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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study to Investigate The Efficacy and Safety of Dupilumab Administered Concomitantly With Topical Corticosteroids in Patients, ≥ 6 Years to < 12 Years of Age, With Severe Atopic Dermatitis

    Summary
    EudraCT number
    2016-004997-16
    Trial protocol
    CZ   DE   GB   PL  
    Global end of trial date
    28 Jun 2019

    Results information
    Results version number
    v3(current)
    This version publication date
    14 Aug 2020
    First version publication date
    26 Mar 2020
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1652
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03345914
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND Number: 107969
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, United States, 10591
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001501-PIP01-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of dupilumab administered concomitantly with topical corticosteroids (TCS) in subjects greater than or equal to (≥) 6 years to less than (<) 12 years of age with severe atopic dermatitis (AD).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    United States: 221
    Worldwide total number of subjects
    367
    EEA total number of subjects
    130
    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)
    367
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 474 subjects were screened for study eligibility at multiple sites in the United States and Europe. Screen failure was mostly due to inclusion/exclusion criteria not met and “other” reasons. The majority of subjects (221/367) were enrolled at study sites in the United States.

    Pre-assignment
    Screening details
    A total of 474 subjects were screened, of which 367 subjects randomized in 1:1:1 ratio to 1 of 3 treatment groups. 5 randomized subjects were not treated (2 in the placebo + TCS group and 3 in the combined dupilumab + TCS group). Subjects randomized to receive Dupilumab 100 mg or 200 mg Q2W + TCS, Dupilumab 300 mg Q4W + TCS or matching 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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + TCS
    Arm description
    Subjects received matching placebo every 2 weeks (Q2W) or every 4 weeks (Q4W) during the 16-week double-blind treatment phase. Matching placebo was administered concomitantly with topical corticosteroids (TCS), including doubling the amount of placebo on Day 1 to match the loading dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injection of the study drug on different quadrants of the abdomen avoiding navel and waist areas), upper thighs, and upper arms so that the same site was not injected for 2 consecutive administrations.

    Arm title
    Dupilumab 300 mg Q4W + TCS
    Arm description
    Subjects received subcutaneous injections of 600 milligrams (mg) loading dose on Day 1, then 300 mg of Dupilumab every 4 weeks (Q4W) from Week 4 to Week 12. Topical corticosteroids (TCS) were administered concomitantly during the 16-week double-blind treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injection of the study drug on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms so that the same site was not injected for 2 consecutive administrations.

    Arm title
    Dupilumab 100 mg or 200 mg Q2W + TCS
    Arm description
    Subjects received subcutaneous injections of 100 milligrams (mg) or 200 mg of Dupilumab every 2 weeks (Q2W). For 100 mg Q2W treatment group, subjects received a 200 mg loading dose on Day 1, then 100 mg Q2W from Week 2 to Week 14. For 200 mg Q2W treatment group, subjects received a 400 mg loading dose on Day 1, then 200 mg Q2W from Week 2 to Week 14. Topical corticosteroids (TCS) were administered concomitantly in all groups during the 16-week double-blind treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received subcutaneous injection of the study drug on different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms so that the same site was not injected for 2 consecutive administrations.

    Number of subjects in period 1
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Started
    123
    122
    122
    Completed Week 16 Study Treatment
    114
    118
    119
    Completed Week 28 End of Study
    0
    0
    0
    Completed
    0
    0
    0
    Not completed
    123
    122
    122
         Physician decision
    -
    1
    1
         Withdrawal by subject
    5
    1
    2
         Transition to another study at week 16
    80
    86
    78
         Ongoing
    -
    -
    1
         Transition to another study during follow-up
    37
    33
    39
         Not Specified
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + TCS
    Reporting group description
    Subjects received matching placebo every 2 weeks (Q2W) or every 4 weeks (Q4W) during the 16-week double-blind treatment phase. Matching placebo was administered concomitantly with topical corticosteroids (TCS), including doubling the amount of placebo on Day 1 to match the loading dose.

    Reporting group title
    Dupilumab 300 mg Q4W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 600 milligrams (mg) loading dose on Day 1, then 300 mg of Dupilumab every 4 weeks (Q4W) from Week 4 to Week 12. Topical corticosteroids (TCS) were administered concomitantly during the 16-week double-blind treatment phase.

    Reporting group title
    Dupilumab 100 mg or 200 mg Q2W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 100 milligrams (mg) or 200 mg of Dupilumab every 2 weeks (Q2W). For 100 mg Q2W treatment group, subjects received a 200 mg loading dose on Day 1, then 100 mg Q2W from Week 2 to Week 14. For 200 mg Q2W treatment group, subjects received a 400 mg loading dose on Day 1, then 200 mg Q2W from Week 2 to Week 14. Topical corticosteroids (TCS) were administered concomitantly in all groups during the 16-week double-blind treatment phase.

    Reporting group values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS Total
    Number of subjects
    123 122 122 367
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.3 ± 1.76 8.5 ± 1.74 8.5 ± 1.68 -
    Gender categorical
    Units: Subjects
        Female
    62 65 57 184
        Male
    61 57 65 183
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    110 106 106 322
        Hispanic or Latino
    13 16 16 45
    Race
    Units: Subjects
        White
    77 89 88 254
        Black or African American
    23 19 20 62
        Asian
    13 5 10 28
        Other
    9 8 2 19
        Not Reported/Missing
    1 1 2 4
    Eczema Area and Severity Index (EASI) Score
    The EASI assesses severity and extent of atopic dermatitis. Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) are assessed for severity on a scale of “0” (absent) through “3” (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs and lower limbs and converted to a score of 0 to 6. Higher score indicates increased extent and severity of atopic dermatitis.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    39.0 ± 12.01 37.4 ± 12.45 37.3 ± 10.86 -
    Investigator’s Global Assessment (IGA) Score
    IGA is an assessment instrument used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 (clear) to 4 (severe).
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    4.0 ± 0.00 4.0 ± 0.09 4.0 ± 0.00 -
    Weekly Average of Daily Worst Itch Score
    The worst itch scale is a simple assessment tool that subjects will use to report the intensity of their pruritus (itch). This is an 11-point scale (0 to 10) in which 0 indicates no itching while 10 indicates worst itching possible. Subjects will be asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score will be calculated as the worse of the scores for the 2 questions.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    7.7 ± 1.54 7.8 ± 1.58 7.8 ± 1.52 -
    Body Surface Area (BSA) of Atopic Dermatitis
    BSA affected by AD will be assessed for each section of the body using the rule of nines (the possible highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and will be reported as a percentage of all major body sections combined. The proportion assigned to different body regions is different in younger children as compared to older children (head and neck area is assigned a higher proportion in younger children as compared to older children).
    Units: Percentage of BSA
        arithmetic mean (standard deviation)
    60.2 ± 21.46 54.8 ± 21.58 57.8 ± 20.04 -
    SCORing Atopic Dermatitis (SCORAD) Score
    SCORAD is used to assess the extent and severity of AD. Extent and severity of eczema as well as subjective symptoms (insomnia, etc) were assessed and scored. SCORAD total score range is from 0 (absent disease) to 103 (severe disease).
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    72.9 ± 12.01 75.6 ± 11.71 72.3 ± 10.83 -
    Patient Oriented Eczema Measure (POEM)
    POEM is a 7-item, validated questionnaire used to assess disease symptoms in children and adults. The format is a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency of these disease symptoms during the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) with a scoring system of 0 to 28; the total score reflects disease-related morbidity. A high score is indicative of a poor quality of life.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    20.7 ± 5.48 21.3 ± 5.51 20.5 ± 5.50 -
    Children's Dermatology Life Quality Index (CDLQI) Total Score
    CDLQI is a validated 10 question tool to measure the impact of skin disease on the quality of life (QOL) in children by assessing how much the skin problem has affected the subject over the past week. Nine questions are scored as follows: Very much = 3, Quite a lot = 2, Only a little = 1, Not at all or unanswered = 0. Question 7 has an added possible response, which is scored as 3. CDLQI equals the sum of the score of each question (maximum = 30, minimum = 0). Higher the score, the greater the impact on QOL. Data presented reflects the mean and standard deviation of the CDLQI total score.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    14.6 ± 7.41 16.2 ± 7.85 14.5 ± 6.78 -
    Dermatitis Family Index (DFI)
    DFI is a 10-item questionnaire with items inquiring about housework, food preparation, sleep, family leisure activity, shopping, expenditure, tiredness, emotional distress, relationships and the impact of helping with treatment on the primary caregiver’s life. The DFI questions are scored on a four-point Likert scale ranging from 0 to 3, so that the total DFI score ranges from 0 to 30. Timeframe of reference is the past week. A higher DFI score indicates greater impairment in family QOL as affected by atopic dermatitis.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    15.0 ± 7.54 16.9 ± 8.65 14.9 ± 7.05 -
    Patient Reported Outcomes Measurements Information Systems (PROMIS) Anxiety Scale
    PROMIS Anxiety instrument measures self-reported fear (fearfulness, panic), anxious misery (worry, dread), hyperarousal (tension, nervousness, restlessness), & somatic symptoms related to arousal (racing heart, dizziness). Each question has 5 response options ranging in value from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5=Almost Always). For an 8-item form, lowest possible total raw score is 8; highest possible total raw score is 40. For a 6-item form, lowest possible total raw score is 6; highest possible total raw score is 30. Higher score indicates greater severity of symptoms.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    57.3 ± 11.62 59.8 ± 13.66 58.6 ± 11.32 -
    Patient Reported Outcomes Measurements Information Systems (PROMIS) Depression Scale
    PROMIS Depression instrument assesses self-reported negative mood (sadness, guilt), views of self (self-criticism, worthlessness) & social cognition (loneliness, interpersonal alienation), & decreased positive affect & engagement (loss of interest, meaning & purpose). Each question has 5 response options ranging in value from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5= Almost Always). For 8-item form, lowest possible total raw score is 8 and highest is 40. For 6-item form, lowest possible total raw score is 6 and highest is 30. Higher score indicates greater severity of symptoms.
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    55.0 ± 12.05 58.1 ± 12.77 56.3 ± 11.22 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo + TCS
    Reporting group description
    Subjects received matching placebo every 2 weeks (Q2W) or every 4 weeks (Q4W) during the 16-week double-blind treatment phase. Matching placebo was administered concomitantly with topical corticosteroids (TCS), including doubling the amount of placebo on Day 1 to match the loading dose.

    Reporting group title
    Dupilumab 300 mg Q4W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 600 milligrams (mg) loading dose on Day 1, then 300 mg of Dupilumab every 4 weeks (Q4W) from Week 4 to Week 12. Topical corticosteroids (TCS) were administered concomitantly during the 16-week double-blind treatment phase.

    Reporting group title
    Dupilumab 100 mg or 200 mg Q2W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 100 milligrams (mg) or 200 mg of Dupilumab every 2 weeks (Q2W). For 100 mg Q2W treatment group, subjects received a 200 mg loading dose on Day 1, then 100 mg Q2W from Week 2 to Week 14. For 200 mg Q2W treatment group, subjects received a 400 mg loading dose on Day 1, then 200 mg Q2W from Week 2 to Week 14. Topical corticosteroids (TCS) were administered concomitantly in all groups during the 16-week double-blind treatment phase.

    Primary: Percentage of Subjects with Investigator’s Global Assessment (IGA) 0 or 1 at Week 16

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    End point title
    Percentage of Subjects with Investigator’s Global Assessment (IGA) 0 or 1 at Week 16
    End point description
    The IGA was an assessment instrument used in clinical studies to rate the severity of AD globally, based on a 5-point scale ranging from 0 (clear) to 4 (severe). The full analysis set (FAS) included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at Week 16 were considered as a non-responder.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    11.4
    32.8
    29.5
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    18.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.28
         upper limit
    27.97
    Notes
    [1] - The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight group (< 30 kilograms (kg) or ≥ 30 kg) and region (North America or Europe) was used for the analysis of percentage of subjects with IGA 0 or 1 at Week 16.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    21.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.36
         upper limit
    31.45
    Notes
    [2] - The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight group (< 30 kg or ≥ 30 kg) and region (North America or Europe) was used for the analysis of percentage of subjects with IGA 0 or 1 at Week 16.

    Primary: Percentage of Subjects with Eczema Area and Severity Index -75 (EASI-75) (≥ 75 percent (%) Improvement From Baseline) at Week 16

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    End point title
    Percentage of Subjects with Eczema Area and Severity Index -75 (EASI-75) (≥ 75 percent (%) Improvement From Baseline) at Week 16
    End point description
    The EASI assesses severity and extent of atopic dermatitis (AD). Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of “0” (absent) through “3” (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder.
    End point type
    Primary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    26.8
    69.7
    67.2
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    40.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.95
         upper limit
    51.82
    Notes
    [3] - The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight group (< 30 kg or ≥ 30 kg) and region (North America or Europe) was used for the analysis of percentage of subjects with EASI-75 at Week 16.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    42.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    31.54
         upper limit
    54.15
    Notes
    [4] - The Cochran-Mantel-Haenszel (CMH) test adjusted by randomization strata (baseline weight group (< 30 kg or ≥ 30 kg) and region (North America or Europe) was used for the analysis of percentage of subjects with EASI-75 at Week 16.

    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 assesses severity and extent of AD. Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of “0” (absent) through “3” (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percent change
        least squares mean (standard error)
    -48.6 ± 2.46
    -82.1 ± 2.37
    -78.4 ± 2.35
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -29.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.33
         upper limit
    -23.24
    Notes
    [5] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -33.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.06
         upper limit
    -26.82
    Notes
    [6] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Percent Change from Baseline in Weekly Average of Daily Worst Itch Score at Week 16

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    End point title
    Percent Change from Baseline in Weekly Average of Daily Worst Itch Score at Week 16
    End point description
    The worst itch scale was a simple assessment tool that subjects used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percent change
        least squares mean (standard error)
    -25.9 ± 2.90
    -54.6 ± 2.89
    -57.0 ± 2.77
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.76
         upper limit
    -23.26
    Notes
    [7] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [8]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -28.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.47
         upper limit
    -20.82
    Notes
    [8] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Percentage of Subjects with Improvement (Reduction from Baseline) of Weekly Average of Daily Worst Itch Score ≥3 Points at Week 16

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    End point title
    Percentage of Subjects with Improvement (Reduction from Baseline) of Weekly Average of Daily Worst Itch Score ≥3 Points at Week 16
    End point description
    The worst itch scale was a simple assessment tool that subjects used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder. Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    121
    120
    Units: Percentage of Subjects
        number (not applicable)
    21.1
    60.3
    67.5
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [9]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    46.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.3
         upper limit
    57.42
    Notes
    [9] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    39.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.88
         upper limit
    50.51
    Notes
    [10] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

    Secondary: Percentage of Subjects with Improvement (Reduction from Baseline) of Weekly Average of Daily Worst Itch Score ≥4 Points at Week 16

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    End point title
    Percentage of Subjects with Improvement (Reduction from Baseline) of Weekly Average of Daily Worst Itch Score ≥4 Points at Week 16
    End point description
    The worst itch scale was a simple assessment tool that subjects used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder. Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    122
    120
    120
    Units: Percentage of Subjects
        number (not applicable)
    12.3
    50.8
    58.3
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    35.47
         upper limit
    56.61
    Notes
    [11] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    38.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    27.86
         upper limit
    49.21
    Notes
    [12] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

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

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    End point title
    Percentage of Subjects Achieving Eczema Area and Severity Index - 50 (EASI-50) (≥ 50% Improvement from Baseline) at Week 16
    End point description
    The EASI assessed severity and extent of AD. Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of “0” (absent) through “3” (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    43.1
    91.0
    82.8
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    39.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    28.68
         upper limit
    50.72
    Notes
    [13] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Dupilumab 300 mg Q4W + TCS v Placebo + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    47.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    37.77
         upper limit
    58.01
    Notes
    [14] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

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

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    End point title
    Percentage of Subjects Achieving Eczema Area and Severity Index - 90 (EASI - 90) (≥ 90% Improvement from Baseline) at Week 16
    End point description
    The EASI assessed the severity and extent of atopic dermatitis (AD). Scores range from 0-72. Four AD disease characteristics (erythema, thickness, scratching, and lichenification) were assessed for severity on a scale of “0” (absent) through “3” (severe). Area of involvement assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and converted to a score of 0 to 6. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Values after first rescue treatment used were set to missing. Subjects with missing score at week 16 were considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    7.3
    41.8
    30.3
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.65
         upper limit
    32.38
    Notes
    [15] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [16]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference
    Point estimate
    34.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    24.6
         upper limit
    44.37
    Notes
    [16] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

    Secondary: Time to Achieve ≥ 4 Point Reduction of Weekly Average of Daily Worst Itch Score from Baseline during the 16-week Treatment Period

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    End point title
    Time to Achieve ≥ 4 Point Reduction of Weekly Average of Daily Worst Itch Score from Baseline during the 16-week Treatment Period
    End point description
    The worst itch scale: a simple assessment tool that subjects used to report intensity of their pruritus (itch). This was an 11-point scale (0 to 10) where 0 (no itching) and 10 (worst itching) possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as worse of scores for 2 questions. FAS was used. Time to event is calculated in weeks as (date of first event - date of first dose)/7. The event of NRS reduction ≥ 4 was based on observed data without setting data to be non-responder after rescue treatment use. Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint and "99999" represents "Not computable" as only 12.3% of subjects achieved NRS reduction during 16-week treatment period & hence median time to achieve ≥ 4-point reduction of NRS for placebo +TCS treated subjects could not be reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    122
    120
    120
    Units: Weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    10.0 (7 to 13)
    10.0 (8 to 12)
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [17]
    Method
    Cox model
    Parameter type
    Hazard ratios
    Point estimate
    3.114
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.097
         upper limit
    4.624
    Notes
    [17] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [18]
    Method
    Cox model
    Parameter type
    Hazard ratios
    Point estimate
    2.921
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.957
         upper limit
    4.36
    Notes
    [18] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

    Secondary: Time to Achieve ≥ 3 Point Reduction of Weekly Average of Daily Worst Itch Score from Baseline during the 16-week Treatment Period

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    End point title
    Time to Achieve ≥ 3 Point Reduction of Weekly Average of Daily Worst Itch Score from Baseline during the 16-week Treatment Period
    End point description
    The worst itch scale: a simple assessment tool that subjects used to report intensity of their pruritus (itch). This was an 11-point scale (0 to 10) where 0 (no itching) and 10 (worst itching) possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as worse of scores for 2 questions. FAS was used. Time to event is calculated in weeks as (date of first event - date of first dose)/7. The event of NRS reduction ≥ 3 was based on observed data without setting data to be non-responder after rescue treatment use. Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint and "99999" represents "Not computable" as only 21.1% of subjects achieved NRS reduction during 16-week treatment period & hence median time to achieve ≥ 3-point reduction of NRS for placebo +TCS treated subjects could not be reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    121
    120
    Units: Weeks
        median (confidence interval 95%)
    99999 (11 to 99999)
    6.0 (5 to 9)
    5.0 (5 to 7)
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [19]
    Method
    Cox model
    Parameter type
    Hazard ratios
    Point estimate
    2.278
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.631
         upper limit
    3.182
    Notes
    [19] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [20]
    Method
    Cox model
    Parameter type
    Hazard ratios
    Point estimate
    2.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.481
         upper limit
    2.908
    Notes
    [20] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

    Secondary: Change from Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16

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    End point title
    Change from Baseline in Percent Body Surface Area (BSA) Affected by Atopic Dermatitis (AD) at Week 16
    End point description
    BSA affected by AD was assessed for each section of the body using the rule of nines (the possible highest score for each region is: head and neck [9%], anterior trunk [18%], back [18%], upper limbs [18%], lower limbs [36%], and genitals [1%]) and were reported as a percentage of all major body sections combined. The proportion assigned to different body regions were different in younger children as compared to older children (head and neck area is assigned a higher proportion in younger children as compared to older children). The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of BSA
        least squares mean (standard error)
    -21.65 ± 1.721
    -40.53 ± 1.648
    -39.37 ± 1.629
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Dupilumab 100 mg or 200 mg Q2W + TCS v Placebo + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -17.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.272
         upper limit
    -13.161
    Notes
    [21] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -18.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.479
         upper limit
    -14.289
    Notes
    [22] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

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

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    End point title
    Percent Change from Baseline in SCORing Atopic Dermatitis (SCORAD) at Week 16
    End point description
    SCORAD was used to assess the extent and severity of AD. Extent and severity of eczema as well as subjective symptoms (insomnia, etc) were assessed and scored. SCORAD total score ranges from 0 (absent disease) to 103 (severe disease). The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percent change
        least squares mean (standard error)
    -29.8 ± 2.26
    -62.4 ± 2.13
    -60.2 ± 2.11
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [23]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -30.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -36.3
         upper limit
    -24.48
    Notes
    [23] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [24]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -32.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.57
         upper limit
    -26.59
    Notes
    [24] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

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

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    End point title
    Change from Baseline in Children’s Dermatology Life Quality Index (CDLQI) at Week 16
    End point description
    CDLQI was a validated 10 question tool to measure the impact of skin disease on the quality of life (QOL) in children by assessing how much the skin problem has affected the subject over the past week. Nine questions were scored as follows: Very much = 3, Quite a lot = 2, Only a little = 1, Not at all or unanswered = 0. Question 7 has an added possible response, which was scored as 3. CDLQI equals the sum of the score of each question (maximum = 30, minimum = 0). Higher the score, the greater the impact on QOL. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Data presented reflects the mean & standard deviation of the CDLQI total scores.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -6.4 ± 0.51
    -10.6 ± 0.47
    -10.7 ± 0.46
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [25]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.62
         upper limit
    -2.99
    Notes
    [25] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [26]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.57
         upper limit
    -2.89
    Notes
    [26] - The confidence interval (CI) with p-value was based on treatment difference (dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

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

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    End point title
    Change from Baseline in Patient Oriented Eczema Measure (POEM) at Week 16
    End point description
    POEM was a 7-item, validated questionnaire used to assess disease symptoms in children and adults. The format was a response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on frequency of these disease symptoms during the past week (ie, 0 = no days, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = all days) with a scoring system of 0 to 28; the total score reflected the disease-related morbidity. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). A high score is indicative of a poor quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -5.3 ± 0.69
    -13.6 ± 0.65
    -13.4 ± 0.65
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [27]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -8.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.96
         upper limit
    -6.31
    Notes
    [27] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [28]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -8.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.13
         upper limit
    -6.43
    Notes
    [28] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Change from Baseline in Weekly Average of Daily Worst Itch Score at Week 16

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    End point title
    Change from Baseline in Weekly Average of Daily Worst Itch Score at Week 16
    End point description
    The worst itch scale was a simple assessment tool that subjects used to report the intensity of their pruritus (itch). This was an 11-point scale (0 to 10) in which 0 indicated no itching while 10 indicated worst itching possible. Subjects were asked to answer 2 questions daily throughout the entire study (screening period, treatment period, and follow-up period). The daily worst itch score was calculated as the worse of the scores for the 2 questions. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -2.05 ± 0.215
    -4.22 ± 0.207
    -4.45 ± 0.206
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [29]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -2.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.984
         upper limit
    -1.831
    Notes
    [29] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [30]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -2.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.754
         upper limit
    -1.599
    Notes
    [30] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Change from Baseline in Dermatitis Family Index (DFI) at Week 16

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    End point title
    Change from Baseline in Dermatitis Family Index (DFI) at Week 16
    End point description
    DFI was a 10-item questionnaire with items inquiring about housework, food preparation, sleep, family leisure activity, shopping, expenditure, tiredness, emotional distress, relationships and the impact of helping with treatment on the primary caregiver’s life. The DFI questions were scored on a four-point Likert scale ranging from 0 to 3, so that the total DFI score ranges from 0 to 30. Timeframe of reference was the past week. A higher DFI score indicated greater impairment in family Quality of life (QOL) as affected by atopic dermatitis. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) , Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -6.77 ± 0.497
    -10.75 ± 0.476
    -10.89 ± 0.469
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [31]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -4.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.434
         upper limit
    -2.796
    Notes
    [31] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [32]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -3.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.298
         upper limit
    -2.657
    Notes
    [32] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Change from Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Anxiety Short Form Scale Total Score at Week 16

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    End point title
    Change from Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Anxiety Short Form Scale Total Score at Week 16
    End point description
    PROMIS Anxiety instrument measures self-reported fear (fearfulness/panic), anxious misery (worry/dread), hyperarousal (tension/nervousness/restlessness), & somatic symptoms related to arousal (racing heart/dizziness). Each question has 5 response options with values from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5=Almost Always). Total raw score calculated using sum of response values: for 8-item form, lowest possible is 8 & highest possible is 40; For 6-item form: lowest possible is 6; highest possible is 30. Higher score indicates greater severity of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -10.17 ± 0.912
    -13.19 ± 0.861
    -13.54 ± 0.860
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0061 [33]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -3.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.779
         upper limit
    -0.962
    Notes
    [33] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0133 [34]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -3.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.414
         upper limit
    -0.629
    Notes
    [34] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Change from Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Depressive Symptoms Short Form Scale Score at Week 16

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    End point title
    Change from Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pediatric Depressive Symptoms Short Form Scale Score at Week 16
    End point description
    PROMIS Depression instrument assesses self-reported negative mood (sadness/guilt), views of self (self-criticism/worthlessness) & social cognition (loneliness/interpersonal alienation), & decreased positive affect & engagement (loss of interest/meaning/purpose). Each question has 5 response options with values from 1-5 (1=Never, 2=Almost never, 3=Sometimes, 4=Often, 5=Almost Always). Total raw score is the sum of response values. For 8-item form, lowest possible is 8, highest is 40; for 6-item form, lowest possible is 6, highest is 30. Higher score indicates greater severity of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Score on a Scale
        least squares mean (standard error)
    -7.42 ± 0.848
    -12.84 ± 0.793
    -11.92 ± 0.790
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [35]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.734
         upper limit
    -2.272
    Notes
    [35] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [36]
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -5.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.641
         upper limit
    -3.207
    Notes
    [36] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANCOVA model with baseline measurement as covariate and the treatment, randomization strata as fixed factors.

    Secondary: Percentage of Subjects Having at Least One Skin Infection Treatment Emergent Adverse Event (TEAE) (Excluding Herpetic Infections) through Week 16

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    End point title
    Percentage of Subjects Having at Least One Skin Infection Treatment Emergent Adverse Event (TEAE) (Excluding Herpetic Infections) through Week 16
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as adverse events (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. 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-subjects 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. Percentage of subjects having at least one skin infection TEAE (Excluding Herpetic Infections) through Week 16 were reported. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline through Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    13.0
    5.7
    8.2
    Statistical analysis title
    Dupilumab 100 mg/200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.222 [37]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Differenece
    Point estimate
    -4.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.49
         upper limit
    2.87
    Notes
    [37] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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.
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0508 [38]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage Differenece
    Point estimate
    -7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.51
         upper limit
    -0.03
    Notes
    [38] - P-values were derived by Cochran-Mantel-Haenszel (CMH) test stratified by region [North America vs Europe] and baseline weight group [< 30 kg vs ≥ 30 kg].

    Secondary: Percentage of Subjects Having at Least One Serious Treatment Emergent Adverse Event (TEAE) through Week 16

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    End point title
    Percentage of Subjects Having at Least One Serious Treatment Emergent Adverse Event (TEAE) through Week 16
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as adverse events (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. 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-subjects 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. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) through Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    122
    Units: Percentage of Subjects
        number (not applicable)
    1.6
    1.6
    0
    No statistical analyses for this end point

    Secondary: Proportion of Topical Corticosteroid (TCS) Medication-free Days from Baseline to Week 16

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    End point title
    Proportion of Topical Corticosteroid (TCS) Medication-free Days from Baseline to Week 16
    End point description
    Proportion of TCS medication-free days is calculated as the number of days that a patient used neither TCS/TCI nor system rescue therapy divided by the study days of each period. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    123
    122
    121
    Units: Proportion of Days
        arithmetic mean (standard deviation)
    0.11 ± 0.185
    0.20 ± 0.230
    0.19 ± 0.207
    No statistical analyses for this end point

    Secondary: Mean Weekly Dose of Topical Corticosteroid (TCS) in Grams for Low or Medium Potency TCS from Baseline to Week 16

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    End point title
    Mean Weekly Dose of Topical Corticosteroid (TCS) in Grams for Low or Medium Potency TCS from Baseline to Week 16
    End point description
    Mean weekly dose of TCS in grams for low or medium potency TCS from baseline to Week 16 were reported. The FAS included all randomized subjects. Efficacy analyses were based on the treatment allocated at randomization (as randomized). Here "Number of subjects analyzed" = number of subjects who were evaluated for this specific endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 16
    End point values
    Placebo + TCS Dupilumab 300 mg Q4W + TCS Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects analysed
    120
    120
    120
    Units: Grams
        least squares mean (standard error)
    20.1 ± 1.37
    15.0 ± 1.36
    14.4 ± 1.38
    Statistical analysis title
    Dupilumab100 mg/ 200 mg Q2W + TCS vs Placebo + TCS
    Statistical analysis description
    A 2-sided hierarchical testing procedure was used for the primary and secondary 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
    Comparison groups
    Placebo + TCS v Dupilumab 100 mg or 200 mg Q2W + TCS
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [39]
    Method
    ANOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.49
         upper limit
    -1.96
    Notes
    [39] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANOVA model with the treatment, randomization strata as fixed factors.
    Statistical analysis title
    Dupilumab 300 mg Q4W + TCS vs Placebo + TCS
    Comparison groups
    Placebo + TCS v Dupilumab 300 mg Q4W + TCS
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    P-value
    = 0.0082 [41]
    Method
    ANOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.8
         upper limit
    -1.31
    Notes
    [40] - A 2-sided hierarchical testing procedure was used for the primary and secondary 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
    [41] - The confidence interval (CI) with p-value was based on treatment difference (Dupilumab group vs placebo) of the LS mean percent change using ANOVA model with the treatment, randomization strata as fixed factors.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reported AEs are treatment-emergent adverse events which were collected for both the 16-week treatment period and the follow-up period for as long as 12 weeks.
    Adverse event reporting additional description
    The safety analysis set (SAF) includes all randomized subjects who received at least one injection of study drug and were analyzed as treated. Treatment compliance/administration and all clinical safety variables were summarized based on the SAF.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo + TCS
    Reporting group description
    Subjects received matching placebo every 2 weeks (Q2W) or every 4 weeks (Q4W) during the 16-week double-blind treatment phase. Matching placebo was administered concomitantly with topical corticosteroids (TCS), including doubling the amount of placebo on Day 1 to match the loading dose.

    Reporting group title
    Dupilumab 100 mg or 200 mg Q2W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 100 milligrams (mg) or 200 mg of Dupilumab every 2 weeks (Q2W). For 100 mg Q2W treatment group, subjects received a 200 mg loading dose on Day 1, then 100 mg Q2W from Week 2 to Week 14. For 200 mg Q2W treatment group, subjects received a 400 mg loading dose on Day 1, then 200 mg Q2W from Week 2 to Week 14. Topical corticosteroids (TCS) were administered concomitantly in all groups during the 16-week double-blind treatment phase.

    Reporting group title
    Dupilumab 300 mg Q4W + TCS
    Reporting group description
    Subjects received subcutaneous injections of 600 milligrams (mg) loading dose on Day 1, then 300 mg of Dupilumab every 4 weeks (Q4W) from Week 4 to Week 12. Topical corticosteroids (TCS) were administered concomitantly during the 16-week double-blind treatment phase.

    Serious adverse events
    Placebo + TCS Dupilumab 100 mg or 200 mg Q2W + TCS Dupilumab 300 mg Q4W + TCS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 122 (0.00%)
    3 / 120 (2.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 122 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 122 (0.00%)
    0 / 120 (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
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 122 (0.00%)
    1 / 120 (0.83%)
         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
    1 / 120 (0.83%)
    0 / 122 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 120 (0.00%)
    0 / 122 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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 + TCS Dupilumab 100 mg or 200 mg Q2W + TCS Dupilumab 300 mg Q4W + TCS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 120 (47.50%)
    50 / 122 (40.98%)
    47 / 120 (39.17%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    11 / 120 (9.17%)
    4 / 122 (3.28%)
    2 / 120 (1.67%)
         occurrences all number
    12
    4
    2
    Cough
         subjects affected / exposed
    9 / 120 (7.50%)
    5 / 122 (4.10%)
    3 / 120 (2.50%)
         occurrences all number
    13
    5
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 120 (8.33%)
    7 / 122 (5.74%)
    6 / 120 (5.00%)
         occurrences all number
    11
    10
    7
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    2 / 120 (1.67%)
    7 / 122 (5.74%)
    5 / 120 (4.17%)
         occurrences all number
    3
    9
    5
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    8 / 120 (6.67%)
    6 / 122 (4.92%)
    6 / 120 (5.00%)
         occurrences all number
    9
    8
    7
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    17 / 120 (14.17%)
    10 / 122 (8.20%)
    8 / 120 (6.67%)
         occurrences all number
    25
    10
    12
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 120 (2.50%)
    7 / 122 (5.74%)
    5 / 120 (4.17%)
         occurrences all number
    3
    8
    5
    Nasopharyngitis
         subjects affected / exposed
    8 / 120 (6.67%)
    8 / 122 (6.56%)
    15 / 120 (12.50%)
         occurrences all number
    11
    10
    16
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 120 (10.00%)
    12 / 122 (9.84%)
    14 / 120 (11.67%)
         occurrences all number
    12
    16
    19
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 122 (0.82%)
    2 / 120 (1.67%)
         occurrences all number
    6
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2017
    • Children who are engaging in heavy exercise can have transient increases in CPK that are not clinically relevant • Added an Ophthalmological Examination section for subjects who have history of certain eye disorders (conjunctivitis, blepharitis or keratitis) within the last 12 months and subjects who experience adverse events of special interest related to eye disorders • Modified the reporting schedule for subjects assessment of pruritus. Subjects will answer both questions in the evening
    20 Nov 2018
    • Included introduction of the modified full analysis set (mFAS), which excludes potentially unblinded subjects, and will be used for sensitivity analysis • Extended the duration of the visit window between Visit 1 and Visit 2 from 21 days to 63 days (ie, changed start of Visit 1 from -35 days to -77 days) and removed the limit of rescreen once to allow for the seamless screening/enrolment of all new subjects into the study • Added rationale for the inclusion of a placebo treatment group in the study design and a description of the risks and benefits to subjects assigned to the placebo treatment group • Corrected the description of age limit of the study population from “aged ≥ 6 to < 12 years at the time of baseline” to “aged ≥ 6 to < 12 years at the time of screening” to be consistent with the wording in the Inclusion Criteria and other sections of the protocol. • Revised language for accelerated reporting of pregnancy to sponsor and the duration subjects who are female of childbearing potential and sexually active are required to use highly effective methods of contraception after the last dose of study drug, to align with the current dupilumab label • Revised text to emphasize that the use of very-highpotency topical corticosteroids (TCS) is prohibited during the study, as their use is not recommended in subjects under 12 years of age. Also included examples of very-high-potency TCS • Included “injection observation” for the every 4 week regimen in the Schedule of Events table, to identify the visits at which the observation occurs • Revised the adverse events of special interest definition for conjunctivitis, keratitis, and blepharitis • Specified the list of potential major protocol violation types for the PPS, per request from the United States Food and Drug Administration

    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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