deviation)
    8.1 ± 8.21 7.9 ± 9.04 9.3 ± 10.51 7.9 ± 9.02 -
    SCORing Atopic Dermatitis (SCORAD) score
    SCORAD was a clinical tool for assessing the severity of AD developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index). Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel) 186 (1): 23–31. 1993. Extent and intensity of eczema as well as subjective signs (insomnia, etc.) were assessed and scored. Total score ranges from 0 (absent disease) to 103 (severe disease).
    Units: units on a scale
        arithmetic mean (standard deviation)
    16.8 ± 10.03 17.1 ± 9.41 17.5 ± 10.59 17.1 ± 10.49 -
    Patient Oriented Eczema Measure (POEM)
    The POEM was a 7-item questionnaire that assessed disease symptoms (dryness,itching, flaking, cracking, sleep loss, bleeding and weeping) with a scoring system of 0 (absent disease) to 28 (severe disease) (high score indicative of poor quality of life [QOL]).
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.1 ± 5.43 6.8 ± 5.88 6.1 ± 5.11 6.4 ± 5.3 -
    Dermatology Life Quality Index (DLQI) Score
    The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on 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 indicative of a poor QOL.
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.4 ± 4.25 3 ± 3.76 3.2 ± 3.93 3.4 ± 4.21 -
    Total Hospital Anxiety Depression Scale (HADS)
    The HADS is a fourteen item scale. Seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3 and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression.
    Units: units on a scale
        arithmetic mean (standard deviation)
    5.9 ± 6.36 7.1 ± 6.87 7.3 ± 7.53 6.4 ± 5.94 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo QW
    Reporting group description
    Subcutaneous injection of Placebo (for Dupilumab) was administered weekly (QW) from Week 1 (Day 1) to Week 36.

    Reporting group title
    Dupilumab 300 mg Q8W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every eight week (Q8W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every four week (Q4W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q2W/QW
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every week (QW) or twice a week (Q2W) from Week 1 to Week 36.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subcutaneous injection of Placebo (for Dupilumab) was administered weekly (QW) from Week 1 (Day 1) to Week 36.

    Subject analysis set title
    Dupilumab 300 mg Q8W
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every eight week (Q8W) from Week 1 to Week 36.

    Subject analysis set title
    Dupilumab 300 mg Q4W
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every four week (Q4W) from Week 1 to Week 36.

    Subject analysis set title
    Dupilumab 300 mg Q2W/QW
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every week (QW) or twice a week (Q2W) from Week 1 to Week 36.

    Primary: Difference Between Current Study Baseline and Week 36 in Percent Change in EASI From Parent Study Baseline (NCT02277743 and NCT02277769)

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    End point title
    Difference Between Current Study Baseline and Week 36 in Percent Change in EASI From Parent Study Baseline (NCT02277743 and NCT02277769)
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Difference of percent change in EASI between current study baseline and week 36 in from parent study baseline (NCT02277743 and NCT02277769) was reported. Values after first rescue treatment used were set to missing before multiple imputation (MI). Full analysis set (FAS) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline (Parent Study), Baseline (Current Study) and Week 36 (Current study)
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: percent change
        least squares mean (standard error)
    21.67 ± 3.134
    6.84 ± 2.434
    3.84 ± 2.283
    0.06 ± 1.736
    Statistical analysis title
    Dupilumab 300 mg Q8W vs Placebo QW
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the co-primary and key secondary efficacy endpoints in a pre-specified order. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Analysis was performed using ANCOVA method.
    Comparison groups
    Dupilumab 300 mg Q8W v Placebo QW
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [1]
    Method
    ANCOVA
    Parameter type
    Percent Change Difference
    Point estimate
    -14.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.34
         upper limit
    -7.33
    Notes
    [1] -  Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo QW
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the co-primary and key secondary efficacy endpoints in a pre-specified order. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Analysis was performed using ANCOVA method.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo QW
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    Percent Change Difference
    Point estimate
    -17.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.33
         upper limit
    -10.34
    Notes
    [2] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W/QW vs Placebo QW
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the co-primary and key secondary efficacy endpoints in a pre-specified order. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.05 level. Analysis was performed using ANCOVA method.
    Comparison groups
    Dupilumab 300 mg Q2W/QW v Placebo QW
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    ANCOVA
    Parameter type
    Percent Change Difference
    Point estimate
    -21.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.36
         upper limit
    -14.87
    Notes
    [3] - Threshold for significance at 0.05 level.

    Primary: Percentage of Subjects With Eczema Area and Severity Index Greater than or Equal to (>=) 75% (EASI-75) at Baseline of Current Study Maintaining EASI-75 at Week 36

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    End point title
    Percentage of Subjects With Eczema Area and Severity Index Greater than or Equal to (>=) 75% (EASI-75) at Baseline of Current Study Maintaining EASI-75 at Week 36
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-75 responders were the subjects who achieved >=75% overall improvement in EASI score at Week 36. Values after first rescue treatment used were set to missing. Subjects with missing value at week 36 were considered as a non- responder. FAS population was used. Here, number of subjects analyzed = subjects with EASI-75 at baseline.
    End point type
    Primary
    End point timeframe
    Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    79
    82
    84
    162
    Units: percentage of subjects
        number (not applicable)
    30.4
    54.9
    58.3
    71.6
    Statistical analysis title
    Dupilumab 300 mg Q8W vs Placebo QW
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q8W v Placebo QW
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    24.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.7
         upper limit
    39.29
    Notes
    [4] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo QW
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo QW
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.32
         upper limit
    42.58
    Notes
    [5] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W/QW vs on Placebo QW
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q2W/QW v Placebo QW
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    41.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.93
         upper limit
    53.52
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Maintaining Investigator Global Assessment (IGA) Response Within 1 Point of Baseline at Week 36

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    End point title
    Percentage of Subjects Maintaining Investigator Global Assessment (IGA) Response Within 1 Point of Baseline at Week 36
    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 36 were reported. Values after first rescue treatment used were set to missing. Subjects with missing value at a visit were considered as a non-responder. FAS population was used. Here, number of subjects analyzed = subjects with IGA 0 or 1 at Baseline from Interactive voice response system (IVRS).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    63
    64
    66
    126
    Units: percentage of subjects
        number (not applicable)
    28.6
    50
    62.1
    70.6
    Statistical analysis title
    Dupilumab 300 mg Q8W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q8W v Placebo QW
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.013 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    21.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.86
         upper limit
    38
    Notes
    [7] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo QW
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [8]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    33.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.38
         upper limit
    49.72
    Notes
    [8] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W/QW vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q2W/QW v Placebo QW
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    42.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.36
         upper limit
    55.76
    Notes
    [9] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Maintaining Investigator Global Assessment (IGA) Response at 0 or 1 Point at Week 36

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    End point title
    Percentage of Subjects Maintaining Investigator Global Assessment (IGA) Response at 0 or 1 Point at Week 36
    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 at week 36 were reported as responders. Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 36 were considered as non-responders. FAS population was used. Here, number of subjects analyzed = subjects with IGA 0 or 1 at Baseline from IVRS.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    63
    64
    66
    126
    Units: Percentage of Subjects
        number (not applicable)
    14.3
    32.8
    43.9
    54
    Statistical analysis title
    Dupilumab 300 mg Q8W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q8W v Placebo QW
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0209 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    18.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.14
         upper limit
    32.91
    Notes
    [10] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo QW
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    29.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.89
         upper limit
    44.42
    Notes
    [11] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W/QW vs on Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q2W/QW v Placebo QW
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    39.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.42
         upper limit
    51.95
    Notes
    [12] - Threshold for significance at 0.05 level

    Secondary: Percentage of Subjects With Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score Increased by 3 or More Points From Baseline to Week 35

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    End point title
    Percentage of Subjects With Weekly Average of Peak Daily Pruritus Numerical Rating Scale (NRS) Score Increased by 3 or More Points From Baseline to Week 35
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subjects'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]). Values after first rescue treatment were set to missing and subjects with missing peak NRS at Week 35 were considered as non-responders. FAS population was used. Here, number of subjects analyzed = subjects with NRS <= 7 at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 35
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    80
    81
    83
    168
    Units: Percentage of Subjects
        number (not applicable)
    70
    55.6
    49.4
    33.9
    Statistical analysis title
    Dupilumab 300 mg Q8W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q8W v Placebo QW
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1048 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    -14.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.21
         upper limit
    0.32
    Notes
    [13] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q4W vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q4W v Placebo QW
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0107 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    -20.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.32
         upper limit
    -5.89
    Notes
    [14] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 300 mg Q2W/QW vs on Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using Cochran-Mantel-Haenszel test stratified by region, baseline disease severity and Dupilumab regimen received in parent studies.
    Comparison groups
    Dupilumab 300 mg Q2W/QW v Placebo QW
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    -36.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -48.4
         upper limit
    -23.74
    Notes
    [15] - Threshold for significance at 0.05 level.

    Secondary: Time to First Event of Investigator's Global Assessment (IGA) >= 2 for Subjects With IGA 0 or 1 at Baseline

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    End point title
    Time to First Event of Investigator's Global Assessment (IGA) >= 2 for Subjects With IGA 0 or 1 at Baseline
    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). FAS population was used. Here, number of subjects analyzed = subjects with IGA 0 or 1 at Baseline from IVRS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    63
    64
    66
    126
    Units: days
        median (confidence interval 95%)
    57 (56 to 58)
    85 (59 to 113)
    80 (55 to 85)
    114 (85 to 169)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Increased Investigator's Global Assessment (IGA) Score 3 or 4 at Week 36

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    End point title
    Percentage of Subjects With Increased Investigator's Global Assessment (IGA) Score 3 or 4 at Week 36
    End point description
    IGA is an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response is an IGA score of 0 (clear) or 1 (almost clear). Values after first rescue treatment were set to missing and subjects with missing IGA scores at Week 36 were considered as responders (i.e. having a increase 3 or 4 of IGA value). FAS population was used. Here, number of subjects analyzed = subjects with IGA 0 or 1 at Baseline from IVRS.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    63
    64
    66
    126
    Units: Percentage of Subjects
        number (not applicable)
    66.7
    48.4
    34.8
    26.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Eczema Area and Severity Index-50 (EASI-50) (>= 50% Reduction in EASI Score) at Week 36

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    End point title
    Percentage of Subjects With Eczema Area and Severity Index-50 (EASI-50) (>= 50% Reduction in EASI Score) at Week 36
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. EASI-50 responders were the subjects who achieved >= 50% overall improvement in EASI score from baseline to Week 36. Values after first rescue treatment were set to missing and subjects with missing EASI-50 scores at Week 36 were considered as non-responders. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: Percentage of subjects
        number (not applicable)
    39.8
    54.8
    60.5
    73.4
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Eczema Area and Severity Index (EASI) at Week 36

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    End point title
    Absolute Change From Baseline in Eczema Area and Severity Index (EASI) at Week 36
    End point description
    The EASI score was used to measure the severity and extent of AD and measured erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Values after first rescue treatment were set to missing and subjects with missing Values at Week 36 were imputed by using multiple imputation method. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    6.61 ± 0.799
    1.75 ± 0.738
    1.37 ± 0.735
    0.09 ± 0.511
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 36

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    End point title
    Absolute Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 36
    End point description
    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). Values after first rescue treatment used were set to missing (censoring) before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    18.61 ± 2.107
    6.62 ± 2.010
    2.25 ± 1.899
    0.99 ± 1.350
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Peak Daily Pruritus Numerical Rating Scale (NRS) Score at Week 35

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    End point title
    Absolute Change From Baseline in Peak Daily Pruritus Numerical Rating Scale (NRS) Score at Week 35
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subjects's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subjects 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]). Values after first rescue treatment used were set to missing before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 35
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    2.5 ± 0.29
    1.1 ± 0.27
    0.6 ± 0.25
    -0.1 ± 0.20
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Percent Body Surface Area (BSA) Through Week 36

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    End point title
    Absolute Change From Baseline in Percent Body Surface Area (BSA) Through Week 36
    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. Values after first rescue treatment used were set to missing (censoring) before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: meter square
        least squares mean (standard error)
    9.16 ± 1.642
    2.74 ± 1.530
    1.74 ± 1.457
    -1.27 ± 1.044
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline Through in Patient Oriented Eczema Measure (POEM) Through Week 36

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    End point title
    Absolute Change From Baseline Through in Patient Oriented Eczema Measure (POEM) Through Week 36
    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]). Values after first rescue treatment used were set to missing (censoring) before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    7 ± 0.9
    2.8 ± 0.78
    0.8 ± 0.73
    -0.3 ± 0.56
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Dermatology Life Quality Index (DLQI) Through Week 36

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    End point title
    Absolute Change From Baseline in Dermatology Life Quality Index (DLQI) Through Week 36
    End point description
    The DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (QOL). The 10 questions assessed QOL over the past week, with an overall scoring of 0 (absent disease) to 30 (severe disease); a high score was indicative of a poor QOL. Values after first rescue treatment used were set to missing before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    3.1 ± 0.52
    1.5 ± 0.46
    0.3 ± 0.48
    -0.2 ± 0.33
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Hospital Anxiety Depression Scale (HADS) Through Week 36

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    End point title
    Absolute Change From Baseline in Hospital Anxiety Depression Scale (HADS) Through Week 36
    End point description
    HADS is a fourteen item scale. Seven of the items relate to anxiety and seven items relate to depression. Each item on the questionnaire is scored from 0 (minimum score) - 3 (maximum score) and this means that a person can score between 0 (no symptoms) and 21 (severe symptoms) for either anxiety or depression. Cut-offs for identifying psychiatric distress has been reported as 7 to 8 for possible presence, 10 to 11 for probable presence, and 14 to 15 for severe anxiety or depression. Values after first rescue treatment used were set to missing before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: units on a scale
        least squares mean (standard error)
    0.8 ± 0.6
    0.7 ± 0.52
    0.2 ± 0.54
    -0.8 ± 0.39
    No statistical analyses for this end point

    Secondary: Difference Between Current Study Baseline and Week 36 in Percent Change in SCORAD From Parent Study Baseline

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    End point title
    Difference Between Current Study Baseline and Week 36 in Percent Change in SCORAD From Parent Study Baseline
    End point description
    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). Values after first rescue treatment used were set to missing before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Parent Study), Baseline (Current Study) and Week 36 (Current study)
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: Percent change
        least squares mean (standard error)
    28.97 ± 3.683
    10.42 ± 2.988
    2.21 ± 2.743
    0.33 ± 2.092
    No statistical analyses for this end point

    Secondary: Difference Between Current Study Baseline and Week 35 in Percent Change in Peak Weekly Pruritus NRS From Parent Study Baseline

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    End point title
    Difference Between Current Study Baseline and Week 35 in Percent Change in Peak Weekly Pruritus NRS From Parent Study Baseline
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of a subject's pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). Values after first rescue treatment used were set to missing before MI. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Parent Study), Baseline (Current Study) and Week 35 (Current study)
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: percent change
        least squares mean (standard error)
    35.6 ± 4.32
    16.7 ± 4.09
    8.6 ± 4.02
    -0.1 ± 3.05
    No statistical analyses for this end point

    Secondary: Annualized Event Rate of Skin Infection Treatment­ Emergent Adverse Events (TEAEs)

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    End point title
    Annualized Event Rate of Skin Infection Treatment­ Emergent Adverse Events (TEAEs)
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment- emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on- treatment period (time from the first dose of study drug up to the end of study [Week 36]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life- threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: events per year
        median (confidence interval 95%)
    0.12 (0.044 to 0.338)
    0.07 (0.024 to 0.226)
    0.02 (0.005 to 0.12)
    0.02 (0.007 to 0.083)
    No statistical analyses for this end point

    Secondary: Annualized Event Rate of Flares

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    End point title
    Annualized Event Rate of Flares
    End point description
    Rate of Flares defined as worsening of disease requiring initiation or escalation of rescue treatment. FAS population was used.
    End point type
    Secondary
    End point timeframe
    Baseline through week 36
    End point values
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    83
    84
    86
    169
    Units: events per year
        median (confidence interval 95%)
    0.75 (0.465 to 1.214)
    0.6 (0.363 to 0.977)
    0.39 (0.231 to 0.661)
    0.24 (0.146 to 0.38)
    No statistical analyses for this end point

    Secondary: Percentage of Well-Controlled Weeks During the On-treatment Period

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    End point title
    Percentage of Well-Controlled Weeks During the On-treatment Period
    End point description
    Well-controlled weeks are those in which subjects during their weekly IVRS call completion has their eczema been well-controlled over the last week during which no rescue treatments were administered. Percentage of well-controlled weeks during the on-treatment period were reported. The safety analysis set (SAF) included all randomized subjects who received any amount of study drug. Here, number of subjects analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 36
    End point values
    Placebo Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Number of subjects analysed
    81
    82
    87
    165
    Units: percentage of weeks
        arithmetic mean (standard deviation)
    40.9 ± 30.35
    53.2 ± 32.95
    52.3 ± 35.96
    63.6 ± 32.08
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Week 36) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent adverse events that developed/worsened during the 'on-treatment period' (time form the first dose of study drug up to the end of study [Week 36]). The safety analysis set (SAF) included all randomized subjects who received any amount of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo QW
    Reporting group description
    Subcutaneous injection of Placebo (for Dupilumab) was administered weekly (QW) from Week 1 (Day 1) to Week 36.

    Reporting group title
    Dupilumab 300 mg Q8W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every eight week (Q8W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q4W
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every four week (Q4W) from Week 1 to Week 36.

    Reporting group title
    Dupilumab 300 mg Q2W/QW
    Reporting group description
    Subcutaneous injection of Dupilumab 300 mg alternatively with placebo (matched to Dupilumab) once every week (QW) or twice a week (Q2W) from Week 1 to Week 36.

    Serious adverse events
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 82 (1.22%)
    3 / 84 (3.57%)
    4 / 87 (4.60%)
    6 / 167 (3.59%)
         number of deaths (all causes)
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gun shot wound
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 84 (1.19%)
    0 / 87 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 84 (2.38%)
    0 / 87 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia induced cardiomyopathy
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    1 / 87 (1.15%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Biochemical pregnancy
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 82 (0.00%)
    0 / 84 (0.00%)
    0 / 87 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo QW Dupilumab 300 mg Q8W Dupilumab 300 mg Q4W Dupilumab 300 mg Q2W/QW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 82 (67.07%)
    43 / 84 (51.19%)
    47 / 87 (54.02%)
    72 / 167 (43.11%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 84 (3.57%)
    5 / 87 (5.75%)
    8 / 167 (4.79%)
         occurrences all number
    6
    3
    7
    12
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 84 (3.57%)
    2 / 87 (2.30%)
    10 / 167 (5.99%)
         occurrences all number
    22
    10
    8
    62
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    40 / 82 (48.78%)
    27 / 84 (32.14%)
    30 / 87 (34.48%)
    34 / 167 (20.36%)
         occurrences all number
    60
    34
    43
    43
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 84 (0.00%)
    5 / 87 (5.75%)
    3 / 167 (1.80%)
         occurrences all number
    1
    0
    6
    4
    Influenza
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 84 (0.00%)
    5 / 87 (5.75%)
    4 / 167 (2.40%)
         occurrences all number
    1
    0
    7
    4
    Nasopharyngitis
         subjects affected / exposed
    11 / 82 (13.41%)
    11 / 84 (13.10%)
    11 / 87 (12.64%)
    32 / 167 (19.16%)
         occurrences all number
    13
    14
    14
    41
    Oral herpes
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 84 (5.95%)
    2 / 87 (2.30%)
    3 / 167 (1.80%)
         occurrences all number
    4
    10
    5
    10
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 82 (7.32%)
    7 / 84 (8.33%)
    5 / 87 (5.75%)
    13 / 167 (7.78%)
         occurrences all number
    6
    7
    6
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2015
    Following changes were made: Added text to indicate that for background treatment with moisturizers (emollients), to allow adequate assessment of skin dryness, moisturizers should not be applied on the area(s) of non-lesional skin designated for such assessments for at least 8 hours before each clinic visit, • Changed the terminology of “European Medicines Agency (EMA) reference market” to “European Union (EU) reference market,” and to add Japan to the countries that will use the co-primary endpoints, • Changed “other endpoints” to “other secondary endpoints” for clarity and consistency with the terminology used in the parent studies (R668-AD-1334 and -1416), • Moved the endpoint “change in SCORing Atopic Dermatitis (SCORAD) from baseline to week 36” from key secondary endpoints section to the “other secondary endpoints” section, and revised the endpoint from “change … from baseline …” to “percent change … from baseline …” • Added per protocol set (PPS) for efficacy analysis, • Clarified the description, using language consistent with that used in the parent studies (R668-AD-1334 and -1416), of methods for missing data imputation (multiple imputation [MI] Statistical Analysis Software [SAS] procedure with Markov Monte Carlo algorithm) and data analysis.
    22 Feb 2015
    • Clarified that subjects who completed the end of treatment visit in SOLO-1 (R668 AD 1334) and SOLO-2, (R668-AD-1416) and who fulfill eligibility criteria, were enrolled in the current study, • Further clarified the definition of adequate birth control for sexually active women of reproductive potential in the “Exclusion Criteria” • Provided more specific guidance on escalation of rescue treatment, • Updated information regarding infections requiring systemic treatment under “Reasons for Temporary Discontinuation of Study Drug” to improve clarity and accuracy, as oral treatment was also a systemic route of administration, • Added an additional restriction to “Prohibited Medications and Procedures” to include all atopic dermatitis (AD) treatments, including off-label treatments, with the exception of those specifically allowed in the protocol, • Removed ACQ-5 and Sinonasal Outcome Test (SNOT)-22 questionnaires from the study visit descriptions of visit 4 and visit 7 to align with the schedule of events • Corrected study drug administration up through week 35, instead of week 36 • Changed the anti-drug antibody (ADA) variables and text throughout the protocol to distinguish between transient and persistent ADA responses, • Made changes throughout the protocol to the follow-up of subjects with positive ADA titer at their last study visit to ensure that subjects with ADA positive titer were not lost to follow-up, • Provided text to clarify the relationship between rescue medications and prohibited medications, • Increased the clarity and accuracy of the conditions for the early termination visit, • Clarified that the sample size was an estimate, based on the anticipated number of eligible subjects enrolled from the SOLO-1 (R668-AD-1334) and SOLO-2 (R668-AD-1416) clinical trials, and not based on a predefined quota.
    11 Oct 2016
    The purpose of amendment 3 was to update and revised the protocol sections addressing study endpoints and statistical considerations, and to ensure concordance with the final Statistical Analysis Plan (SAP). The primary objective of the study was to assess the ability of different Dupilumab dose regimens, administered as monotherapy, to maintain the treatment response achieved after 16 weeks of initial treatment. One of the current co-primary endpoints, IGA(0,1) had been helpful to assess initial treatment response but lacks adequate sensitivity to optimally characterize maintenance of response over time for different dosing regimens. As such, a more sensitive co-primary endpoint had been selected to better support the above study objective. The main changes were as follows: • Downgraded the Investigator’s Global Assessment (IGA)(0,1) from co-primary to a key secondary endpoint. This endpoint could not be analyzed in the entire randomized population (required subset analysis in subjects with IGA 0,1 at baseline), it did not adequately characterize Dupilumab’s clinical effect over time, and it lacked the sensitivity necessary to support the objective of the study, which was to differentiate between the treatment groups analyzed with respect to maintenance vs. loss of response • Added a co-primary endpoint based on percent change in Eczema Area and Severity Index (EASI) score, which was analyzed in the entire randomized population (full analysis set [FAS]). This endpoint provided improved sensitivity to differentiate between maintenance vs. loss of response and better support for the study objective. • Changed the statistical testing methodology of multiplicity control, ie, from parallel testing of each of the 3 dose groups vs. placebo (with a 3-way alpha split and 0.0167 significance level) to hierarchical testing at a 0.05 significance level.

    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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