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    Clinical Trial Results:
    A Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Assess the Safety of REGN668 Administered Concomitantly with Topical Corticosteroids to Patients with Moderate-to-severe Atopic Dermatitis

    Summary
    EudraCT number
    2012-000946-37
    Trial protocol
    HU   DE  
    Global end of trial date
    19 Dec 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Dec 2019
    First version publication date
    09 May 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    R668-AD-1121
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01639040
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Rd, Tarrytown, United States, 10591
    Public contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trial Management, Regeneron Pharmaceuticals, Inc., clinicaltrials@regeneron.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
    30 Jan 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the safety of repeated subcutaneous doses of Dupilumab (REGN668/SAR231893) administered concomitantly with topical corticosteroids (TCS) in adult subjects with moderate-to-severe atopic dermatitis (AD).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    All subjects received concomitant, open-label, daily treatment for up to 28 days with Class 3 or 4 midpotency a topical corticosteroid (TCS) such as methylprednisolone aceponate 0.1%, mometasone furoate 0.1%, or betamethasone valerate 0.1%.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jul 2012
    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: 15
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Poland: 13
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    30
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 38 subjects were screened in the study between 30 July 2012 and 20 December 2012.

    Pre-assignment
    Screening details
    Out of 38 subjects, 31 were randomized and treated in the study. Subjects were randomized in 2:1 ratio to receive Dupilumab 300 mg or Placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo QW
    Arm description
    Placebo (for Dupilumab) once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent topical corticosteroid (TCS) for up to 28 days
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Dupilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single subcutaneous injection in the abdomen or thigh.

    Arm title
    Dupilumab 300 mg QW
    Arm description
    Dupilumab 300 mg once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent TCS for up to 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    REGN668/SAR231893
    Other name
    Dupixent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single subcutaneous injection in the abdomen or thigh.

    Number of subjects in period 1
    Placebo QW Dupilumab 300 mg QW
    Started
    10
    21
    Completed
    9
    21
    Not completed
    1
    0
         Adverse event
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo QW
    Reporting group description
    Placebo (for Dupilumab) once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent topical corticosteroid (TCS) for up to 28 days

    Reporting group title
    Dupilumab 300 mg QW
    Reporting group description
    Dupilumab 300 mg once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent TCS for up to 28 days

    Reporting group values
    Placebo QW Dupilumab 300 mg QW Total
    Number of subjects
    10 21 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.8 ± 16.73 36 ± 11.26 -
    Gender categorical
    Units: Subjects
        Female
    5 13 18
        Male
    5 8 13
    Eczema Area and Severity Index (EASI) score
    The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score range from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD.
    Units: units on a scale
        arithmetic mean (standard deviation)
    24.1 ± 12.7 23.1 ± 12.35 -
    Investigator’s Global Assessment (IGA) Score
    IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 6-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe; and 5 = very severe disease) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear).
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.4 ± 0.47 3.4 ± 0.6 -
    Pruritus Numerical Rating Scale (NRS) score
    Pruritus NRS was an assessment tool that was used to report intensity of subject’s pruritus (itch), both maximum and average intensity during a 24-hour recall period. Subjects were asked following question: how would a subject rate his itch at worst moment during previous 24 hours (for maximum itch intensity on a scale of 0–10 [0 = no itch; 10 = worst itch imaginable]).
    Units: units on a scale
        arithmetic mean (standard deviation)
    5 ± 1.39 6.4 ± 2 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo QW
    Reporting group description
    Placebo (for Dupilumab) once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent topical corticosteroid (TCS) for up to 28 days

    Reporting group title
    Dupilumab 300 mg QW
    Reporting group description
    Dupilumab 300 mg once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent TCS for up to 28 days

    Primary: Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Subjects With Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    Any untoward medical occurrence in a subject who received investigational medicinal product (IMP) was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during on-treatment period (from start of administration of first dose of study drug to the end of study [up to Day 78]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included subjects with both serious and non-serious AEs. Safety population included all randomized subjects who received any study drug, based on treatment received.
    End point type
    Primary
    End point timeframe
    Baseline up to the end of study (up to Day 78)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: percentage of subjects
    number (not applicable)
        With at least one TEAE
    70
    57.1
        With study drug related TEAEs
    40
    28.6
        With serious TEAEs
    10
    0
        With TEAEs resulting in study discontinuation
    10
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Achieving Eczema Area and Severity Index (EASI) Score: Reduction of ≥50 at Day 29 - Censored Last Observation Carried Forward (LOCF)

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    End point title
    Percentage of Subjects Achieving Eczema Area and Severity Index (EASI) Score: Reduction of ≥50 at Day 29 - Censored Last Observation Carried Forward (LOCF)
    End point description
    The EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score range from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Efficacy data were set to missing after prohibited medication was used or after subject was discontinued from the study. All missing values were imputed by simple LOCF. Full analysis set (FAS) included all randomized subjects received at least 1 dose of study drug and had at least 1 post-baseline assessment, based on the treatment allocated (as randomized).
    End point type
    Other pre-specified
    End point timeframe
    Day 29
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: percentage of subjects
        number (confidence interval 95%)
    50 (18.7 to 81.3)
    100 (83.9 to 100)
    No statistical analyses for this end point

    Other pre-specified: Percent Change in Pruritus Numerical Rating Scale (NRS) From Day 1 (Baseline) to Day 29 (Week 4)

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    End point title
    Percent Change in Pruritus Numerical Rating Scale (NRS) From Day 1 (Baseline) to Day 29 (Week 4)
    End point description
    Pruritus NRS was an assessment tool that was used to report the intensity of subject’s pruritus (itch), both maximum and average intensity, during a 24-hour recall period. Subjects were asked the following question: how would a subject rate his itch at the worst moment during the previous 24 hours (for maximum itch intensity on a scale of 0 – 10 [0 = no itch; 10 = worst itch imaginable]). FAS included all randomized subjects received at least 1 dose of study drug and had at least 1 post-baseline assessment, based on the treatment allocated (as randomized).
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 29
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: percent change
        arithmetic mean (standard deviation)
    -24.7 ± 47.3
    -70.7 ± 21.45
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Achieving an Investigator’s Global Assessment (IGA) Score of "0" or "1" at Day 29

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    End point title
    Percentage of Subjects Achieving an Investigator’s Global Assessment (IGA) Score of "0" or "1" at Day 29
    End point description
    IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). FAS included all randomized subjects received at least 1 dose of study drug and had at least 1 post-baseline assessment, based on the treatment allocated (as randomized).
    End point type
    Other pre-specified
    End point timeframe
    Day 29
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: percentage of subjects
        number (confidence interval 95%)
    30 (6.7 to 65.2)
    52.4 (29.8 to 74.3)
    No statistical analyses for this end point

    Other pre-specified: Percent Change in Investigator’s Global Assessment (IGA) Score From Day 1 (Baseline) to Day 29 (Week 4) - Censored LOCF

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    End point title
    Percent Change in Investigator’s Global Assessment (IGA) Score From Day 1 (Baseline) to Day 29 (Week 4) - Censored LOCF
    End point description
    IGA was an assessment scale used to determine severity of AD and clinical response to treatment on a 5-point scale (0 = clear; 1 = almost clear; 2 = mild; 3 = moderate; 4 = severe) based on erythema and papulation/infiltration. Therapeutic response was an IGA score of 0 (clear) or 1 (almost clear). The efficacy data were set to missing after prohibited medication was used or after the subject was discontinued from the study. Then, all missing values were imputed by simple LOCF. FAS included all randomized subjects received at least 1 dose of study drug and had at least 1 post-baseline assessment, based on the treatment allocated (as randomized).
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 29
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: percent change
        arithmetic mean (standard deviation)
    -30.6 ± 39
    -52.5 ± 21.44
    No statistical analyses for this end point

    Other pre-specified: Percent Change in Eczema Area and Severity Index (EASI) Score From Day 1 (Baseline) to Day 29 (Week 4) - Censored LOCF

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    End point title
    Percent Change in Eczema Area and Severity Index (EASI) Score From Day 1 (Baseline) to Day 29 (Week 4) - Censored LOCF
    End point description
    EASI score was used to measure the severity and extent of atopic dermatitis (AD) and measures erythema, infiltration, excoriation and lichenification on 4 anatomic regions of the body: head, trunk, upper and lower extremities. The total EASI score ranges from 0 (minimum) to 72 (maximum) points, with the higher scores reflecting the worse severity of AD. Efficacy data were set to missing after prohibited medication was used or after subject was discontinued from study. All missing values were imputed by simple LOCF. FAS included all randomized subjects received at least 1 dose of study drug and had at least 1 post-baseline assessment, based on the treatment allocated (as randomized).
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 29
    End point values
    Placebo QW Dupilumab 300 mg QW
    Number of subjects analysed
    10
    21
    Units: Percent Change
        arithmetic mean (standard deviation)
    -52.5 ± 39.53
    -75.6 ± 13.29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit (Day 78) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that are AEs that developed/worsened during the ‘on treatment period’ (day from first dose of study drug to the end of study visit [up to Day 78]).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Dupilumab 300 mg QW
    Reporting group description
    Dupilumab 300 mg once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent TCS for up to 28 days

    Reporting group title
    Placebo QW
    Reporting group description
    Placebo (for Dupilumab) once weekly (QW) for 4 weeks by subcutaneous injection with the background therapy of potent topical corticosteroid (TCS) for up to 28 days

    Serious adverse events
    Dupilumab 300 mg QW Placebo QW
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         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
    Dupilumab 300 mg QW Placebo QW
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 21 (38.10%)
    7 / 10 (70.00%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    4
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    8
    6
    Loss of consciousness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    4
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 21 (23.81%)
    2 / 10 (20.00%)
         occurrences all number
    6
    2
    Rhinitis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    Sinusitis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2012
    The purpose of the amendment was to indicate that collection of RNA samples (part of the research samples collected during the study) could have required separate informed consent, as required by local regulatory authorities.

    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.
    This was a small safety study that was not adequately powered to assess efficacy.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25006719
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