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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-controlled, Multi-center, Parallel Group Study to Evaluate the Efficacy and Safety of Dupilumab in Patients with Prurigo Nodularis who are Inadequately Controlled on Topical Prescription Therapies or When those Therapies are not Advisable

    Summary
    EudraCT number
    		 2019-003801-90
    Trial protocol
    		 FR   GB   PT   HU   ES   IT  
    Global end of trial date
    22 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC16460
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04202679
    WHO universal trial number (UTN)
    		 U1111-1241-8174
    Other trial identifiers
    		 STUDY NAME: LIBERTY-PN PRIME2
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 Avenue Pierre Brossolette, Chilly Mazarin, 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
    20 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of dupilumab on itch response in subjects with prurigo nodularis (PN), inadequately controlled on topical prescription therapies or when those therapies were not advisable.
    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
    		 Subjects continued the background therapy dose regimen as maintained in the parent study or as modified based on Investigator's judgment throughout the study i.e. stable regimen of low to medium potency topical corticosteroids/topical calcineurin inhibitors (TCS/TCI).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jan 2020
    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
    France: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    160
    EEA total number of subjects
    74
    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)
    132
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 57 sites in 11 countries. A total of 221 subjects were screened from 16 January 2020 to 24 February 2021, out of which 61 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 160 subjects were randomised in 1:1 ratio to receive study interventions (placebo or dupilumab) by interactive response technology (IRT).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to dupilumab 600 milligrams (mg) (loading dose), subcutaneously (SC) on Day 1 followed by placebo matched to dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of TCS/TCI at stable dose.
    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
    Placebo matched to dupilumab 300 mg q2w for 24 weeks on top of moisturisers and if applicable low to medium potent TCS/TCI at stable dose.

    Arm title
    		 Dupilumab 300 mg Q2W
    Arm description
    		 Subjects received dupilumab at a loading dose of 600 mg, SC on Day 1 followed by dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.
    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
    Dupilumab 600 mg loading dose SC injection on Day 1 of Week 0 and 300 mg q2w up to Week 24 on top of moisturisers and if applicable low to medium potent TCS/TCI at stable dose.

    Number of subjects in period 1
    		Placebo Dupilumab 300 mg Q2W
    Started
    82
    78
    Treated
    82
    77
    Completed
    56
    72
    Not completed
    26
    6
         Consent withdrawn by subject
    23
    6
         Adverse event, non-fatal
    2
    -
         Poor compliance to protocol
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to dupilumab 600 milligrams (mg) (loading dose), subcutaneously (SC) on Day 1 followed by placebo matched to dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Subjects received dupilumab at a loading dose of 600 mg, SC on Day 1 followed by dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Reporting group values
    		 Placebo Dupilumab 300 mg Q2W Total
    Number of subjects
    		 82 78 160
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.7 ( 15.2 ) 51.0 ( 15.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 51 52 103
        Male
    		 31 26 57
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 27 25 52
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 5 3 8
        White
    		 48 48 96
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to dupilumab 600 milligrams (mg) (loading dose), subcutaneously (SC) on Day 1 followed by placebo matched to dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Subjects received dupilumab at a loading dose of 600 mg, SC on Day 1 followed by dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Primary: Percentage of Subjects With Greater Than or Equal to (>=) 4 Points Improvement (Reduction) From Baseline in Worst-Itch Numeric Rating Scale (WI-NRS) Scores at Week 12

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    End point title
    		 Percentage of Subjects With Greater Than or Equal to (>=) 4 Points Improvement (Reduction) From Baseline in Worst-Itch Numeric Rating Scale (WI-NRS) Scores at Week 12
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of subjects with >=4 points improvement (reduction) from baseline in WI-NRS scores at Week 12 is reported in this endpoint. Analysis was performed on intent-to-treat (ITT) population which included all subjects with a treatment kit number allocated and recorded in the IRT database analysed according to the treatment group allocated by randomisation regardless of if treatment kit was used or not.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    22.0
    37.2
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when primary endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0216 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 5
    Notes
    [1] - Threshold of significance at 0.05 level.

    Secondary: Percentage of Subjects With >=4 Points Improvement (Reduction) From Baseline in WI-NRS Scores at Week 24

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    End point title
    		 Percentage of Subjects With >=4 Points Improvement (Reduction) From Baseline in WI-NRS Scores at Week 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of subjects with >=4 points improvement (reduction) from baseline in WI-NRS scores at Week 24 is reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    19.5
    57.7
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.56
         upper limit
    		 22.66
    Notes
    [2] - Threshold of significance at 0.05 level.

    Secondary: Percentage of Subjects With Investigator's Global Assessment For Prurigo Nodularis-Stage (IGA PN-S) Scores of 0 or 1 at Week 24

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    End point title
    		 Percentage of Subjects With Investigator's Global Assessment For Prurigo Nodularis-Stage (IGA PN-S) Scores of 0 or 1 at Week 24
    End point description
    IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4 where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. In this endpoint, percentage of subjects with IGA PN-S score of either 0 (clear) or 1 (almost clear) has been reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    15.9
    44.9
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 9.55
    Notes
    [3] - Threshold of significance at 0.05 level.

    Secondary: Percentage of Subjects With Both an Improvement (Reduction) in WI-NRS by >=4 Points and an IGA PN-S Score of 0 or 1 From Baseline at Week 24

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    End point title
    		 Percentage of Subjects With Both an Improvement (Reduction) in WI-NRS by >=4 Points and an IGA PN-S Score of 0 or 1 From Baseline at Week 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch), higher scores indicated more severity. IGA PN-S assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4 where 0 = clear, 1 = almost clear, 2 =mild, 3 = moderate and 4 = severe. Higher scores indicated greater severity. Percentage of subjects with both an improvement (reduction) in WI-NRS by >=4 Points (from Baseline) and an IGA PN-S score of 0 or 1 were reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    8.5
    32.1
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.03
         upper limit
    		 18.11
    Notes
    [4] - Threshold of significance at 0.05 level.

    Secondary: Percentage of Subjects With IGA PN-S Scores of 0 or 1 at Week 12

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    End point title
    		 Percentage of Subjects With IGA PN-S Scores of 0 or 1 at Week 12
    End point description
    IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4 where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. In this endpoint, percentage of subjects with IGA PN-S score of either 0 (clear) or 1 (almost clear) has been reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    At Week 12
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    12.2
    25.6
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0194 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 7.52
    Notes
    [5] - Threshold of significance at 0.05 level.

    Secondary: Percent Change From Baseline in WI-NRS Scores at Week 24

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    End point title
    		 Percent Change From Baseline in WI-NRS Scores at Week 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Least squares (LS) means and standard error (SE) were obtained from Analysis of covariance (ANCOVA) model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    74
    76
    Units: percent change
        least squares mean (standard error)
    -36.18 ( 6.21 )
    -59.34 ( 6.39 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -23.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.81
         upper limit
    		 -12.51
    Notes
    [6] - Threshold of significance at 0.05 level.

    Secondary: Change From Baseline in Health-related Quality of Life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) at Week 24

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    End point title
    		 Change From Baseline in Health-related Quality of Life (HRQoL) as Measured by Dermatology Life Quality Index (DLQI) at Week 24
    End point description
    DLQI is developed to measure dermatology specific HRQoL in adult subjects. It comprises of set of 10 questions assessing the impact of skin disease on subject’ HRQoL over the previous week. Responses to each question were assessed on a 4-point Likert scale ranged from 0 (not at all) to 3 (very much). Scores from all 10 questions added up to give total DLQI scores ranged from 0 (not at all) to 30 (very much), higher scores indicated more impact on quality of life. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    75
    77
    Units: score on a scale
        least squares mean (standard error)
    -6.77 ( 1.18 )
    -13.16 ( 1.21 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -6.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.42
         upper limit
    		 -4.36
    Notes
    [7] - Threshold of significance at 0.05 level.

    Secondary: Change From Baseline in Skin Pain-NRS at Week 24

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    End point title
    		 Change From Baseline in Skin Pain-NRS at Week 24
    End point description
    Skin Pain-NRS was used to measure skin pain intensity. Subjects were asked daily to rate the intensity of their worst skin pain over the past 24 hours, using a 11-point scale ranging from 0 (“No pain”) to 10 (“Worst possible pain”). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    74
    76
    Units: score on a scale
        least squares mean (standard error)
    -2.74 ( 0.51 )
    -4.35 ( 0.53 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.49
         upper limit
    		 -0.73
    Notes
    [8] - Threshold of significance at 0.05 level.

    Secondary: Change From Baseline in Sleep-NRS at Week 24

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    End point title
    		 Change From Baseline in Sleep-NRS at Week 24
    End point description
    Sleep-NRS was used to measure sleep intensity. Subjects were asked to rate their sleep quality on their past night upon awakening, using a 11-point NRS ranging from 0 to 10, where 0 = worst possible sleep and 10 = best possible sleep. Higher scores indicated less severity. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    74
    76
    Units: score on a scale
        least squares mean (standard error)
    0.76 ( 0.45 )
    1.30 ( 0.46 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W 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 were reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1658 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 1.3
    Notes
    [9] - Threshold of significance at 0.05 level.

    Secondary: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 24

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    End point title
    		 Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 24
    End point description
    HADS is a 14-item self-administered questionnaire that consists of 2 scales, one measuring anxiety (HADS-A), and the other measuring depression (HADS-D). Each subscale comprised of 7 items with a scoring range from 0 (less severity of anxiety and depression) to 21 (greater severity of anxiety and depression symptoms) for each subscale. The total HADS score ranges from 0 (less severity) to 42 (more severity), with a high score indicative of a severe anxiety and/or depression level. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    76
    77
    Units: score on a scale
        least squares mean (standard error)
    -2.59 ( 1.03 )
    -5.55 ( 1.06 )
    No statistical analyses for this end point

    Secondary: Probability of Subjects With an Improvement (Reduction) in WI-NRS by >=4 From Baseline at Week 24

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    End point title
    		 Probability of Subjects With an Improvement (Reduction) in WI-NRS by >=4 From Baseline at Week 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Probability of subjects with an improvement (reduction) in WI-NRS at Week 24 was based on Kaplan-Meier estimates and was reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: probability of subjects
        number (confidence interval 95%)
    0.353 (0.250 to 0.457)
    0.670 (0.552 to 0.764)
    No statistical analyses for this end point

    Secondary: Change From Baseline in WI-NRS Scores at Weeks 12 and 24

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    End point title
    		 Change From Baseline in WI-NRS Scores at Weeks 12 and 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint and ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    79
    77
    Units: score on a scale
    least squares mean (standard error)
        Week 12 (n=79,77)
    -3.04 ( 0.46 )
    -4.11 ( 0.47 )
        Week 24 (n=74,76)
    -3.10 ( 0.53 )
    -5.05 ( 0.54 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in WI-NRS Scores at Weeks 2, 4 and 12

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    End point title
    		 Percent Change From Baseline in WI-NRS Scores at Weeks 2, 4 and 12
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint and ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4 and 12
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    81
    77
    Units: percent change
    least squares mean (standard error)
        Week 2 (n=81,77)
    -15.61 ( 3.06 )
    -17.41 ( 3.15 )
        Week 4 (n=81,77)
    -22.61 ( 4.00 )
    -30.09 ( 4.12 )
        Week 12 (n=79,77)
    -35.83 ( 5.42 )
    -48.86 ( 5.59 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24

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    End point title
    		 Percent Change From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percent change
    least squares mean (standard error)
        Week 1 (n=82,78)
    -9.49 ( 2.12 )
    -8.66 ( 2.18 )
        Week 2 (n=81,77)
    -15.61 ( 3.06 )
    -17.41 ( 3.15 )
        Week 3 (n=81,77)
    -20.44 ( 3.66 )
    -25.26 ( 3.77 )
        Week 4 (n=81,77)
    -22.61 ( 4.00 )
    -30.09 ( 4.12 )
        Week 5 (n=81,77)
    -25.21 ( 4.21 )
    -34.41 ( 4.33 )
        Week 6 (n=80,77)
    -27.87 ( 4.33 )
    -36.98 ( 4.46 )
        Week 7 (n=78,76)
    -28.99 ( 4.69 )
    -39.30 ( 4.84 )
        Week 8 (n=79,77)
    -30.45 ( 4.56 )
    -41.32 ( 4.70 )
        Week 9 (n=79,77)
    -34.86 ( 4.89 )
    -47.08 ( 5.04 )
        Week 10 (n=78,76)
    -32.90 ( 5.04 )
    -44.65 ( 5.20 )
        Week 11 (n=79,77)
    -34.64 ( 5.25 )
    -45.98 ( 5.41 )
        Week 12 (n=79,77)
    -35.83 ( 5.42 )
    -48.86 ( 5.59 )
        Week 13 (n=79,77)
    -34.49 ( 5.69 )
    -48.32 ( 5.86 )
        Week 14 (n=79,77)
    -36.60 ( 5.71 )
    -50.67 ( 5.88 )
        Week 15 (n=79,77)
    -35.96 ( 5.74 )
    -51.89 ( 5.91 )
        Week 16 (n=77,77)
    -37.80 ( 5.74 )
    -54.36 ( 5.91 )
        Week 17 (n=77,77)
    -39.15 ( 5.98 )
    -55.95 ( 6.15 )
        Week 18 (n=77,77)
    -40.38 ( 6.15 )
    -56.80 ( 6.32 )
        Week 19 (n=76,77)
    -40.03 ( 6.05 )
    -57.75 ( 6.23 )
        Week 20 (n=74,77)
    -36.12 ( 5.94 )
    -56.80 ( 6.10 )
        Week 21 (n=74,76)
    -36.43 ( 6.16 )
    -56.91 ( 6.34 )
        Week 22 (n=74,76)
    -37.34 ( 6.19 )
    -58.78 ( 6.33 )
        Week 23 (n=73,75)
    -36.87 ( 6.19 )
    -59.43 ( 6.32 )
        Week 24 (n=74,76)
    -36.18 ( 6.21 )
    -59.34 ( 6.39 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement (Reduction) in WI-NRS >=4 Points From Baseline at Week 4

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    End point title
    		 Percentage of Subjects With Improvement (Reduction) in WI-NRS >=4 Points From Baseline at Week 4
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of subjects with improvement (Reduction) in WI-NRS scale by >=4 Points at Week 4 is reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
        number (not applicable)
    7.3
    16.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving >=4 Points Improvement (Reduction) From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24

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    End point title
    		 Percentage of Subjects Achieving >=4 Points Improvement (Reduction) From Baseline in WI-NRS Scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24
    End point description
    WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated more severity. Percentage of subjects achieving >=4 points improvement (reduction) from Baseline in WI-NRS scores at Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 is reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
    number (not applicable)
        Week 1
    1.2
    1.3
        Week 2
    1.2
    5.1
        Week 3
    6.1
    12.8
        Week 4
    7.3
    16.7
        Week 5
    4.9
    17.9
        Week 6
    13.4
    23.1
        Week 7
    15.9
    24.4
        Week 8
    14.6
    28.2
        Week 9
    24.4
    32.1
        Week 10
    18.3
    32.1
        Week 11
    17.1
    33.3
        Week 12
    22.0
    37.2
        Week 13
    19.5
    39.7
        Week 14
    22.0
    39.7
        Week 15
    20.7
    44.9
        Week 16
    19.5
    44.9
        Week 17
    23.2
    47.4
        Week 18
    24.4
    48.7
        Week 19
    23.2
    51.3
        Week 20
    20.7
    51.3
        Week 21
    20.7
    48.7
        Week 22
    22.0
    50.0
        Week 23
    20.7
    55.1
        Week 24
    19.5
    57.7
    No statistical analyses for this end point

    Secondary: Onset of Action Based on Change From Baseline in WI-NRS at Week 4

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    End point title
    		 Onset of Action Based on Change From Baseline in WI-NRS at Week 4
    End point description
    Onset of action was defined as the first p<0.05 difference from placebo in the weekly average WI-NRS that remained significant at subsequent measurements. WI-NRS is a validated measure of itch severity. Subjects were asked daily to rate the intensity of their worst pruritus (itch) over the past 24 hours, using a 11-point scale ranging from 0 (no itch) to 10 (worst imaginable itch). Higher scores indicated greater severity. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    81
    77
    Units: score on a scale
        least squares mean (standard error)
    -1.94 ( 0.33 )
    -2.55 ( 0.34 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Comparison groups
    Placebo v Dupilumab 300 mg Q2W
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 -0.04
    Notes
    [10] - Threshold of significance was <0.05.

    Secondary: Percentage of Subjects With Investigator's Global Assessment for PN-Stage (IGA PN-S) Score of 0 or 1 at Weeks 4 and 8

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    End point title
    		 Percentage of Subjects With Investigator's Global Assessment for PN-Stage (IGA PN-S) Score of 0 or 1 at Weeks 4 and 8
    End point description
    IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. In this endpoint, percentage of subjects with IGA PN-S score of either 0 (clear) or 1 (almost clear) has been reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    At Weeks 4 and 8
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
    number (not applicable)
        Week 4
    6.1
    7.7
        Week 8
    9.8
    15.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in IGA PN-S Scores at Weeks 4, 8, 12, and 24

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    End point title
    		 Change From Baseline in IGA PN-S Scores at Weeks 4, 8, 12, and 24
    End point description
    IGA PN-S is an instrument used to assess the overall number and thickness of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. Higher scores indicate severe PN. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint and ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, and 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    80
    77
    Units: score on a scale
    least squares mean (standard error)
        Week 4 (n=80,77)
    -0.54 ( 0.13 )
    -0.69 ( 0.13 )
        Week 8 (n=76,76)
    -0.79 ( 0.17 )
    -1.19 ( 0.17 )
        Week 12 (n=78,77)
    -0.86 ( 0.18 )
    -1.47 ( 0.18 )
        Week 24 (n=74,77)
    -1.07 ( 0.20 )
    -2.03 ( 0.20 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Investigator's Global Assessment for PN-Activity (IGA PN-A) Score of 0 or 1 at Weeks 4, 8, 12 and 24

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    End point title
    		 Percentage of Subjects With Investigator's Global Assessment for PN-Activity (IGA PN-A) Score of 0 or 1 at Weeks 4, 8, 12 and 24
    End point description
    The IGA PN-A is an instrument used to assess the overall activity of PN lesions at a given time point, as determined by the investigator. It consists of a 5-point scale ranging from 0 to 4: where 0 = clear (0% nodules showing excoriations/crusts), 1 = almost clear (up to 10% nodules showing excoriations/crusts), 2 = mild (11-25% nodules showing excoriations/crusts), 3 = moderate (26-75% nodules showing excoriations/crusts) and 4 = severe (76-100% of nodules showing excoriations/crusts). Higher scores indicate severe PN. In this endpoint, percentage of subjects with IGA PN-A score of either 0 (clear) or 1 (almost clear) has been reported. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    At Weeks 4, 8, 12 and 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    78
    Units: percentage of subjects
    number (not applicable)
        Week 4
    4.9
    14.1
        Week 8
    15.9
    23.1
        Week 12
    19.5
    42.3
        Week 24
    18.3
    51.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQoL, as Measured by DLQI at Week 12

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    End point title
    		 Change From Baseline in HRQoL, as Measured by DLQI at Week 12
    End point description
    DLQI is developed to measure dermatology specific HRQoL in adult subjects. It comprises of set of 10 questions assessing the impact of skin disease on subjects’ HRQoL over the previous week. Responses to each question were assessed on a 4-point Likert scale which ranged from 0 (not at all) to 3 (very much). Scores from all 10 questions added up to give total DLQI scores ranged from 0 (not at all) to 30 (very much), higher scores indicated more impact on quality of life. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. 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
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    78
    77
    Units: score on a scale
        least squares mean (standard error)
    -7.05 ( 1.12 )
    -12.07 ( 1.16 )
    No statistical analyses for this end point

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

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    End point title
    		 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) was 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 treatment-emergent (TE) period (time from the first investigational medicinal product [IMP] administration to the last IMP administration + 14 weeks). Analysis was performed on safety population which included all subjects who received at least 1 dose of study intervention analysed according to the intervention actually received.
    End point type
    Secondary
    End point timeframe
    From the first IMP administration to the last IMP administration + 14 weeks (i.e., up to 36 weeks)
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    82
    77
    Units: subjects
        TEAEs
    47
    47
        TESAEs
    4
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent and Treatment Boosted Antidrug Antibodies (ADA)

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    End point title
    		 Number of Subjects With Treatment-emergent and Treatment Boosted Antidrug Antibodies (ADA)
    End point description
    ADA response was categorised as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs were defined as a subject with no positive assay response at baseline but with a positive assay response during the entire TEAE period. Treatment boosted ADAs: defined as subjects with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the TE period (time from the first IMP administration to the last IMP administration + 14 weeks). Titer values were defined as low titer (< 1,000); moderate (1,000 <= titer <=10,000) and high titer (> 10,000). Analysis was performed on ADA population which included all subjects who received at least one dose of the study drug and had at least one non missing ADA result after first dose of study drug. Subjects were analysed according to the intervention actually received.
    End point type
    Secondary
    End point timeframe
    From the first IMP administration to the last IMP administration + 14 weeks (i.e., up to 36 weeks)
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    80
    76
    Units: subjects
        Treatment-emergent ADAs
    1
    7
        Treatment-boosted ADAs
    0
    0
    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 to the last IMP administration + 14 weeks (i.e., up to 36 weeks)
    Adverse event reporting additional description
    Reported AEs were TEAEs that developed/worsened in grade or became serious during TE period (defined as the time from the first IMP administration to the last IMP administration + 14 weeks). Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to dupilumab 600 mg (loading dose), SC on Day 1 followed by placebo matched to dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Subjects received dupilumab at a loading dose of 600 mg, SC on Day 1 followed by dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.

    Serious adverse events
    		 Placebo Dupilumab 300 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 82 (4.88%)
    2 / 77 (2.60%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cutaneous T-Cell Lymphoma
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Granular Lymphocytosis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda Equina Syndrome
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pelvic Inflammatory Disease
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Dupilumab 300 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 82 (12.20%)
    11 / 77 (14.29%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 77 (5.19%)
         occurrences all number
    5
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 77 (5.19%)
         occurrences all number
    9
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2020
    Following changes were made: added “proportion of subjects with Investigator’s Global Assessment 0 or 1 score for PN-Stage (IGA PN-S) at Week 24” as another key secondary endpoint; corrected rescue medication use start date to Day 1 (Visit 2); removed the endpoint “Change from baseline in PAS total score at Week 4, Week 8, Week 12, and Week 24” in exploratory endpoint and modified exploratory endpoint regarding the healed lesions from PAS questionnaire analysis; broke out secondary endpoints with multiple measuring timepoints into individual endpoints; updated inclusion and exclusion criteria; clarified the use of non-investigational medicinal products and rescue medication; clarified permitted and prohibited concomitant medications; added that a pre-specified algorithm would be used to classify rescue and a blinded review of all post-baseline medications, based on medical judgment, would be performed to adjudicate rescue; clarified the treatment discontinuation criteria regarding the missing doses; updated assessments and procedures to describe alternative temporary mechanism that could be implemented in the study conduct in case of pandemic requiring public health emergency e.g., Coronavirus Disease-19 (COVID-19); updated the adverse event of special interest (AESI) “any type of conjunctivitis or blepharitis (severe or serious)” to “any severe type of conjunctivitis or blepharitis”; added the sensitivity analysis for secondary endpoints information, and separated key secondary endpoints in a different row; added covariate “baseline antidepressant use (yes or no)” to primary and secondary endpoint analyses; updated section other analyses; updated the unblinding plan to “Unblinding plan is not applicable for this study”; removed the description about false positivity; added “tetranor PGDM” into urinalysis; updated the AE and SAE recording; removed the “Acceptable methods” in contraception guidance; added the copyright information.

    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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