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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
    		 2019-003774-41
    Trial protocol
    		 FR   HU  
    Global end of trial date
    03 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2025
    First version publication date
    19 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC16459
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04183335
    WHO universal trial number (UTN)
    		 U1111-1241-8153
    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
    03 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2022
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Dec 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
    France: 3
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    China: 15
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    151
    EEA total number of subjects
    3
    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)
    117
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 58 active sites in 8 countries. A total of 200 subjects were screened from 12 December 2019 to 11 May 2021, out of which 49 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 151 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 topical corticosteroids/topical calcineurin inhibitors (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
    76
    75
    Treated
    75
    75
    Completed
    63
    72
    Not completed
    13
    3
         Adverse event
    1
    -
         Withdrawal by subject
    12
    3

    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 topical corticosteroids/topical calcineurin inhibitors (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
    		 76 75 151
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.1 ( 15.8 ) 49.2 ( 17.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 52 100
        Male
    		 28 23 51
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 3 5
        Asian
    		 25 29 54
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 8 11
        White
    		 45 35 80
        More than one race
    		 0 0 0
        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 topical corticosteroids/topical calcineurin inhibitors (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 Improvement (Reduction) in Worst Itch Numeric Rating Scale (WI-NRS) by Greater Than or Equal to (>=) 4 From Baseline to Week 24

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    End point title
    		 Percentage of Subjects With Improvement (Reduction) in Worst Itch Numeric Rating Scale (WI-NRS) by Greater Than or Equal to (>=) 4 From Baseline to 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 improvement (reduction) in WI-NRS scores by >=4 from Baseline to Week 24 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 and were 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 24
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    76
    75
    Units: percentage of subjects
        number (not applicable)
    18.4
    60.0
    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 are reported and continued when primary endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.78
         upper limit
    		 15.41
    Notes
    [1] - Threshold of significance at 0.05.

    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 prurigo nodularis (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
    76
    75
    Units: percentage of subjects
        number (not applicable)
    18.4
    48.0
    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 are reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 8.98
    Notes
    [2] - Threshold of significance at 0.05.

    Secondary: Percentage of Subjects With Both an Improvement (Reduction) in WI-NRS by >=4 Points and an IGA PN-S Scores 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 Scores 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 scores by >=4 Points (from Baseline) and an IGA PN-S scores 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
    76
    75
    Units: percentage of subjects
        number (not applicable)
    9.2
    38.7
    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 are reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.49
         upper limit
    		 19.05
    Notes
    [3] - Threshold of significance at 0.05.

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

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    End point title
    		 Percent Change From Baseline in WI-NRS 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 evaluable 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
    66
    75
    Units: percent change
        least squares mean (standard error)
    -22.22 ( 5.74 )
    -48.89 ( 5.61 )
    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 are reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -26.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.44
         upper limit
    		 -14.9
    Notes
    [4] - Threshold of significance at 0.05.

    Secondary: Change From Baseline in Health-Related Quality of Life (HRQoL) 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) 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 subjects’ HRQoL over the previous week. Responses to each question were assessed on a scale of 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 evaluable 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
    69
    75
    Units: score on a scale
        least squares mean (standard error)
    -5.77 ( 1.05 )
    -11.97 ( 1.02 )
    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 are reported and continued when endpoint measure was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -6.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.34
         upper limit
    		 -4.05
    Notes
    [5] - Threshold of significance at 0.05.

    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 evaluable 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
    66
    75
    Units: score on a scale
        least squares mean (standard error)
    -2.16 ( 0.44 )
    -4.33 ( 0.43 )
    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 are reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.07
         upper limit
    		 -1.28
    Notes
    [6] - Threshold of significance at 0.05.

    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 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 evaluable 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
    69
    75
    Units: score on a scale
        least squares mean (standard error)
    -2.02 ( 0.94 )
    -4.62 ( 0.93 )
    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 are reported and continued when previous endpoint was statistically significant at two-sided 0.05.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0082 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.52
         upper limit
    		 -0.67
    Notes
    [7] - Threshold of significance at 0.05.

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

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    End point title
    		 Probability of Subjects With an Improvement (Reduction) in WI-NRS Scores 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 scores 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
    76
    75
    Units: probability of subjects
        number (confidence interval 95%)
    0.363 (0.253 to 0.473)
    0.667 (0.548 to 0.761)
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in WI-NRS Scores at Week 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 evaluable 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
    72
    75
    Units: score on a scale
    least squares mean (standard error)
        Week 12 (n=72,75)
    -1.84 ( 0.38 )
    -3.87 ( 0.38 )
        Week 24 (n=66,75)
    -2.28 ( 0.43 )
    -4.56 ( 0.42 )
    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 evaluable 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
    75
    75
    Units: percent change
    least squares mean (standard error)
        Week 2 (n=75,75)
    -7.98 ( 3.70 )
    -13.57 ( 3.64 )
        Week 4 (n=75,75)
    -9.09 ( 4.07 )
    -22.23 ( 4.00 )
        Week 12 (n=72,75)
    -17.05 ( 5.31 )
    -41.05 ( 5.21 )
    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 evaluable for this endpoint.
    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
    76
    75
    Units: percent change
    least squares mean (standard error)
        Week 1 (n=76,75)
    -5.77 ( 2.24 )
    -6.68 ( 2.21 )
        Week 2 (n=75,75)
    -7.98 ( 3.70 )
    -13.57 ( 3.64 )
        Week 3 (n=75,75)
    -9.27 ( 3.92 )
    -17.67 ( 3.86 )
        Week 4 (n=75,75)
    -9.09 ( 4.07 )
    -22.23 ( 4.00 )
        Week 5 (n=74,74)
    -8.49 ( 4.43 )
    -23.87 ( 4.36 )
        Week 6 (n=74,75)
    -10.56 ( 4.79 )
    -26.94 ( 4.71 )
        Week 7 (n=73,75)
    -12.22 ( 5.02 )
    -29.20 ( 4.93 )
        Week 8 (n=73,75)
    -13.78 ( 5.06 )
    -32.51 ( 4.97 )
        Week 9 (n=72,75)
    -15.34 ( 5.14 )
    -34.26 ( 5.03 )
        Week 10 (n=72,75)
    -16.32 ( 5.12 )
    -36.96 ( 5.00 )
        Week 11 (n=73,75)
    -16.71 ( 5.35 )
    -38.06 ( 5.22 )
        Week 12 (n=72,75)
    -17.05 ( 5.31 )
    -41.05 ( 5.21 )
        Week 13 (n=73,75)
    -17.66 ( 5.35 )
    -41.23 ( 5.26 )
        Week 14 (n=73,75)
    -18.64 ( 5.40 )
    -40.55 ( 5.30 )
        Week 15 (n=72,75)
    -19.69 ( 5.51 )
    -42.37 ( 5.42 )
        Week 16 (n=71,75)
    -18.10 ( 5.54 )
    -43.29 ( 5.44 )
        Week 17 (n=71,75)
    -19.06 ( 5.62 )
    -42.33 ( 5.52 )
        Week 18 (n=71,75)
    -19.93 ( 5.75 )
    -43.27 ( 5.65 )
        Week 19 (n=70,74)
    -20.99 ( 5.80 )
    -43.35 ( 5.69 )
        Week 20 (n=69,75)
    -19.90 ( 5.83 )
    -43.79 ( 5.72 )
        Week 21 (n=68,75)
    -20.51 ( 5.80 )
    -44.85 ( 5.69 )
        Week 22 (n=68,75)
    -23.30 ( 5.90 )
    -44.84 ( 5.78 )
        Week 23 (n=68,75)
    -23.08 ( 5.79 )
    -48.65 ( 5.68 )
        Week 24 (n=66,75)
    -22.22 ( 5.74 )
    -48.89 ( 5.61 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement (Reduction) in WI-NRS Scores >=4 Points From Baseline at Week 12

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    End point title
    		 Percentage of Subjects With Improvement (Reduction) in WI-NRS Scores >=4 Points From Baseline 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 improvement (reduction) in WI-NRS score by >=4 from Baseline to Week 12 is reported in this endpoint. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    76
    75
    Units: percentage of subjects
        number (not applicable)
    15.8
    44.0
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Improvement (Reduction) in WI-NRS Scores >=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 scores 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
    76
    75
    Units: percentage of subjects
        number (not applicable)
    3.9
    18.7
    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
    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
    76
    75
    Units: percentage of subjects
    number (not applicable)
        Week 1
    0
    4.0
        Week 2
    2.6
    10.7
        Week 3
    3.9
    12.0
        Week 4
    3.9
    18.7
        Week 5
    5.3
    21.3
        Week 6
    6.6
    33.3
        Week 7
    7.9
    29.3
        Week 8
    10.5
    33.3
        Week 9
    13.2
    38.7
        Week 10
    10.5
    40.0
        Week 11
    14.5
    44.0
        Week 12
    15.8
    44.0
        Week 13
    13.2
    50.7
        Week 14
    19.7
    45.3
        Week 15
    18.4
    52.0
        Week 16
    17.1
    50.7
        Week 17
    21.1
    50.7
        Week 18
    21.1
    54.7
        Week 19
    22.4
    54.7
        Week 20
    21.1
    54.7
        Week 21
    18.4
    56.0
        Week 22
    22.4
    56.0
        Week 23
    19.7
    58.7
        Week 24
    18.4
    60.0
    No statistical analyses for this end point

    Secondary: Onset of Action Based on Change From Baseline in WI-NRS Scores at Week 3

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    End point title
    		 Onset of Action Based on Change From Baseline in WI-NRS Scores at Week 3
    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. LS means and SE were obtained from ANCOVA model. Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 3
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    75
    75
    Units: score on a scale
        least squares mean (standard error)
    -1.10 ( 0.27 )
    -1.80 ( 0.26 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0119 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 -0.15
    Notes
    [8] - Threshold of significance at <0.05 level.

    Secondary: Percentage of Subjects With Investigator’s Global Assessment for PN-Stage (IGA PN-S) 0 or 1 Score at Weeks 4, 8, and 12

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    End point title
    		 Percentage of Subjects With Investigator’s Global Assessment for PN-Stage (IGA PN-S) 0 or 1 Score at Weeks 4, 8, and 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 Weeks 4, 8 and 12
    End point values
    		 Placebo Dupilumab 300 mg Q2W
    Number of subjects analysed
    76
    75
    Units: percentage of subjects
    number (not applicable)
        Week 4
    1.3
    9.3
        Week 8
    3.9
    16.0
        Week 12
    11.8
    32.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in IGA PN-S Scores of 0 and 1 at Weeks 4, 8, 12, and 24

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    End point title
    		 Change From Baseline in IGA PN-S Scores of 0 and 1 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 evaluable 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
    74
    75
    Units: score on a scale
    least squares mean (standard error)
        Week 4 (n=70,74)
    -0.15 ( 0.10 )
    -0.44 ( 0.10 )
        Week 8 (n=72,72)
    -0.29 ( 0.13 )
    -0.79 ( 0.13 )
        Week 12 (n=74,75)
    -0.52 ( 0.15 )
    -1.13 ( 0.15 )
        Week 24 (n=69,75)
    -0.62 ( 0.17 )
    -1.59 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Investigator’s Global Assessment for PN-Activity (IGA PN-A) 0 or 1 Score 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) 0 or 1 Score 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
    76
    75
    Units: percentage of subjects
    number (not applicable)
        Week 4
    3.9
    10.7
        Week 8
    3.9
    22.7
        Week 12
    14.5
    34.7
        Week 24
    19.7
    60.0
    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 scale of 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 evaluable 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
    74
    75
    Units: score on a scale
        least squares mean (standard error)
    -5.67 ( 0.90 )
    -10.95 ( 0.89 )
    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 (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 and 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
    75
    75
    Units: subjects
        TEAEs
    47
    53
        TESAEs
    8
    5
    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 intervention and had at least one non-missing ADA result after first dose of IMP. 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
    67
    68
    Units: subjects
        Treatment-emergent ADAs
    3
    8
        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
    8 / 75 (10.67%)
    5 / 75 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hodgkin's Disease
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal Ulcer Perforation
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory Bowel Disease
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteritis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Neurodermatitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (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
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Covid-19
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         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
    15 / 75 (20.00%)
    14 / 75 (18.67%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    2 / 75 (2.67%)
    5 / 75 (6.67%)
         occurrences all number
    2
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 75 (5.33%)
         occurrences all number
    6
    9
    Skin and subcutaneous tissue disorders
    Neurodermatitis
         subjects affected / exposed
    7 / 75 (9.33%)
    2 / 75 (2.67%)
         occurrences all number
    8
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 75 (4.00%)
    4 / 75 (5.33%)
         occurrences all number
    3
    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, permitted and prohibited concomitant medications and rescue medication; 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 prostaglandin D2 metabolite” into urinalysis; updated the AE and SAE recording; removed the “Acceptable methods” in contraception guidance; added the copyright information.
    21 Oct 2021
    Following changes were made: promoted “proportion of subjects with improvement (reduction) in WI-NRS by >= 4 from Baseline to Week 24 as primary endpoint and moved “proportion of subjects with improvement (reduction) in WI-NRS by >= 4 from Baseline to Week 12” to a secondary endpoint. Updated sample size calculation based on the observed effect sizes from EFC16460. Updated the primary analysis considerations to Week 24 timepoint. Updated Week 24 timepoint as the primary endpoint. Removed the sentence “A key secondary endpoint will be the responder analyses of itch improvement of at least 4 points at Week 24.” as it was now the primary endpoint, and provided rationale for choosing the primary endpoint timepoint at Week 24 with the following language: “The timing of the primary assessment, i.e., at Week 24, was based on the results of the primary analysis of EFC16460, showing that the effect of dupilumab over time showed continuous improvement after Week 12 across all endpoints, with a similar time course of improvement in both itch and lesion endpoints through at least Week 24. Since improvement of itch and lesions may occur prior to Week 24, responder analyses assessments will be performed at earlier time points as well, starting at Week 2 for itch, and Week 4 for lesions.” Specified that the rationale for a 24-week duration of the trial was an appropriate duration based on data observed from EFC16460 and removed references to atopic dermatitis trials. Reflected that the primary endpoint timepoint was Week 24. Removed the the possibility of re-evaluating the timing of the primary database lock of EFC16459 based on the observed treatment effect size in EFC16460, that was added per Amendment 02 and consequently removed the 2 populations (ITT-Week 12 and ITT-Week 24) that were added per Amendment 02. Minor editorial and formatting changes were made.

    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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