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    Clinical Trial Results:
    A Randomized Double-blind Placebo Controlled Study Evaluating the Effect of Dupilumab on Sleep in Adult Patients With Moderate to Severe Atopic Dermatitis

    Summary
    EudraCT number
    		 2018-004705-26
    Trial protocol
    		 GB   DE   FR   IT  
    Global end of trial date
    06 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2022
    First version publication date
    21 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS15497
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04033367
    WHO universal trial number (UTN)
    		 U1111-1223-4147
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin Cedex, France, 91385
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of dupilumab on sleep quality in adult subjects with moderate to severe atopic dermatitis (AD).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Australia: 38
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Arab Emirates: 10
    Country: Number of subjects enrolled
    United States: 43
    Worldwide total number of subjects
    188
    EEA total number of subjects
    75
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    174
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 46 centres in 10 countries. A total of 267 subjects were screened between 22 August 2019 and 13 April 2021, of which 188 subjects were enrolled and randomised. A total of 79 subjects failed screening mainly due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 Subjects were randomly assigned to receive either dupilumab or placebo in a 2:1 ratio via interactive voice response system.

    Period 1
    Period 1 title
    Double-blind Period (Up to Week 12)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dupilumab
    Arm description
    		 Subjects received dupilumab 600 milligrams (mg) (loading dose) injection subcutaneously (SC) on Day 1 followed by dupilumab 300 mg injection SC every 2 weeks (q2w) up to Week 10 in the double-blind (DB) period of 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received dupilumab 600 mg (loading dose) injection SC on Day 1 followed by dupilumab 300 mg injection SC q2w up to Week 10.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matching to dupilumab injection SC on day 1 then followed by placebo injection SC q2w up to Week 10 in the DB period of 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo matching to dupilumab injection SC on day 1 then followed by placebo injection SC q2w up to Week 10.

    Number of subjects in period 1
    		Dupilumab Placebo
    Started
    127
    61
    Completed
    122
    60
    Not completed
    5
    1
         Adverse event
    1
    1
         Withdrawal by Subject
    4
    -
    Period 2
    Period 2 title
    OLE Period (Week 12 to Week 24)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dupilumab/Dupilumab
    Arm description
    		 Subjects previously treated with dupilumab during the DB period, entered in the OLE period and continued to receive dupilumab 300 mg injection SC q2w from Week 12 up to Week 22 in the OLE period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received dupilumab 300 mg injection SC q2w from Week 12 to Week 22.

    Arm title
    		 Placebo/Dupilumab
    Arm description
    		 Subjects previously treated with placebo during the DB period, entered in the OLE period and received dupilumab 600 mg (loading dose) at Week 12 followed by dupilumab 300 mg injection SC q2w up to Week 22 in the OLE period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received dupilumab 600 mg (loading dose) at Week 12 and then dupilumab 300 mg injection SC q2w up to Week 22.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo matched to dupilumab q2w during the DB period.

    Number of subjects in period 2
    		Dupilumab/Dupilumab Placebo/Dupilumab
    Started
    122
    60
    Completed
    117
    59
    Not completed
    5
    1
         Withdrawal by Subject
    4
    1
         Other-Unspecified
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dupilumab
    Reporting group description
    		 Subjects received dupilumab 600 milligrams (mg) (loading dose) injection subcutaneously (SC) on Day 1 followed by dupilumab 300 mg injection SC every 2 weeks (q2w) up to Week 10 in the double-blind (DB) period of 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to dupilumab injection SC on day 1 then followed by placebo injection SC q2w up to Week 10 in the DB period of 12 weeks.

    Reporting group values
    		 Dupilumab Placebo Total
    Number of subjects
    		 127 61 188
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.2 ± 14.68 34.5 ± 15.36 -
    Gender categorical
    Units: Subjects
        Female
    		 66 31 97
        Male
    		 61 30 91
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 13 11 24
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 6 1 7
        White
    		 103 46 149
        More than one race
    		 2 0 2
        Unknown or Not Reported
    		 3 3 6

    End points

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    End points reporting groups
    Reporting group title
    Dupilumab
    Reporting group description
    		 Subjects received dupilumab 600 milligrams (mg) (loading dose) injection subcutaneously (SC) on Day 1 followed by dupilumab 300 mg injection SC every 2 weeks (q2w) up to Week 10 in the double-blind (DB) period of 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matching to dupilumab injection SC on day 1 then followed by placebo injection SC q2w up to Week 10 in the DB period of 12 weeks.
    Reporting group title
    Dupilumab/Dupilumab
    Reporting group description
    		 Subjects previously treated with dupilumab during the DB period, entered in the OLE period and continued to receive dupilumab 300 mg injection SC q2w from Week 12 up to Week 22 in the OLE period.

    Reporting group title
    Placebo/Dupilumab
    Reporting group description
    		 Subjects previously treated with placebo during the DB period, entered in the OLE period and received dupilumab 600 mg (loading dose) at Week 12 followed by dupilumab 300 mg injection SC q2w up to Week 22 in the OLE period.

    Primary: DB Period: Percent Change From Baseline in Sleep Quality Numerical Rating Scale (NRS) at Week 12

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    End point title
    		 DB Period: Percent Change From Baseline in Sleep Quality Numerical Rating Scale (NRS) at Week 12
    End point description
    Sleep quality NRS was used to assess the quality of the subject’s previous night’s sleep. It was collected on an 11-point scale ranged from 0 (worst possible sleep) to 10 (best possible sleep), where higher score indicated better outcome. Percent change from Baseline in sleep quality NRS at Week 12 was reported in this endpoint. Analysis was performed on modified intent-to-treat (mITT) analysis set which included all randomised subjects with a treatment kit number allocated and recorded in the interactive response technology database, regardless of whether the treatment kit was used or not, who had a Baseline and at least one post-baseline measurement. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    122
    60
    Units: percent change
        arithmetic mean (standard deviation)
    -47.71 ± 27.240
    -32.98 ± 29.536
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when primary endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    Placebo v Dupilumab
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -15.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.13
         upper limit
    		 -6.9
    Notes
    [1] - Threshold of significance at 0.05.

    Secondary: DB Period: Percent Change From Baseline in Peak Pruritus NRS at Week 12

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    End point title
    		 DB Period: Percent Change From Baseline in Peak Pruritus NRS at Week 12
    End point description
    Peak Pruritus NRS was an assessment tool that was used by subjects to report the intensity of their pruritus (itch) during a 24-hour recall period. Subjects were asked the following question: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the ‘worst itch imaginable’, how would you rate your itch at the worst moment during the previous 24 hours?”. Subjects answered the question at the specified time point (for the last 24 hours) on the scale of 0 (no itch) to 10 (worst itch imaginable), where higher scores indicated greater severity. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    110
    48
    Units: percent change
        arithmetic mean (standard deviation)
    -52.45 ± 30.614
    -23.29 ± 30.075
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoints was statistically significant at two-sided 0.05 level.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -27.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.96
         upper limit
    		 -17.78
    Notes
    [2] - Threshold of significance at 0.05.

    Secondary: DB Period: Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Total Score at Week 12

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    End point title
    		 DB Period: Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Total Score at Week 12
    End point description
    SCORAD a validated scoring index for AD, consists of 3 components i.e., A =extent or affected body surface area (BSA) assessed as percentage of each defined body area and reported as sum of all areas, with maximum score of 100%. B=severity of 6 specific symptoms of AD (redness, swelling, oozing/crusting, excoriation, skin thickening/lichenification, dryness) assessed using following scale: none(0), mild(1), moderate(2), or severe(3)(for maximum of 18 total points) and C=subjective assessment of itch and sleep loss on VAS where 0 = no itching or no trouble sleeping and 10 = unbearable itching or a lot of trouble sleeping with maximum score of 20 . These 3 aspects: extent (A: 0-100), severity (B: 0-18), and subjective symptoms (C: 0-20) combined using A/5 + 7*B/2+ C to give maximum possible total score of 103, where 0 = no disease and 103 = severe disease. Higher values of SCORAD = worse outcome. mITT set. 'Number of subjects analyzed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    109
    48
    Units: score on a scale
        arithmetic mean (standard deviation)
    -37.78 ± 17.743
    -20.55 ± 17.944
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -15.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.56
         upper limit
    		 -9.56
    Notes
    [3] - Threshold of significance at 0.05.

    Secondary: DB Period: Change From Baseline in SCORAD Sleep Visual Analog Scale (VAS) at Week 12

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    End point title
    		 DB Period: Change From Baseline in SCORAD Sleep Visual Analog Scale (VAS) at Week 12
    End point description
    SCORAD is a validated scoring index for AD, which combines extent (A, 0-100), severity (B, 0-18), and subjective symptoms (C, 0-20) based on itch and sleeplessness, each scored (0-10). The SCORAD for an individual was calculated by the formula: A/5 + 7B/2 + C (can range from 0 to 103). Subjective symptoms (i.e., itch and sleeplessness/sleep loss) were each scored by the subject using a VAS ranging from 0 to 10, where “0” is no itch (or no sleep loss) and “10” is the worst imaginable itch (or sleeplessness). Change from Baseline in SCORAD sleeplessness/sleep loss VAS score is reported in this endpoint. Analysis was performed on mITT set. Here, 'number of subjets analyzed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    108
    47
    Units: score on a scale
        arithmetic mean (standard deviation)
    -4.85 ± 2.953
    -2.31 ± 3.024
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -2.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 -1.18
    Notes
    [4] - Threshold of significance at 0.05.

    Secondary: DB Period: Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Related Impairment Short Form 8a (SF8a) Total T-Score at Week 12

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    End point title
    		 DB Period: Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Related Impairment Short Form 8a (SF8a) Total T-Score at Week 12
    End point description
    PROMIS is a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Level 2, sleep disturbance measure. In this study, 8- item PROMIS Sleep Related Impairment SF8a that assesses the domain of sleep related impairment in the past 7 days in individuals aged 18 and older, was used. Each item asks the subject to rate the severity of the subject’s sleep related impairment during the past 7 days (at each specified visit) on a 5-point scale (1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; and 5 = very much) with raw score ranging from 8 to 40; higher scores indicating greater severity of sleep impairment. PROMIS T-score rescales the raw score into a standardised score with a mean of 50 and a standard deviation of 10. Possible range for T-score is 30 to 80, with higher scores indicating greater severity of sleep impairment. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    103
    54
    Units: T-score
        arithmetic mean (standard deviation)
    -11.42 ± 6.710
    -7.77 ± 7.240
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.68
         upper limit
    		 -1.53
    Notes
    [5] - Threshold of significance at 0.05.

    Secondary: DB Period: Change From Baseline in Total Sleep Time (TST) at Week 12

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    End point title
    		 DB Period: Change From Baseline in Total Sleep Time (TST) at Week 12
    End point description
    A sleep diary was designed to gather information about subject’s daily sleep pattern. It measured night-time sleep assessments. TST (in minutes) was calculated using the formula: Time of waking up for the day minus time of falling sleep minus Wake After Sleep Onset (WASO), where WASO = time awake after initial sleep onset but before the final awakening for the day. Data for WASO was collected from Question 3 of the Sleep Diary: “Considering all the times you woke up last night, how much time were you awake in total?”. Baseline and Post-baseline weekly average data were calculated based on the mean of the data over the 7 days prior to and including the day at the Baseline or at the end of the corresponding week. In this endpoint, change from Baseline in TST at Week 12 is reported. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    108
    47
    Units: minutes
        arithmetic mean (standard deviation)
    9.00 ± 70.987
    -6.36 ± 55.620
    Statistical analysis title
    		 Dupilumab versus Placebo
    Statistical analysis description
    A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05 level.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.297 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    9.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.86
         upper limit
    		 28.79
    Notes
    [6] - Threshold of significance at 0.05.

    Secondary: DB Period: Change From Baseline in Weekly Average Sleep Efficiency (SE) at Week 12

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    End point title
    		 DB Period: Change From Baseline in Weekly Average Sleep Efficiency (SE) at Week 12
    End point description
    A sleep diary was designed to gather information about subject’s daily sleep pattern. It measured night-time sleep assessments. SE was calculated using the formula: (TST divided by [Time of waking up for the day − Time of trying to fall sleep]) multiplied by 100 percent (%). TST (in minutes) was calculated using the formula: Time of waking up for the day minus time of falling sleep minus Wake After Sleep Onset (WASO), where WASO = time awake after initial sleep onset but before the final awakening for the day. Baseline and Post-baseline weekly average data were calculated based on the mean of the data over the 7 days prior to and including the day at the Baseline or at the end of the corresponding week. In this endpoint, change from Baseline in SE at Week 12 is reported. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    108
    47
    Units: percentage of time in bed spent asleep
        arithmetic mean (standard deviation)
    1.81 ± 6.593
    1.53 ± 6.018
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Weekly Average Wake After Sleep Onset (WASO) at Week 12

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    End point title
    		 DB Period: Change From Baseline in Weekly Average Wake After Sleep Onset (WASO) at Week 12
    End point description
    A sleep diary was designed to gather information about subject’s daily sleep pattern. It measured night-time sleep assessments. WASO = time awake (in minutes) after initial sleep onset but before the final awakening for the day. Data for WASO was collected from Question 3 of the Sleep Diary: “Considering all the times you woke up last night, how much time were you awake in total?”. Baseline and Post-baseline weekly average data were calculated based on the mean of the data over the 7 days prior to and including the day at the Baseline or at the end of the corresponding week. In this endpoint, change from Baseline in WASO at Week 12 is reported. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    108
    47
    Units: minutes
        arithmetic mean (standard deviation)
    -6.79 ± 22.786
    -9.19 ± 24.661
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Weekly Average Sleep Onset Latency (SOL) at Week 12

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    End point title
    		 DB Period: Change From Baseline in Weekly Average Sleep Onset Latency (SOL) at Week 12
    End point description
    A sleep diary was designed to gather information about subject’s daily sleep pattern. It measured night-time sleep assessments. SOL (in minutes) was calculated using the formula: Time of falling sleep – Time of trying to fall sleep. Baseline and Post-baseline weekly average data were calculated based on the mean of the data over the 7 days prior to and including the day at the Baseline or at the end of the corresponding week. In this endpoint, change from Baseline in SOL at Week 12 is reported. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    108
    47
    Units: minutes
        arithmetic mean (standard deviation)
    -1.44 ± 19.983
    -3.37 ± 21.477
    No statistical analyses for this end point

    Secondary: DB Period: Percentage of Subjects With Eczema Area Severity Index-50 (EASI-50) (Greater Than or Equal to [>=] 50% Improvement From Baseline) at Week 12

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    End point title
    		 DB Period: Percentage of Subjects With Eczema Area Severity Index-50 (EASI-50) (Greater Than or Equal to [>=] 50% Improvement From Baseline) at Week 12
    End point description
    EASI evaluates severity of subjects with AD (excluded scalp, palms, soles) based on severity of AD clinical signs and % BSA affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin] and lower limbs [including buttocks]) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in each body region: 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), and 6 (90% to 100%). Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD. Percentage of subjects with EASI-50 (>=50% improvement from Baseline) at Week 12 is reported in this endpoint. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    109
    48
    Units: percentage of subjects
        number (not applicable)
    89.0
    58.3
    No statistical analyses for this end point

    Secondary: DB Period: Percentage of Subjects With Eczema Area Severity Index-75 (EASI-75) (>= 75% Improvement From Baseline) at Week 12

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    End point title
    		 DB Period: Percentage of Subjects With Eczema Area Severity Index-75 (EASI-75) (>= 75% Improvement From Baseline) at Week 12
    End point description
    EASI evaluates severity of subjects with AD (excluded scalp, palms, soles) based on severity of AD clinical signs and % BSA affected. Severity of clinical signs of AD (erythema, induration/papulation, excoriation and lichenification) scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin] and lower limbs [including buttocks]) on 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based upon % BSA with AD in each body region: 0, 1 (1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), and 6 (90% to 100%). Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD. Percentage of subjects with EASI-75 (>=75% improvement from Baseline) at Week 12 is reported in this endpoint. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    109
    48
    Units: percentage of subjects
        number (not applicable)
    60.6
    29.2
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Patient Oriented Eczema Measure (POEM) Total Score at Week 12

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    End point title
    		 DB Period: Change From Baseline in Patient Oriented Eczema Measure (POEM) Total Score at Week 12
    End point description
    The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults with AD. The format is subject response to 7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) based on symptom frequency during the past week (i.e., 0 = 'no days', 1 = '1 to 2 days', 2 = '3 to 4 days', 3 = '5 to 6' days, and 4 = 'every day'). The sum of the 7 items gives the total POEM score of 0 (absent disease) to 28 (severe disease). Higher scores indicated more severe disease and poor quality of life. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    90
    39
    Units: score on a scale
        arithmetic mean (standard deviation)
    -13.63 ± 7.496
    -4.44 ± 6.824
    No statistical analyses for this end point

    Secondary: DB Period: Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score at Week 12

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    End point title
    		 DB Period: Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score at Week 12
    End point description
    DLQI was a 10-item questionnaire that measures the impact of skin disease. Each question was evaluated on a 4-point scale ranged 0 to 3 where, 0 = not at all, 1= a little, 2= a lot, 3= very much, where higher scores indicated more impact on quality of life. Scores from all 10 questions were added up to give DLQI total score range from 0 (not at all) to 30 (very much). Higher scores indicated more impact on quality of life of subjects. Analysis was performed on mITT set. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    90
    39
    Units: score on a scale
        arithmetic mean (standard deviation)
    -11.82 ± 6.503
    -7.54 ± 6.801
    No statistical analyses for this end point

    Secondary: DB Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 DB Period: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) were defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (from the first investigational medicinal product [IMP] administration to the last IMP administration + 14 days) in DB period. Analysis was performed on safety analysis set (SAS) which included all randomised subjects who received at least 1 dose or partial dose of the IMP, analysed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Baseline up to up to 14 days after last IMP administration (i.e., up to Week 12)
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    127
    61
    Units: subjects
        Any TEAEs
    72
    41
        Any TESAEs
    2
    1
    No statistical analyses for this end point

    Secondary: Entire Study Duration: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Entire Study Duration: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily have to have a causal relationship with the treatment. SAEs were defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (from the first IMP administration to the last IMP administration + 14 days).
    End point type
    Secondary
    End point timeframe
    Baseline up to up to 14 days after last IMP administration (i.e., up to Week 24)
    End point values
    		 Dupilumab Placebo
    Number of subjects analysed
    127
    61
    Units: subjects
        Any TEAEs
    89
    46
        Any TESAEs
    3
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first IMP administration up to Week 12 (for DB period arms) and from first IMP administration in OLE period up to Week 24 (for OLE period arms)
    Adverse event reporting additional description
    Reported AEs were TEAEs that occurred/worsened in grade or became serious during TEAE period (defined as the time from the first IMP administration in DB period to the last IMP administration in OLE period + 14 days). Analysis was performed on SAS.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    DB period: Placebo
    Reporting group description
    		 Subjects received placebo matching to dupilumab injection SC on day 1 then followed by placebo injection SC q2w up to Week 10 in the DB period of 12 weeks.

    Reporting group title
    DB period: Dupilumab
    Reporting group description
    		 Subjects received dupilumab 600 mg (loading dose) injection SC on Day 1 followed by dupilumab 300 mg injection SC q2w up to Week 10 in the DB period of 12 weeks.

    Reporting group title
    OLE period: Placebo/Dupilumab
    Reporting group description
    		 Subjects received placebo matching to dupilumab injection SC on Day 1 then followed by placebo injection SC q2w up to Week 10 in the DB period of 12 weeks. After completion of DB period, subjects entered in the OLE period (Week 12 to 24) and received dupilumab 600 mg (loading dose) at Week 12 followed by dupilumab 300 mg SC q2w up to Week 22.

    Reporting group title
    OLE period: Dupilumab/Dupilumab
    Reporting group description
    		 Subjects received dupilumab 600 mg (loading dose) injection SC on Day 1 followed by dupilumab 300 mg injection SC q2w up to Week 10 in the DB period of 12 weeks. After completion of DB period, subjects entered in the OLE period (Week 12 to 24) and continued to receive dupilumab 300 mg SC q2w from Week 12 up to Week 22.

    Serious adverse events
    		 DB period: Placebo DB period: Dupilumab OLE period: Placebo/Dupilumab OLE period: Dupilumab/Dupilumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 127 (1.57%)
    0 / 60 (0.00%)
    1 / 122 (0.82%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 127 (0.00%)
    0 / 60 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 127 (0.00%)
    0 / 60 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Fractures
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 127 (0.00%)
    0 / 60 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 127 (0.79%)
    0 / 60 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polyarthritis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 127 (0.79%)
    0 / 60 (0.00%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DB period: Placebo DB period: Dupilumab OLE period: Placebo/Dupilumab OLE period: Dupilumab/Dupilumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 61 (29.51%)
    26 / 127 (20.47%)
    17 / 60 (28.33%)
    24 / 122 (19.67%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 127 (0.79%)
    6 / 60 (10.00%)
    15 / 122 (12.30%)
         occurrences all number
    0
    1
    6
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 61 (8.20%)
    9 / 127 (7.09%)
    3 / 60 (5.00%)
    2 / 122 (1.64%)
         occurrences all number
    5
    10
    3
    2
    Skin and subcutaneous tissue disorders
    Dermatitis Atopic
         subjects affected / exposed
    8 / 61 (13.11%)
    4 / 127 (3.15%)
    1 / 60 (1.67%)
    3 / 122 (2.46%)
         occurrences all number
    10
    6
    1
    4
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 61 (4.92%)
    12 / 127 (9.45%)
    7 / 60 (11.67%)
    3 / 122 (2.46%)
         occurrences all number
    3
    12
    7
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 61 (4.92%)
    2 / 127 (1.57%)
    4 / 60 (6.67%)
    2 / 122 (1.64%)
         occurrences all number
    3
    2
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2020
    Following changes were done: • For subjects in the polysomnography (PSG) sub-study, the sleep quality NRS and the peak pruritus NRS were to be completed for 5 days prior to Baseline. Inclusion criteria was updated accordingly. • Inclusion criterion updated to reduce the period of AD diagnosis to 2 years before the screening instead of 3 years. • Inclusion criterion was updated to allow an EASI score >= 12 instead of >= 16 at screening and Baseline to enter the study. • Exclusion criterion 14 was updated to allow subjects taking sedative anxiolytic or hypnotic treatments other than melatonin within 3 months before randomisation, to be included in the study if this intake was occasional (i.e., no more than twice a week) except within 2 weeks before randomisation. • Previous scale was replaced by the one actually used in the study in the section of Appendix 9 clinician-reported outcome-EASI.

    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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