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    Clinical Trial Results:
    A randomized, placebo-controlled phase IIa clinical trial to evaluate the efficacy and safety of subcutaneous Dupilumab in localized scleroderma

    Summary
    EudraCT number
    		 2019-002036-90
    Trial protocol
    		 DE  
    Global end of trial date
    30 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2026
    First version publication date
    04 Apr 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-3815
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04200755
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Sponsor representative, University Hospital Cologne Department of Dermatology, +49 02214783196, sabine.eming@uni-koeln.de
    Scientific contact
    Sponsor representative, University Hospital Cologne Department of Dermatology, +49 02214783196, sabine.eming@uni-koeln.de
    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
    30 Apr 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate, in comparison with placebo, the efficacy of Dupilumab in patients with Morphea (plaque type) or Generalized localized scleroderma (affecting at least three anatomic sites).
    Protection of trial subjects
    This trial was conducted according to the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirement(s) including the German Drug Law and applicable European Directives. This trial was approved by the national regulatory authority and ethics committee. With the help of the Informed Consent Form (ICF) the subjects were informed about the investigational medicinal products and anticipated effects and the reason, design and implication of the trial. All subjects gave their consent to participate prior to any trial specific investigations. Neither the investigators, nor the trial staff, have coerced or unduly influenced a subject to participate or to continue to participate in the trial. Permission for direct access to patient’s data was sought in writing by the investigator and from the subject as part of the informed consent procedure. It was ensured by the investigators that documents that are given to the sponsor or their representatives do not contain the name or address of the subjects, or other information that would affect the anonymity of the subject (apart from the subject’s trial ID). If a clinically meaningful worsening of the disease occured, rescue medication was offered to the patient.
    Background therapy
    		 Forbidden therapy: Use of any systemic or topical immunosuppressive therapy, concurrent phototherapy
    Evidence for comparator
    		 A placebo was used as comparator in this trial.
    Actual start date of recruitment
    19 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    38
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Screening/recruitment was active from January 15th, 2020 to March 15, 2023. Subjects were screened at 4 sites in Germany: University Hospital Cologne, Helios St. Elisabeth Klinik Oberhausen, Universitäts-Hautklinik Tübingen, Charité - Universitätsmedizin Berlin.

    Pre-assignment
    Screening details
    		 Screened patients: 50 Subjects had to meet a set of criteria in order to enroll in the study; including being 18 years of age or older and being diagnosed with Morphea (plaque type) or Generalized localized scleroderma (affecting at least three anatomic sites).

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Permuted blocks of varying length with allocation ratio (verum:placebo = 2:1); double-blind, i.e. patients and investigators are masked

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum
    Arm description
    		 Subjects which received Dupilumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    EU/1/17/1229/005
    Other name
    Dupixent® 300mg
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IMP is injected subcutaneously (s.c.) in healthy skin (thigh, abdomen or upper arm). Injection site should not be affected by scleroderma. Test IMP and reference IMP: s.c. injection; 2 ready-to-use syringes initial (V1), 1 ready-to-use syringe every 14 days (V2-V13). 1 ready-to-use syringe contains 300mg Dupilumab in 2ml aqueous solution

    Arm title
    		 Placebo
    Arm description
    		 Subjects which received Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    placebo s.c. injection; 2 ready-to-use syringes initial (V1), 1 ready-to-use syringe every 14 days (V2-V13) placebo s.c. injection in healthy skin, 24 weeks

    Number of subjects in period 1
    		Verum Placebo
    Started
    30
    15
    Completed
    30
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Subjects which received Dupilumab

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects which received Placebo

    Reporting group values
    		 Verum Placebo Total
    Number of subjects
    		 30 15 45
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 24 14 38
        From 65-84 years
    		 6 1 7
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.6 ( 14.4 ) 48.0 ( 15.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 26 15 41
        Male
    		 4 0 4
    Study centre
    Units: Subjects
        Berlin
    		 4 2 6
        Koeln
    		 11 5 16
        Oberhausen
    		 9 4 13
        Tuebingen
    		 6 4 10
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.6 ( 5.3 ) 27.6 ( 7.5 ) -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary analysis set is derived from the intention-to-treat (ITT) population. This Full-analysis-set (FAS) includes all randomized subjects who received IMP at least once.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The secondary analysis set is derived from the per-protocol (PP) population. This dataset is a subset of the FAS subjects except for those who are excluded because of major efficacy related protocol violations. Subjects will be excluded if a subject received less than 11 out of 14 IMP injections or more than 16 IMP injections. Furthermore, subjects will be excluded for major violations of efficacy-related entry criteria, such as a misdiagnosis of the underlying medical indication. Subjects who did not receive treatment as assigned will not be excluded, as no risk of bias is expected due to the double-blind design. If time-schedules for IMP injection could not be met, this is also not considered a major protocol violation.

    Subject analysis sets values
    		 ITT PP
    Number of subjects
    45
    39
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    38
    33
        From 65-84 years
    7
    6
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.1 ( 14.8 )
    50.9 ( 14.5 )
    Gender categorical
    Units: Subjects
        Female
    41
    36
        Male
    4
    3
    Study centre
    Units: Subjects
        Berlin
    6
    6
        Koeln
    16
    13
        Oberhausen
    13
    12
        Tuebingen
    10
    8
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.3 ( 6.1 )
    26.1 ( 6.3 )

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Subjects which received Dupilumab

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects which received Placebo

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary analysis set is derived from the intention-to-treat (ITT) population. This Full-analysis-set (FAS) includes all randomized subjects who received IMP at least once.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The secondary analysis set is derived from the per-protocol (PP) population. This dataset is a subset of the FAS subjects except for those who are excluded because of major efficacy related protocol violations. Subjects will be excluded if a subject received less than 11 out of 14 IMP injections or more than 16 IMP injections. Furthermore, subjects will be excluded for major violations of efficacy-related entry criteria, such as a misdiagnosis of the underlying medical indication. Subjects who did not receive treatment as assigned will not be excluded, as no risk of bias is expected due to the double-blind design. If time-schedules for IMP injection could not be met, this is also not considered a major protocol violation.

    Primary: Treatment response

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    End point title
    		 Treatment response
    End point description
    At baseline visit (V1) a single existing lesion with the highest mLoSSI activity index will be defined as target lesion. Treatment response is determined by change in mLoSSI (size of lesion, erythema, skin thickening) or LoSDI (dermal athrophy, subcutaneous atrophy, dyspigmentation) of the target lesion; score reduction by 50% after 24 weeks (EoT V14) compared to baseline. Subjects who received rescue medication (e.g. topical steroids, systemic immunosuppressive therapy) or withdrawed from the trial were counted as non-responder.
    End point type
    Primary
    End point timeframe
    24 weeks (EoT V14) compared to baseline
    End point values
    		 Verum Placebo ITT PP
    Number of subjects analysed
    30
    15
    45
    39
    Units: Subjects with Response
    17
    6
    23
    22
    Attachments
    		 Untitled (Filename: Table1.docx)
    Statistical analysis title
    		 Treatment Response at EoT
    Statistical analysis description
    In the ITT analysis of the primary endpoint (proportion of treatment responders) the proportion of treatment responders in the verum group was 56.7% (17/30) and in the placebo group 40.0% (6/15). Tested against the test value of 30% there is a significant difference for the verum group with p=0.003. The between group difference in response rates is not statistically significant (p=0.292).
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.292 [1]
    Method
    		 Wald test with Newcombe CI
    Parameter type
    		 Difference in proportions
    Point estimate
    0.167
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.132
         upper limit
    		 0.424
    Variability estimate
    Standard error of the mean
    Notes
    [1] - PP analysis: The proportion of treatment responders in the verum group was 68.0% (17/25) and in the placebo group 35.7% (5/14). Tested against the test value of 30%, there is a significant increased response proportion for dupilumab group (p<0.001).

    Secondary: Count of all lesions

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    End point title
    		 Count of all lesions
    End point description
    Count of all existing non-target and new lesions on the entire integument during treatment, at EoT and during follow-up
    End point type
    Secondary
    End point timeframe
    At Baseline, EoT and last Follow-Up
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [2]
    15 [3]
    Units: Lesions
    arithmetic mean (standard deviation)
        Baseline
    12.9 ( 9.2 )
    11.3 ( 5.7 )
        EoT
    12.0 ( 8.4 )
    11.8 ( 6.8 )
        Follow-Up
    11.0 ( 9.2 )
    12.5 ( 7.6 )
    Notes
    [2] - EoT: 29; LFU: 24
    [3] - EoT: 14; LFU: 13
    Statistical analysis title
    		 Comparison between Verum and Placebo
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.866 [4]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [4] - The number of all lesions did not differ between verum and placebo (Baseline: p=0.866, EoT: p=0.835, LFU: p=0.381)

    Secondary: DermatoLogy Quality of life Index (DLQI):

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    End point title
    		 DermatoLogy Quality of life Index (DLQI):
    End point description
    End point type
    Secondary
    End point timeframe
    At Baseline, EoT and last Follow-Up
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [5]
    15 [6]
    Units: DLQI Score
    arithmetic mean (standard deviation)
        Baseline
    4.7 ( 4.5 )
    5.5 ( 4.3 )
        EoT
    2.5 ( 4.0 )
    4.4 ( 4.7 )
        Follow-Up
    1.5 ( 2.5 )
    3.8 ( 3.9 )
    Attachments
    		 Untitled (Filename: Table1.docx)
    Notes
    [5] - Eot: 29; LFU: 24
    [6] - EoT: 14; LFU: 13
    Statistical analysis title
    		 Comparison between Verum and Placebo group
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.403 [7]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [7] - In the PP analysis mean DLQI index at end of treatment (Visit 14) was 2.2 ± 4.2 in the dupilumab group vs. 4.5 ± 4.9 in the placebo group (p=0.018) thus the difference is statistically significant in favor of the dupilumab group (Table 2).

    Secondary: Anti-nuclear antibodies titer

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    End point title
    		 Anti-nuclear antibodies titer
    End point description
    Titer of ANAs in subjects with positive ANA test result.
    End point type
    Secondary
    End point timeframe
    At Baseline and at End of Treatment Visit (EoT)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    5 [8]
    1
    Units: Antibody Titer
    median (full range (min-max))
        Baseline
    320 (160 to 5120)
    160 (160 to 160)
        EoT
    160 (80 to 640)
    160 (160 to 160)
    Notes
    [8] - Baseline: 3
    No statistical analyses for this end point

    Secondary: Anti-nuclear antibodies

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    End point title
    		 Anti-nuclear antibodies
    End point description
    End point type
    Secondary
    End point timeframe
    At Baseline and End of Treatment Visit (EoT)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [9]
    14 [10]
    Units: Subjects
        Baseline negative test result
    27
    13
        Baseline positive test result
    3
    1
        EoT negative test result
    23
    12
        EoT positive test result
    5
    1
    Notes
    [9] - EoT: 28
    [10] - EoT: 13
    No statistical analyses for this end point

    Secondary: Cytokine serum levels IL-4, IL-5, IL-13

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    End point title
    		 Cytokine serum levels IL-4, IL-5, IL-13
    End point description
    End point type
    Secondary
    End point timeframe
    At baseline, EoT and Follow-Up
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [11]
    15 [12]
    Units: pg/ml
    median (inter-quartile range (Q1-Q3))
        IL-4 Baseline
    0.05 (0.05 to 0.05)
    0.05 (0.05 to 0.05)
        IL-4 EoT
    0.05 (0.05 to 0.30)
    0.05 (0.05 to 0.05)
        IL-4 Follow-Up
    0.05 (0.05 to 0.31)
    0.05 (0.05 to 0.05)
        IL-5 Baseline
    0.75 (0.75 to 0.75)
    0.75 (0.75 to 0.75)
        IL-5 EoT
    0.75 (0.75 to 2.81)
    0.75 (0.75 to 0.75)
        IL-5 Follow-Up
    0.75 (0.75 to 2.23)
    0.75 (0.75 to 0.75)
        IL-13 Baseline
    0.35 (0.35 to 9.04)
    11.44 (0.35 to 15.92)
        IL-13 EoT
    0.35 (0.35 to 7.66)
    6.27 (0.35 to 17.51)
        IL-13 Follow-Up
    0.35 (0.35 to 12.66)
    2.20 (0.35 to 10.22)
    Notes
    [11] - LFU: 24
    [12] - EoT: 14; LFU: 13
    No statistical analyses for this end point

    Secondary: Treatment response (all lesions) at EoT

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    End point title
    		 Treatment response (all lesions) at EoT
    End point description
    Treatment response is determined by change in whole body mLoSSI (size of lesion, erythema, skin thickening) or LoSDI (dermal athrophy, subcutaneous atrophy, dyspigmentation); score reduction by 50% after 24 weeks (EoT V14) compared to baseline. Subjects who received rescue medication (e.g. topical steroids, systemic immunosuppressive therapy) or withdrawed from the trial were counted as non-responder.
    End point type
    Secondary
    End point timeframe
    24 weeks (EoT V14) compared to baseline
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30
    15
    Units: Subjects
    12
    7
    Statistical analysis title
    		 Treatment response (all lesions) at EoT
    Statistical analysis description
    In the ITT analysis the proportion of treatment responders at end of treatment including all lesions in the verum group was 40.0% (12/30) and in the placebo group 46.7% (7/15). Tested against the test value of 30% there is no significant difference for the verum group (p=0.244).
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.244 [14]
    Method
    		 One-sample proportions test
    Parameter type
    		 Proportion
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.227
         upper limit
    		 0.594
    Notes
    [13] - Proportion of responders for the verum group was tested against the test value of 30%.
    [14] - PP analysis: The proportion of treatment responders including all lesions in the verum group was 48.0% (12/25) and in the placebo group 42.9% (6/14). There is no significant difference for the verum group (p=0.062).

    Secondary: Treatment response (all lesions) at LFU

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    End point title
    		 Treatment response (all lesions) at LFU
    End point description
    Treatment response is determined by change in whole body mLoSSI (size of lesion, erythema, skin thickening) or LoSDI (dermal athrophy, subcutaneous atrophy, dyspigmentation); score reduction by 50% at last follow-up (V16) compared to baseline. Subjects who received rescue medication (e.g. topical steroids, systemic immunosuppressive therapy) or withdrawed from the trial were counted as non-responder.
    End point type
    Secondary
    End point timeframe
    Last follow-up (V16)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30
    15
    Units: Subjects
    15
    6
    Statistical analysis title
    		 Treatment response (all lesions) at LFU
    Statistical analysis description
    In the ITT analysis the proportion of treatment responders at last follow-up including all lesions in the verum group was 50.0% (15/30) and in the placebo group 40.0% (6/15). Tested against the test value of 30% there is a significant difference for the verum group (p=0.023).
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.023 [16]
    Method
    		 One-sample proportions test
    Parameter type
    		 Proportion
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.313
         upper limit
    		 0.687
    Notes
    [15] - Proportion of responders for the verum group was tested against the test value of 30%.
    [16] - PP analysis: The proportion of treatment responders including all lesions in the verum group was 60.0% (15/25) and in the placebo group 35.7% (5/14). There is a significant difference for the verum group (p=0.002).

    Secondary: Cytokine serum levels Periostin, DPP4

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    End point title
    		 Cytokine serum levels Periostin, DPP4
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, End of Treatement Visit (24 weeks), Last Follow-Up Visit (48 weeks)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [17]
    15 [18]
    Units: ng/ml
    median (inter-quartile range (Q1-Q3))
        Periostin Baseline
    15.98 (6.82 to 53.25)
    68.56 (15.70 to 137.16)
        Periostin EoT
    18.74 (8.34 to 56.62)
    59.87 (22.17 to 98.48)
        Periostin LFU
    12.75 (6.38 to 53.63)
    58.78 (11.86 to 99.47)
        CD26 (DPP4) Baseline
    366.65 (298.49 to 475.35)
    412.19 (328.50 to 471.55)
        CD26 (DPP4) EoT
    383.03 (343.42 to 469.87)
    412.54 (318.26 to 510.78)
        CD26 (DPP4) LFU
    402.16 (328.52 to 496.15)
    470.55 (333.54 to 522.78)
    Notes
    [17] - EoT: 30; LFU: 24
    [18] - EoT: 14; LFU: 13
    No statistical analyses for this end point

    Secondary: mLoSSI of Target Lesion

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    End point title
    		 mLoSSI of Target Lesion
    End point description
    Modified LS Skin Severity Index (mLoSSI) includes the sums of 3 separate activity scores as follows: (1) erythema, using the color of the lesion's edge with 0 = no erythema, 1 = slight erythema/pink, 2 = red/clearly erythema, and 3 = dark red or marked erythema/violaceous; (2) skin thickness with 0 = normal skin thickness and freely mobile, 1 = mild increase of thickness–mobile, 2 = moderate increase of thickness–impaired skin mobility, and 3 = marked increase of thickness or no mobility of skin; and (3) new lesion/lesion extension: new lesion development and/or enlargement of an existing lesion within the past month (score of 3). Maximum value: 9
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Visit (24 weeks) and Last Follow-Up (48 weeks)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [19]
    15 [20]
    Units: Score on scale
    arithmetic mean (standard deviation)
        Baseline
    5.20 ( 1.00 )
    4.87 ( 1.30 )
        EoT
    2.97 ( 2.47 )
    3.29 ( 2.67 )
        LFU
    1.96 ( 2.22 )
    3.23 ( 2.86 )
    Notes
    [19] - EoT: 29, LFU: 24
    [20] - EoT: 14, LFU: 13
    No statistical analyses for this end point

    Secondary: LoSDI of target lesion

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    End point title
    		 LoSDI of target lesion
    End point description
    LS Damage Index (LoSDI) includes: (1) dermal atrophy with 0 = normal-appearing skin, 1 = mild skin atrophy (ie, shiny skin), 2 = moderate atrophy (ie, visible blood vessels or mild “cliff-drop” sign), and 3 = severe skin atrophy (ie, obvious cliff-drop sign); (2) subcutaneous atrophy with 0 = normal subcutaneous thickness, 1 = flattening or 1/3 fat loss, 2 = obvious concave surface or 1/3 to 2/3 fat loss, and 3 = severe subcutaneous fat loss (>2/3 loss); and (3) dyspigmentation, assessing hyperpigmentation or hypopigmentation, whichever is most prominent with 0 = normal skin pigment, 1 = mild dyspigmentation, 2 = moderate dyspigmentation, and 3 = severe dyspigmentation. Maximum value: 9.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Visit (24 weeks) and Last Follow-Up Visit (48 weeks)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [21]
    15 [22]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    6.23 ( 2.22 )
    5.67 ( 2.38 )
        EoT
    4.69 ( 3.12 )
    3.79 ( 3.33 )
        LFU
    3.54 ( 2.89 )
    3.77 ( 3.09 )
    Notes
    [21] - EoT: 29, LFU: 24
    [22] - EoT: 14; LFU: 13
    No statistical analyses for this end point

    Secondary: Physician Global Assessment of Disease Activity

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    End point title
    		 Physician Global Assessment of Disease Activity
    End point description
    Physicians Assessment of Disease Activity on a Scale from 0 (inactive) to 100 (markedly active).
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Visit (EoT) and Last Follow-Up Visit (V16)
    End point values
    		 Verum Placebo
    Number of subjects analysed
    30 [23]
    15 [24]
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline
    74.3 ( 20.6 )
    73.8 ( 19.1 )
        EoT
    40.6 ( 29.9 )
    36.6 ( 28.8 )
        LFU
    19.1 ( 24.4 )
    43.2 ( 32.8 )
    Notes
    [23] - EoT: 29; LFU: 24
    [24] - EoT: 14; LFU: 13
    Statistical analysis title
    		 Comparison between Verum and Placebo group
    Comparison groups
    Placebo v Verum
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.923 [25]
    Method
    		 Kruskal-wallis
    Confidence interval
    Notes
    [25] - For PP analysis: At last follow up (Visit 16, 6 months after last IMP injection), PGA activity was significantly lower for dupilumab group (20.0±24.6) vs Placebo (42.6±34.2; p=0.032).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reporting period for all adverse events (AEs) and serious adverse events (SAEs) is from the first IMP treatment until last study visit (24 weeks after last IMP administration) for each subject, regardless of the relationship to IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 Subjects which received Dupilumab

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects which received Placebo

    Serious adverse events
    		 Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oral papilloma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 15 (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
    COVID-19
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    		 Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    15 / 15 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 30 (33.33%)
    6 / 15 (40.00%)
         occurrences all number
    33
    22
    Migraine
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 15 (13.33%)
         occurrences all number
    2
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    16
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Toothache
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Eczema
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    5
    Erythema
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Pruritus
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 15 (20.00%)
         occurrences all number
    9
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 30 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    11
    14
    Back pain
         subjects affected / exposed
    6 / 30 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    14
    2
    Morphoea
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Neck pain
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Pain in extremity
         subjects affected / exposed
    6 / 30 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    7
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    7 / 30 (23.33%)
    3 / 15 (20.00%)
         occurrences all number
    7
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    Oral herpes
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2019
    Amd1 (Qualification PI/deputy at site 002)
    07 Jul 2020
    Amd2 (Trial Protocol V04_0) - Study timelines - Exclusion criteria - Study schedule - Laboratory monitoring
    03 Sep 2020
    Amd3 (Information Letter for local dermatologists to enhance recruitment)
    16 Dec 2020
    Amd4 (IB V14_0, ICF V05_0)
    06 Jul 2021
    Amd5 (trial protocol V05_0) - Study timelines - Clarification In-/Exclusioncriteria
    06 Sep 2021
    Amd6 (additional trial site 004)
    02 Sep 2022
    Amd7 (trial protocol V07_0) - Study timelines - Clarification exclusion criteria

    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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