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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate Dupilumab in Patients with Moderate to Severe Uncontrolled Asthma

    Summary
    EudraCT number
    2013-000856-16
    Trial protocol
    IT   ES   PL  
    Global end of trial date
    08 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Apr 2016
    First version publication date
    20 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DRI12544
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01854047
    WHO universal trial number (UTN)
    U1111-1138-3962
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    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
    04 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of different doses and regimens of Dupilumab in subjects with moderate-to-severe, uncontrolled asthma.
    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
    Inhaled corticosteroid (ICS)/long-acting beta-2 agonist (LABA) therapy, stable moderate- or high-dose for at least 1 month prior to screening and continued throughout the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Jun 2013
    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
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Argentina: 64
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Chile: 68
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Japan: 80
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Russian Federation: 72
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Turkey: 41
    Country: Number of subjects enrolled
    Ukraine: 62
    Country: Number of subjects enrolled
    United States: 193
    Worldwide total number of subjects
    776
    EEA total number of subjects
    112
    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)
    702
    From 65 to 84 years
    73
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 174 centers in 15 countries. A total of 1532 subjects were screened between June 2013 and June 2014, of which, 776 subjects were randomized and 769 were treated. 756 subjects were screen failure mainly due to exclusion criteria met and inclusion criteria not met.

    Pre-assignment
    Screening details
    Randomization was stratified according to blood eosinophils count [high eosinophils(HEos)≥0.3 G/L; eosinophils 0.2 to 0.299 G/L; eosinophils<0.2 G/L] and country. Assignment to arms was done centrally using Interactive Voice/Web Response System in 1:1:1:1:1 ratio for Placebo and Dupilumab [300 mg q2w; 200 mg q2w; 300 mg q4w and 200 mg q4w].

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo q2w
    Arm description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection every 2 weeks (q2w) from Week 2 to Week 22 in combination with stable ICS/LABA therapy.
    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
    Subcutaneous injection (2 ml) in the abdomen or upper thigh.

    Arm title
    Dupilumab 300 mg q2w
    Arm description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893, REGN668
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (300 mg/2 ml) in the abdomen or upper thigh.

    Arm title
    Dupilumab 200 mg q2w
    Arm description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 200 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893, REGN668
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (200 mg/2 ml) in the abdomen or upper thigh.

    Arm title
    Dupilumab 300 mg q4w
    Arm description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893; REGN668
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (300 mg/2 ml) in the abdomen or upper thigh.

    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
    Subcutaneous injection (2 ml) in the abdomen or upper thigh.

    Arm title
    Dupilumab 200 mg q4w
    Arm description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893; REGN668
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (200 mg/ 2 ml) in the abdomen or upper thigh.

    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
    Subcutaneous injection (2 ml) in the abdomen or upper thigh.

    Number of subjects in period 1
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Started
    158
    157
    150
    157
    154
    Treated
    158
    156
    148
    157
    150
    Completed 12-week study treatment
    153
    149
    141
    146
    143
    Completed
    146
    149
    137
    142
    135
    Not completed
    12
    8
    13
    15
    19
         Randomized but not treated
             -
             1
             2
             -
             4
         Other than specified
             3
             3
             3
             5
             8
         Lack of efficacy
             1
             -
             -
             -
             -
         Poor compliance to protocol
             3
             -
             2
             -
             -
         Adverse Event
             5
             4
             6
             10
             7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection every 2 weeks (q2w) from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 200 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 300 mg q4w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 200 mg q4w
    Reporting group description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w Total
    Number of subjects
    158 157 150 157 154 776
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49 ± 12.7 47.5 ± 12.4 51 ± 13.4 47.9 ± 13.1 47.9 ± 13.1 -
    Gender categorical
    Units: Subjects
        Female
    104 103 96 100 87 490
        Male
    54 54 54 57 67 286
    Number of Subjects with Blood Eosinphil Count
    Units: Subjects
        <0.3 Giga/L
    90 93 85 91 92 451
        ≥ 0.3 Giga/L
    68 64 65 66 62 325

    End points

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    End points reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1 followed by a single injection every 2 weeks (q2w) from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1, followed by a single 200 mg injection q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 300 mg q4w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 300 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Reporting group title
    Dupilumab 200 mg q4w
    Reporting group description
    2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 followed by a Placebo alternating with single 200 mg injection of Dupilumab q2w from Week 2 to Week 22 in combination with stable ICS/LABA therapy.

    Primary: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12 - Intent-to-Treat (ITT) Population

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    End point title
    Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 12 - Intent-to-Treat (ITT) Population
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Analysis was performed on ITT population that included all randomized population analyzed according to the treatment group allocated by randomization, regardless of whether the treatment was actually received. Number of subjects analyzed = subjects of ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    157
    150
    157
    154
    Units: Liter
    arithmetic mean (standard deviation)
        Baseline (n=158,157,150,157,154)
    1.82 ± 0.55
    1.85 ± 0.53
    1.79 ± 0.52
    1.86 ± 0.57
    1.88 ± 0.54
        Week 12 (n=129,146,136,134,134)
    2.01 ± 0.69
    2.12 ± 0.59
    2.12 ± 0.68
    2.14 ± 0.69
    2.07 ± 0.63
        Change from baseline (n=129,146,136,134,134)
    0.13 ± 0.37
    0.26 ± 0.39
    0.32 ± 0.38
    0.24 ± 0.4
    0.2 ± 0.41
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo q2w
    Statistical analysis description
    Analysis was performed using mixed-effect model with repeated measures (MMRM) model including available FEV1 data from baseline to Week 12 and treatment group as a factor. A step-down procedure was used to strongly control the overall type I error rate for testing multiple doses against placebo. The hierarchy was 300 mg q2w, 200 mg q2w, 300 mg q4w and 200 mg q4w.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [1]
    Method
    Mixed models analysis
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.25
    Notes
    [1] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 200 mg q2w vs Placebo q2w
    Comparison groups
    Dupilumab 200 mg q2w v Placebo q2w
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.28
    Notes
    [2] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 300 mg q4w vs Placebo q2w
    Comparison groups
    Dupilumab 300 mg q4w v Placebo q2w
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0048 [3]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.04
         upper limit
    0.21
    Notes
    [3] - Threshold for significance at 0.05. 
    Statistical analysis title
    Dupilumab 200 mg q4w vs Placebo q2w
    Comparison groups
    Dupilumab 200 mg q4w v Placebo q2w
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0304 [4]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.18
    Notes
    [4] - Threshold for significance at 0.05.

    Primary: Change From Baseline in FEV1 at Week 12 - ITT Population with Elevated Baseline Blood Eosinophils (HEos-ITT Population)

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    End point title
    Change From Baseline in FEV1 at Week 12 - ITT Population with Elevated Baseline Blood Eosinophils (HEos-ITT Population)
    End point description
    Analysis was performed on HEos ITT population defined as the ITT population with baseline blood eosinophils ≥0.3 G/L. Number of subjects analyzed = subjects of HEos-ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    68
    64
    65
    66
    62
    Units: Liter
    arithmetic mean (standard deviation)
        Baseline (n=68,64,65,66,62)
    1.86 ± 0.68
    1.77 ± 0.5
    1.8 ± 0.52
    1.87 ± 0.6
    1.8 ± 0.49
        Week 12 (n=58,59,57,55,53)
    2.13 ± 0.78
    2.12 ± 0.54
    2.26 ± 0.68
    2.26 ± 0.7
    2.09 ± 0.54
        Change from baseline (n=58,59,57,55,53)
    0.18 ± 0.38
    0.36 ± 0.46
    0.45 ± 0.4
    0.35 ± 0.43
    0.26 ± 0.47
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo q2w
    Statistical analysis description
    Analysis was performed using MMRM model including available FEV1 data from baseline to Week 12 and treatment group as a factor. A step-down procedure was used to strongly control the overall type I error rate for testing multiple doses against placebo. The hierarchy was 300 mg q2w, 200 mg q2w, 300 mg q4w, and 200 mg q4w.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0063 [5]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.36
    Notes
    [5] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 200 mg q2w vs Placebo q2w
    Comparison groups
    Dupilumab 200 mg q2w v Placebo q2w
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008 [6]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    0.4
    Notes
    [6] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 300 mg q4w vs Placebo q2w
    Comparison groups
    Dupilumab 300 mg q4w v Placebo q2w
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0212 [7]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    0.32
    Notes
    [7] - Threshold for significance at 0.05.
    Statistical analysis title
    Dupilumab 200 mg q4w vs Placebo q2w
    Comparison groups
    Dupilumab 200 mg q4w v Placebo q2w
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2774 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.23
    Notes
    [8] - Threshold for significance at 0.05.

    Secondary: Relative Change From Baseline in FEV1 at Week 12

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    End point title
    Relative Change From Baseline in FEV1 at Week 12
    End point description
    Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed=subjects of ITT population. Here "n" signifies number of subjects with available data at Week 12 for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    157
    150
    157
    154
    Units: Percent change
    arithmetic mean (standard deviation)
        ITT Population (n=129,146,136,134,134)
    7.04 ± 19.26
    16.64 ± 27.78
    19.15 ± 23.53
    13.55 ± 23.01
    13.04 ± 24.21
        HEos ITT Population (n=58,59,57,55,53)
    10.07 ± 19.65
    25.29 ± 36.15
    27.42 ± 25.68
    20.68 ± 24.86
    18.07 ± 29.18
    No statistical analyses for this end point

    Secondary: Annualized Event Rate of Loss of Asthma Control (LOAC) During The Treatment Period

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    End point title
    Annualized Event Rate of Loss of Asthma Control (LOAC) During The Treatment Period
    End point description
    LOAC was defined as any of following: ≥6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; increase in inhaled corticosteroid ≥4 times the dose at randomization; use of systemic corticosteroids for ≥3 days; hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of LOAC that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed=subjects of the ITT population who were treated. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    156
    148
    157
    150
    Units: LOAC per subject-year
    number (confidence interval 95%)
        ITT Population (n=158,156,148,157,150)
    1.107 (0.801 to 1.53)
    0.326 (0.206 to 0.515)
    0.347 (0.217 to 0.555)
    0.73 (0.508 to 1.048)
    0.563 (0.378 to 0.839)
        HEos ITT Population (n=68,64,64,66,59)
    1.312 (0.804 to 2.142)
    0.322 (0.153 to 0.677)
    0.446 (0.231 to 0.864)
    0.788 (0.458 to 1.355)
    0.424 (0.212 to 0.851)
    No statistical analyses for this end point

    Secondary: Time to First LOAC Event During the Treatment Period: Kaplan-Meier Estimates at Week 12 and Week 24

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    End point title
    Time to First LOAC Event During the Treatment Period: Kaplan-Meier Estimates at Week 12 and Week 24
    End point description
    The time-to-event variable was defined as the time from the date of first dose to the date of the first LOAC event. For subjects who had no LOAC event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. The probability of LOAC at Week 12 and Week 24 was provided. Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed=subjects of the ITT population who were treated. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    156
    148
    157
    150
    Units: Probability of LOAC
    number (confidence interval 95%)
        ITT Population at Week 12(n=158,156,148,157,150)
    0.258 (0.192 to 0.329)
    0.112 (0.068 to 0.168)
    0.09 (0.051 to 0.144)
    0.145 (0.095 to 0.206)
    0.096 (0.055 to 0.15)
        ITT Population at Week 24(n=158,156,148,157,150)
    0.338 (0.265 to 0.413)
    0.146 (0.095 to 0.207)
    0.112 (0.067 to 0.169)
    0.242 (0.177 to 0.314)
    0.209 (0.147 to 0.279)
        HEos ITT Population at Week 12 (n=68,64,64,66,59)
    0.3 (0.195 to 0.411)
    0.115 (0.05 to 0.208)
    0.113 (0.05 to 0.206)
    0.126 (0.059 to 0.22)
    0.052 (0.014 to 0.13)
        HEos ITT Population at Week 24 (n=68,64,64,66,59)
    0.392 (0.275 to 0.507)
    0.166 (0.085 to 0.269)
    0.113 (0.05 to 0.206)
    0.207 (0.117 to 0.314)
    0.162 (0.079 to 0.269)
    No statistical analyses for this end point

    Secondary: Annualized Event Rate of Severe Exacerbation During The Treatment Period

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    End point title
    Annualized Event Rate of Severe Exacerbation During The Treatment Period
    End point description
    A severe exacerbation was defined as a deterioration of asthma requiring: use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed=subjects of the ITT population who were treated. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    156
    148
    157
    150
    Units: Exacerbation per subject-year
    number (confidence interval 95%)
        ITT Population (n=158,156,148,157,150)
    0.897 (0.619 to 1.3)
    0.265 (0.157 to 0.445)
    0.269 (0.157 to 0.461)
    0.599 (0.396 to 0.907)
    0.415 (0.26 to 0.664)
        HEos ITT Population (n=68,64,64,66,59)
    1.044 (0.572 to 1.904)
    0.201 (0.078 to 0.517)
    0.3 (0.133 to 0.678)
    0.678 (0.356 to 1.29)
    0.358 (0.158 to 0.809)
    No statistical analyses for this end point

    Secondary: Time to First Severe Exacerbation Event During the Treatment Period: Kaplan-Meier Estimates at Week 12 and 24

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    End point title
    Time to First Severe Exacerbation Event During the Treatment Period: Kaplan-Meier Estimates at Week 12 and 24
    End point description
    The time-to-event variable was defined as the time from the date of first dose to the date of the first severe exacerbation event. For subjects who had no severe exacerbation event on or before last dose date + 14 days, it was censored at the date of last dose date + 14 days. Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed=subjects of the ITT population who were treated. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    156
    148
    157
    150
    Units: Probability of Severe Exacerbation
    number (confidence interval 95%)
        ITT Population at Week 12 (n=158,156,148,157,150)
    0.207 (0.147 to 0.274)
    0.092 (0.053 to 0.145)
    0.07 (0.036 to 0.119)
    0.112 (0.068 to 0.168)
    0.075 (0.04 to 0.125)
        ITT Population at Week 24 (n=158,156,148,157,150)
    0.266 (0.199 to 0.338)
    0.112 (0.068 to 0.169)
    0.091 (0.051 to 0.145)
    0.195 (0.136 to 0.262)
    0.16 (0.106 to 0.225)
        HEos ITT Population at Week 12 (n=68,64,64,66,59)
    0.21 (0.122 to 0.314)
    0.082 (0.03 to 0.167)
    0.082 (0.03 to 0.167)
    0.094 (0.038 to 0.181)
    0.052 (0.014 to 0.13)
        HEos ITT Population at Week 24 (n=68,64,64,66,59)
    0.287 (0.184 to 0.398)
    0.116 (0.051 to 0.21)
    0.082 (0.03 to 0.167)
    0.175 (0.093 to 0.278)
    0.125 (0.055 to 0.226)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Morning Asthma Symptom Score at Week 12

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    End point title
    Change From Baseline in Morning Asthma Symptom Score at Week 12
    End point description
    AM (ante meridiem) symptom scoring system rates were subject’s overall asthma symptoms experienced during the night. It ranges from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning. No nighttime awakenings,2= Woke up once because of asthma (including early awakening),3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma. Analysis was performed on ITT population and HEos-ITT population. Number of subjects analyzed = subjects of ITT population. Here 'n' signifies number of subjects with available data at Week 12 for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    157
    150
    157
    154
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        ITT Population (n=143,148,138,148,140)
    -0.23 ± 0.7
    -0.43 ± 0.7
    -0.46 ± 0.75
    -0.52 ± 0.65
    -0.54 ± 0.64
        HEos ITT Population (n=62,59,58,61,56)
    -0.29 ± 0.7
    -0.66 ± 0.67
    -0.55 ± 0.75
    -0.57 ± 0.63
    -0.57 ± 0.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Evening Asthma Symptom Score at Week 12

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    End point title
    Change From Baseline in Evening Asthma Symptom Score at Week 12
    End point description
    PM (post meridiem) symptom scoring system rates were subject’s overall asthma symptoms experienced during the day. It ranges from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual. Analysis was performed on ITT population and HEos ITT population. Number of subjects analyzed = subjects of ITT population. Here 'n' signifies number of subjects with available data at Week 12 for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    158
    157
    150
    157
    154
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        ITT Population (n=143,148,136,148,140)
    -0.27 ± 0.76
    -0.52 ± 0.79
    -0.52 ± 0.8
    -0.59 ± 0.79
    -0.54 ± 0.71
        HEos ITT Population (n=62,59,58,61,56)
    -0.35 ± 0.71
    -0.84 ± 0.87
    -0.62 ± 0.7
    -0.73 ± 0.77
    -0.69 ± 0.7
    No statistical analyses for this end point

    Post-hoc: Change From Baseline in FEV1 at Week 12 - ITT Population With Baseline Blood Eosinophil <0.3 Giga/L

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    End point title
    Change From Baseline in FEV1 at Week 12 - ITT Population With Baseline Blood Eosinophil <0.3 Giga/L
    End point description
    Analysis was performed on ITT population with baseline blood eosinophil count <0.3 Giga/L. Number of subjects analyzed = subjects of ITT population with baseline blood eosinophil count <0.3 Giga/L. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Post-hoc
    End point timeframe
    Baseline to Week 12
    End point values
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Number of subjects analysed
    90
    93
    85
    91
    92
    Units: Liter
    arithmetic mean (standard deviation)
        Baseline (n=90,93,85,91,92)
    1.79 ± 0.42
    1.9 ± 0.55
    1.79 ± 0.53
    1.85 ± 0.56
    1.94 ± 0.56
        Week 12 (n=71,87,79,79,81)
    1.92 ± 0.61
    2.12 ± 0.63
    2.02 ± 0.67
    2.05 ± 0.68
    2.06 ± 0.68
        Change from Baseline (n=71,87,79,79,81)
    0.09 ± 0.36
    0.19 ± 0.31
    0.23 ± 0.33
    0.16 ± 0.36
    0.17 ± 0.36
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 40) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths were treatment emergent AEs developed/worsened & deaths occurred during 'treatment-emergent period'(from first dose of study drug injection up to end of 16-week post-treatment period).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    Subjects exposed to Placebo (for Dupilumab) in combination with stable ICS/LABA therapy (mean exposure of 23 weeks).

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    Subjects exposed to Dupilumab 300 mg q2w in combination with stable ICS/LABA therapy (mean exposure of 23 weeks).

    Reporting group title
    Dupilumab 200 mg q2w
    Reporting group description
    Subjects exposed to Dupilumab 200 mg q2w in combination with stable ICS/LABA therapy (mean exposure of 23 weeks).

    Reporting group title
    Dupilumab 300 mg q4w
    Reporting group description
    Subjects exposed to Dupilumab 300 mg alternating with placebo q2w in combination with stable ICS/LABA therapy (mean exposure of 23 weeks).

    Reporting group title
    Dupilumab 200 mg q4w
    Reporting group description
    Subjects exposed to Dupilumab 200 mg alternating with placebo q2w in combination with stable ICS/LABA therapy (mean exposure of 23 weeks).

    Serious adverse events
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 158 (5.70%)
    13 / 156 (8.33%)
    10 / 148 (6.76%)
    16 / 157 (10.19%)
    6 / 150 (4.00%)
         number of deaths (all causes)
    0
    0
    0
    2
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    1 / 148 (0.68%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Neoplasm Of Thyroid Gland
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer Metastatic
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypergammaglobulinaemia Benign Monoclonal
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic Gastric Cancer
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    2 / 148 (1.35%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Prolapse
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bone Fissure
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Comminuted Fracture
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Intestinal Perforation
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    1 / 148 (0.68%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood Pressure Increased
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular Block Complete
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cor Pulmonale Acute
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 158 (2.53%)
    1 / 156 (0.64%)
    5 / 148 (3.38%)
    2 / 157 (1.27%)
    2 / 150 (1.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 5
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Organising Pneumonia
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    1 / 148 (0.68%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis Cholestatic
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermal Cyst
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 158 (0.63%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    1 / 148 (0.68%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 158 (0.00%)
    2 / 156 (1.28%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 158 (0.63%)
    0 / 156 (0.00%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    1 / 157 (0.64%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 158 (0.00%)
    1 / 156 (0.64%)
    0 / 148 (0.00%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 158 (0.00%)
    0 / 156 (0.00%)
    1 / 148 (0.68%)
    0 / 157 (0.00%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo q2w Dupilumab 300 mg q2w Dupilumab 200 mg q2w Dupilumab 300 mg q4w Dupilumab 200 mg q4w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 158 (55.70%)
    95 / 156 (60.90%)
    81 / 148 (54.73%)
    96 / 157 (61.15%)
    74 / 150 (49.33%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 158 (3.16%)
    11 / 156 (7.05%)
    4 / 148 (2.70%)
    7 / 157 (4.46%)
    3 / 150 (2.00%)
         occurrences all number
    7
    12
    4
    7
    3
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 158 (1.90%)
    6 / 156 (3.85%)
    1 / 148 (0.68%)
    9 / 157 (5.73%)
    3 / 150 (2.00%)
         occurrences all number
    3
    6
    1
    9
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 158 (12.66%)
    17 / 156 (10.90%)
    17 / 148 (11.49%)
    19 / 157 (12.10%)
    9 / 150 (6.00%)
         occurrences all number
    26
    21
    28
    32
    14
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    12 / 158 (7.59%)
    34 / 156 (21.79%)
    21 / 148 (14.19%)
    12 / 157 (7.64%)
    13 / 150 (8.67%)
         occurrences all number
    15
    130
    81
    25
    34
    Injection Site Oedema
         subjects affected / exposed
    1 / 158 (0.63%)
    8 / 156 (5.13%)
    4 / 148 (2.70%)
    0 / 157 (0.00%)
    2 / 150 (1.33%)
         occurrences all number
    2
    16
    15
    0
    3
    Injection Site Pain
         subjects affected / exposed
    7 / 158 (4.43%)
    14 / 156 (8.97%)
    7 / 148 (4.73%)
    6 / 157 (3.82%)
    5 / 150 (3.33%)
         occurrences all number
    18
    28
    16
    13
    8
    Injection Site Pruritus
         subjects affected / exposed
    5 / 158 (3.16%)
    12 / 156 (7.69%)
    10 / 148 (6.76%)
    0 / 157 (0.00%)
    3 / 150 (2.00%)
         occurrences all number
    7
    40
    25
    0
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 158 (5.70%)
    3 / 156 (1.92%)
    3 / 148 (2.03%)
    7 / 157 (4.46%)
    7 / 150 (4.67%)
         occurrences all number
    9
    3
    3
    7
    7
    Back Pain
         subjects affected / exposed
    6 / 158 (3.80%)
    12 / 156 (7.69%)
    8 / 148 (5.41%)
    4 / 157 (2.55%)
    7 / 150 (4.67%)
         occurrences all number
    6
    12
    8
    5
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    16 / 158 (10.13%)
    19 / 156 (12.18%)
    11 / 148 (7.43%)
    11 / 157 (7.01%)
    10 / 150 (6.67%)
         occurrences all number
    19
    21
    14
    14
    13
    Influenza
         subjects affected / exposed
    5 / 158 (3.16%)
    9 / 156 (5.77%)
    6 / 148 (4.05%)
    13 / 157 (8.28%)
    10 / 150 (6.67%)
         occurrences all number
    5
    9
    6
    14
    12
    Nasopharyngitis
         subjects affected / exposed
    15 / 158 (9.49%)
    16 / 156 (10.26%)
    15 / 148 (10.14%)
    19 / 157 (12.10%)
    9 / 150 (6.00%)
         occurrences all number
    18
    23
    18
    24
    15
    Pharyngitis
         subjects affected / exposed
    8 / 158 (5.06%)
    5 / 156 (3.21%)
    3 / 148 (2.03%)
    7 / 157 (4.46%)
    3 / 150 (2.00%)
         occurrences all number
    9
    5
    7
    8
    4
    Sinusitis
         subjects affected / exposed
    11 / 158 (6.96%)
    6 / 156 (3.85%)
    5 / 148 (3.38%)
    13 / 157 (8.28%)
    12 / 150 (8.00%)
         occurrences all number
    14
    7
    7
    14
    14
    Upper Respiratory Tract Infection
         subjects affected / exposed
    28 / 158 (17.72%)
    20 / 156 (12.82%)
    22 / 148 (14.86%)
    19 / 157 (12.10%)
    22 / 150 (14.67%)
         occurrences all number
    39
    29
    35
    26
    33

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2013
    Following changes were made: Increase in the total expected number of subjects from 600 to 750 subjects to have 300 subjects with HEos due to lower rate for HEos subjects than expected; reliever medication collection data was changed to specify the criterion for qualifying an asthma exacerbation event based on nebulizer use using the nebulizer-to-puff conversion factor for application to LOAC definition; permitted concomitant medications were changed to provide more information on the potential effect of dupilumab on cytochrome P450 (CYP450) and a list of CYP450 substrates with narrow therapeutic window and dose adjustment following the initiation and stopping of dupilumab; exclusion criteria was changed to minimize the impact on the primary endpoint, additional exclusion criteria were implemented for oral corticosteroids and methylxanthines prior to the screening period: pregnancy and breast-feeding were also added; dosing schedule was changed to provide additional instructions on the invetigational medicinal product (IMP) administration related to administration of loading dose and q2w injections; prohibited concomitant medication was changed to correct information for lipoxygenase inhibitor examples.

    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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