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    Clinical Trial Results:
    A Randomized, Double Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Dupilumab in Patients with Persistent Asthma

    Summary
    EudraCT number
    2014-004940-36
    Trial protocol
    GB   Outside EU/EEA   IT   DE   ES   PL   HU  
    Global end of trial date
    23 Nov 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    10 Apr 2019
    First version publication date
    07 Jun 2018
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Subject Disposition corrected. Baseline Characteristics corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13579
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02414854
    WHO universal trial number (UTN)
    U1111-1163-1293
    Other trial identifiers
    Study Name: LIBERTY ASTHMA QUEST
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001501-PIP02-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of dupilumab (SAR231893 [REGN668]) in subjects with persistent asthma.
    Protection of trial subjects
    Paediatric Subjects: The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anaesthesia may have been used to minimize distress and discomfort. Adult 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. The following applies to both Paediatric and Adult Subjects: 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
    Stable dose of medium to high dose inhaled corticosteroid (ICS) in combination with a second controller medication (for example; long-acting beta agonist [LABA], long-acting muscarinic antagonist [LAMA], leukotriene receptor antagonist [LTRA] and methylxanthines) for at least 1 month prior to screening and continued throughout the study. Use of a third controller medication was also allowed. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Apr 2015
    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
    Argentina: 156
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Brazil: 72
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Chile: 162
    Country: Number of subjects enrolled
    Colombia: 25
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Japan: 114
    Country: Number of subjects enrolled
    Korea, Republic of: 74
    Country: Number of subjects enrolled
    Mexico: 115
    Country: Number of subjects enrolled
    Poland: 96
    Country: Number of subjects enrolled
    Russian Federation: 123
    Country: Number of subjects enrolled
    South Africa: 61
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Turkey: 74
    Country: Number of subjects enrolled
    Ukraine: 181
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 423
    Worldwide total number of subjects
    1902
    EEA total number of subjects
    251
    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)
    107
    Adults (18-64 years)
    1544
    From 65 to 84 years
    251
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    4148 subjects were screened from Apr 2015-Sep 2016. 1902 were randomized at 321 centers/22 countries. 2246 were screen failures. 1897 subjects were treated; some received a different treatment than that assigned at randomization and for adverse event (AE) analysis were allocated to treatment actually received.

    Pre-assignment
    Screening details
    Randomization was stratified by age (<18 years, ≥18 years), blood eosinophil count (<0.3 Giga/L, ≥0.3 Giga/L), ICS dose level (medium, high), and country. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:2:1:1 ratio to Dupilumab 200 mg q2w, Dupilumab 300 mg q2w, Placebo (for 200 mg)q2w, Placebo (for 300 mg)q2w

    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 (for Dupilumab 200 mg) q2w
    Arm description
    2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection every 2 weeks (q2w) from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Dupilumab 200 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (1.14 mL) in the abdomen, upper thigh or upper arm.

    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 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    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 (1.14 mL of 175 mg/mL solution) in the abdomen, upper thigh or upper arm.

    Arm title
    Placebo (for Dupilumab 300 mg) q2w
    Arm description
    2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for Dupilumab 300 mg)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (2.0 mL) in the abdomen, upper thigh or upper arm.

    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 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    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 (2.0 mL of 150 mg/mL solution) in the abdomen, upper thigh or upper arm.

    Number of subjects in period 1
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Started
    317
    631
    321
    633
    Treated
    315
    629
    321
    632
    Completed
    295
    586
    301
    582
    Not completed
    22
    45
    20
    51
         Adverse event
             9
             7
             1
             12
         Poor compliance to protocol
             1
             1
             2
             2
         Other than specified above
             12
             37
             17
             37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (for Dupilumab 200 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection every 2 weeks (q2w) from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    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 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    Reporting group title
    Placebo (for Dupilumab 300 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    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 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    Reporting group values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w Total
    Number of subjects
    317 631 321 633 1902
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    21 34 18 34 107
        Adults (18-64 years)
    253 512 263 516 1544
        From 65-84 years
    43 85 40 83 251
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.2 ± 15.6 47.9 ± 15.3 48.2 ± 14.7 47.7 ± 15.6 -
    Gender categorical
    Units: Subjects
        Female
    198 387 218 394 1197
        Male
    119 244 103 239 705
    Race
    Units: Subjects
        Caucasian/White
    265 510 273 529 1577
        Black/of African descent
    14 33 12 21 80
        Asian/Oriental
    33 78 33 79 223
        American Indian or Alaska Native
    1 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    0 1 0 0 1
        Other
    4 9 3 4 20
    Ethnicity
    Units: Subjects
        Hispanic
    81 171 79 159 490
        Not Hispanic
    236 460 242 474 1412
    Blood Eosinophil Group
    Units: Subjects
        <0.15 Giga/L
    85 193 83 181 542
        ≥0.15 - <0.3 Giga/L
    84 173 95 175 527
        ≥0.3 Giga/L
    148 264 142 277 831
        Missing
    0 1 1 0 2
    ICS Dose Level
    Units: Subjects
        High
    172 317 167 323 979
        Medium
    144 310 151 303 908
        Low
    1 4 3 7 15

    End points

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    End points reporting groups
    Reporting group title
    Placebo (for Dupilumab 200 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection every 2 weeks (q2w) from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    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 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    Reporting group title
    Placebo (for Dupilumab 300 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    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 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    Primary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population

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    End point title
    Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: Intent-to-Treat (ITT) Population
    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 that included all randomized population analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    0.871 (0.724 to 1.048)
    0.456 (0.389 to 0.534)
    0.970 (0.810 to 1.160)
    0.524 (0.450 to 0.611)
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 1 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    954
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    Negative binomial regression model
    Parameter type
    Relative risk
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    0.68
    Notes
    [1] - Hierarchical testing procedure was used to control type I error rate at 0.05 level. The procedure included the 2 primary endpoints and the first 13 secondary endpoints reported and considered 2 pair-wise comparisons: Dupilumab 200 mg q2w vs Placebo (for Dupilumab 200 mg) q2w and Dupilumab 300 mg q2w vs Placebo (for Dupilumab 300 mg) q2w. Testing order is specified in analysis description.
    [2] - Hierarchical testing sequence performed continued only when previous endpoint was statistically significant at 0.05. Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 200 mg q2w vs Placebo (for 200 mg) q2w
    Statistical analysis description
    Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 3 of testing order.
    Comparison groups
    Dupilumab 200 mg q2w v Placebo (for Dupilumab 200 mg) q2w
    Number of subjects included in analysis
    948
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    Negative binomial regression model
    Parameter type
    Relative risk
    Point estimate
    0.523
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.413
         upper limit
    0.662
    Notes
    [3] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [4] - Threshold for significance at 0.05 level.

    Primary: Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: ITT Population

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12: 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liter
    arithmetic mean (standard deviation)
        Baseline (n=317,631,321,633)
    1.76 ± 0.61
    1.78 ± 0.62
    1.75 ± 0.57
    1.78 ± 0.60
        Week 12 (n=307,611,313,610)
    1.92 ± 0.70
    2.07 ± 0.76
    1.93 ± 0.68
    2.09 ± 0.70
        Change at Week 12 (n=307,611,313,610)
    0.15 ± 0.36
    0.28 ± 0.45
    0.18 ± 0.39
    0.31 ± 0.43
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using mixed-effect model with repeated measures (MMRM) model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 2 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    954
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001 [6]
    Method
    Mixed models analysis
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.18
    Notes
    [5] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [6] - Threshold for significance at 0.05 level.
    Statistical analysis title
    Dupilumab 200 mg q2w vs Placebo (for 200 mg) q2w
    Statistical analysis description
    Analysis was performed using MMRM model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 4 of testing order.
    Comparison groups
    Dupilumab 200 mg q2w v Placebo (for Dupilumab 200 mg) q2w
    Number of subjects included in analysis
    948
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.19
    Notes
    [7] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [8] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population

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    End point title
    Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: 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. Number of subjects analyzed=subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    307
    611
    313
    610
    Units: percent change
        arithmetic mean (standard deviation)
    10.16 ± 23.88
    18.74 ± 30.86
    11.87 ± 26.40
    20.89 ± 34.14
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis performed using MMRM model(n=954 for 300 vs placebo)with percent change from baseline in FEV1 values up to Week 12 as response variable; & treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value & baseline-by-visit interaction as covariates. Hierarchical testing procedure used to control type I error & handle multiple secondary endpoint analyses. Here, it is test no. 5 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    923
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.0001 [10]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    9.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.74
         upper limit
    13.07
    Notes
    [9] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [10] - Threshold for significance at 0.05 level.

    Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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    End point title
    Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.15 Giga/L
    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 ITT population with baseline eosinophil ≥0.15 Giga/L.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    232
    437
    237
    452
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    1.007 (0.814 to 1.245)
    0.445 (0.368 to 0.538)
    1.081 (0.879 to 1.329)
    0.434 (0.359 to 0.525)
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 6 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001 [12]
    Method
    Negative binomial regression model
    Parameter type
    Relative risk
    Point estimate
    0.402
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.307
         upper limit
    0.526
    Notes
    [11] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [12] - Threshold for significance at 0.05 level.

    Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L
    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 ITT population with baseline eosinophil ≥0.15 Giga/L. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    232
    437
    237
    452
    Units: liter
    arithmetic mean (standard deviation)
        Baseline (n=232,437,237,452)
    1.77 ± 0.63
    1.81 ± 0.63
    1.75 ± 0.55
    1.79 ± 0.59
        Change at Week 12 (n=224,425,229,434)
    0.17 ± 0.36
    0.34 ± 0.46
    0.21 ± 0.38
    0.35 ± 0.45
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using MMRM model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 7 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    689
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.0001 [14]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.21
    Notes
    [13] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [14] - Threshold for significance at 0.05 level.

    Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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    End point title
    Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil ≥0.3 Giga/L
    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 with baseline eosinophil ≥0.3 Giga/L.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    148
    264
    142
    277
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    1.081 (0.846 to 1.382)
    0.370 (0.289 to 0.475)
    1.236 (0.972 to 1.571)
    0.403 (0.317 to 0.512)
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 8 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001 [16]
    Method
    Negative binomial regression model
    Parameter type
    Relative risk
    Point estimate
    0.326
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.234
         upper limit
    0.454
    Notes
    [15] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [16] - Threshold for significance at 0.05 level.

    Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L
    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 ITT population with baseline eosinophil ≥0.3 Giga/L. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    148
    264
    142
    277
    Units: liter
    arithmetic mean (standard deviation)
        Baseline (n=148,264,142,277)
    1.78 ± 0.66
    1.81 ± 0.64
    1.73 ± 0.54
    1.75 ± 0.59
        Change at Week 12 (n=144,256,139,266)
    0.19 ± 0.39
    0.39 ± 0.45
    0.20 ± 0.40
    0.43 ± 0.43
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using MMRM model with change from baseline in FEV1 values up to Week 12 as response variable; and treatment, age, sex, baseline height, region, baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. Here, it is test no. 9 of testing order.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo (for Dupilumab 300 mg) q2w
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    < 0.0001 [18]
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    0.32
    Notes
    [17] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [18] - Threshold for significance at 0.05 level.

    Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L

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    End point title
    Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With Baseline Eosinophil <0.3 Giga/L
    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 with baseline eosinophil <0.3 Giga/L.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    169
    366
    178
    356
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    0.675 (0.515 to 0.884)
    0.512 (0.418 to 0.628)
    0.732 (0.562 to 0.954)
    0.610 (0.502 to 0.742)
    Statistical analysis title
    Dupilumab 300 mg q2w vs Placebo (for 300 mg) q2w
    Statistical analysis description
    Analysis was performed using negative binomial model with total number of events onset from randomization up to Week 52 or last contact date (whichever comes earlier) as response variable; with 4 treatment groups, age, region, baseline eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year prior to study as covariates; and log transformed standardized observation duration as an offset variable. Here, it is test no. 10 of testing order.
    Comparison groups
    Placebo (for Dupilumab 300 mg) q2w v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.2599 [20]
    Method
    Negative binomial regression model
    Parameter type
    Relative risk
    Point estimate
    0.834
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.608
         upper limit
    1.144
    Notes
    [19] - Testing according to the hierarchical testing procedure (performed only if previous endpoints were statistically significant).
    [20] - Threshold for significance at 0.05 level.

    Secondary: Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline

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    End point title
    Annualized Rate of Severe Exacerbation Events During The 52-Week Treatment Period: ITT Population With High Dose ICS at Baseline
    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 with high dose ICS at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    172
    317
    167
    323
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    1.040 (0.824 to 1.314)
    0.560 (0.455 to 0.690)
    1.038 (0.818 to 1.317)
    0.639 (0.523 to 0.780)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline
    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 with high dose ICS at baseline. Number of subjects analysed=subjects evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    167
    310
    162
    309
    Units: liter
        arithmetic mean (standard deviation)
    0.14 ± 0.34
    0.27 ± 0.42
    0.20 ± 0.40
    0.32 ± 0.43
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population

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    End point title
    Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ [S]) Self- Administered Global Score at Week 24: ITT Population
    End point description
    The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to subjects with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n=299,591,314,603)
    4.26 ± 1.02
    4.31 ± 1.08
    4.30 ± 1.03
    4.28 ± 1.05
        Week 24 (n=298,592,302,596)
    5.23 ± 1.07
    5.46 ± 1.12
    5.30 ± 1.15
    5.47 ± 1.09
        Change at Week 24 (n=281,560,295,569)
    0.95 ± 1.03
    1.13 ± 1.14
    1.02 ± 1.10
    1.17 ± 1.11
    No statistical analyses for this end point

    Secondary: Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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    End point title
    Change From Baseline in AQLQ (S) Self- Administered Global Score at Week 24: ITT Population With Baseline Eosinophil ≥0.3 Giga/L
    End point description
    The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to subjects with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. Analysis was performed on ITT population with baseline eosinophil ≥0.3 Giga/L. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    148
    264
    142
    277
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n=136,254,138,263)
    4.24 ± 0.98
    4.24 ± 1.11
    4.21 ± 0.97
    4.36 ± 1.05
        Change at Week 24 (n=129,241,130,244)
    0.97 ± 1.01
    1.39 ± 1.15
    1.02 ± 1.25
    1.30 ± 1.15
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population

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    End point title
    Change From Baseline in Asthma Control Questionnaire 5-item Version (ACQ-5) Score at Week 24: ITT Population
    End point description
    The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Subjects were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (n=317,631,321,633)
    2.71 ± 0.73
    2.76 ± 0.80
    2.77 ± 0.77
    2.77 ± 0.76
        Week 24 (n=296,590,297,585)
    1.67 ± 1.06
    1.33 ± 1.05
    1.58 ± 1.08
    1.37 ± 1.10
        Change at Week 24 (n=296,590,297,585)
    -1.06 ± 1.01
    -1.43 ± 1.05
    -1.19 ± 1.10
    -1.38 ± 1.10
    No statistical analyses for this end point

    Secondary: Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population

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    End point title
    Annualized Rate of Severe Exacerbation Events Resulting in Hospitalization or Emergency Room Visit During The 52-Week Treatment Period: ITT Population
    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 (resulted hospitalization or emergency room visit) that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: Exacerbation per subject-year
        number (confidence interval 95%)
    0.081 (0.049 to 0.135)
    0.043 (0.027 to 0.068)
    0.034 (0.017 to 0.066)
    0.025 (0.014 to 0.043)
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil <0.3 Giga/L
    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 ITT population with baseline eosinophil <0.3 Giga/L. Number of subjects analysed=subjects evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    163
    354
    173
    344
    Units: liter
        arithmetic mean (standard deviation)
    0.12 ± 0.32
    0.21 ± 0.43
    0.17 ± 0.39
    0.21 ± 0.41
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L

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    End point title
    Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.3 Giga/L
    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 with baseline eosinophil ≥0.3 Giga/L. Number of subjects analyzed=subjects evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    144
    256
    139
    266
    Units: percent change
        arithmetic mean (standard deviation)
    13.40 ± 27.01
    26.41 ± 33.69
    13.05 ± 25.27
    30.58 ± 38.22
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline

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    End point title
    Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With High Dose ICS at Baseline
    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 with high dose ICS at baseline. Number of subjects analysed=subjects evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    167
    310
    162
    309
    Units: percent change
        arithmetic mean (standard deviation)
    8.47 ± 20.94
    17.99 ± 28.43
    13.22 ± 26.52
    23.41 ± 37.26
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L

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    End point title
    Percent Change From Baseline in Pre-Bronchodilator FEV1 at Week 12: ITT Population With Baseline Eosinophil ≥0.15 Giga/L
    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 with baseline eosinophil ≥0.15 Giga/L. Number of subjects analyzed=subjects evaluable for this endpoint at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    224
    425
    229
    434
    Units: percent change
        arithmetic mean (standard deviation)
    11.43 ± 24.71
    22.04 ± 31.96
    13.49 ± 25.18
    24.04 ± 35.71
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

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    End point title
    Absolute Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liter
    arithmetic mean (standard deviation)
        Change at Week 2 (n=315,610,313,625)
    0.08 ± 0.35
    0.22 ± 0.38
    0.10 ± 0.34
    0.25 ± 0.40
        Change at Week 4 (n=307,613,311,614)
    0.13 ± 0.35
    0.24 ± 0.40
    0.13 ± 0.34
    0.27 ± 0.41
        Change at Week 8 (n=305,604,311,609)
    0.15 ± 0.38
    0.28 ± 0.42
    0.19 ± 0.40
    0.29 ± 0.43
        Change at Week 24 (n=300,599,296,596)
    0.13 ± 0.40
    0.31 ± 0.45
    0.19 ± 0.44
    0.30 ± 0.44
        Change at Week 36 (n=289,590,301,584)
    0.14 ± 0.41
    0.31 ± 0.48
    0.21 ± 0.42
    0.32 ± 0.45
        Change at Week 52 (n=240,477,250,488)
    0.12 ± 0.38
    0.31 ± 0.50
    0.20 ± 0.42
    0.32 ± 0.44
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: ITT Population

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    End point title
    Percent Change From Baseline in Pre-Bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52: 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Week 2 (n=315,610,313,625)
    5.78 ± 23.36
    14.32 ± 26.55
    6.60 ± 21.84
    17.38 ± 30.82
        Change at Week 4 (n=307,613,311,614)
    9.61 ± 25.54
    16.11 ± 28.12
    8.67 ± 23.55
    18.77 ± 32.73
        Change at Week 8 (n=305,604,311,609)
    10.27 ± 25.60
    18.81 ± 29.80
    12.24 ± 25.78
    19.85 ± 33.63
        Change at Week 24 (n=300,599,296,596)
    9.42 ± 26.76
    19.76 ± 30.64
    12.86 ± 28.14
    20.75 ± 35.35
        Change at Week 36 (n=289,590,301,584)
    10.57 ± 26.41
    19.92 ± 32.26
    13.45 ± 27.69
    22.08 ± 35.93
        Change at Week 52 (n=240,477,250,488)
    8.37 ± 23.59
    19.96 ± 33.35
    12.89 ± 27.70
    21.57 ± 34.08
    No statistical analyses for this end point

    Secondary: Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Percent Predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: percent predicted of FEV1
    arithmetic mean (standard deviation)
        Change at Week 2 (n=315,610,313,625)
    2.58 ± 11.36
    7.10 ± 12.28
    3.32 ± 10.98
    8.44 ± 13.20
        Change at Week 4 (n=307,613,311,614)
    4.55 ± 11.69
    7.92 ± 12.81
    4.13 ± 11.41
    9.20 ± 14.10
        Change at Week 8 (n=305,604,311,609)
    4.93 ± 12.30
    9.27 ± 13.13
    6.08 ± 12.55
    9.70 ± 14.15
        Change at Week 12 (n=307,611,313,610)
    5.02 ± 12.10
    9.22 ± 13.87
    5.90 ± 13.02
    10.28 ± 14.44
        Change at Week 24 (n=300,599,296,596)
    4.38 ± 12.85
    9.98 ± 13.94
    6.41 ± 14.02
    10.14 ± 14.75
        Change at Week 36 (n=289,590,301,584)
    5.09 ± 12.99
    10.12 ± 14.61
    6.82 ± 13.54
    10.94 ± 15.06
        Change at Week 52 (n=240,477,250,488)
    4.25 ± 12.06
    10.08 ± 14.79
    6.68 ± 13.56
    11.02 ± 14.59
    No statistical analyses for this end point

    Secondary: Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Morning (AM)/Evening (PM) Peak Expiratory Flow (PEF) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    The PEF is a subject’s maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at home (morning and evening) while sitting or standing prior to using any medication (if needed) for asthma. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liters/min
    arithmetic mean (standard deviation)
        AM: Change at Week 2 (n=314,620,320,630)
    4.19 ± 31.30
    15.21 ± 39.45
    3.45 ± 28.95
    14.46 ± 36.29
        AM: Change at Week 4 (n=313,619,319,625)
    6.23 ± 42.42
    21.81 ± 53.85
    5.55 ± 43.69
    19.67 ± 46.47
        AM: Change at Week 8 (n=308,614,318,613)
    7.42 ± 49.30
    25.70 ± 58.52
    12.22 ± 50.50
    23.18 ± 52.65
        AM: Change at Week 12 (n=305,608,314,608)
    9.85 ± 50.40
    27.81 ± 65.30
    14.23 ± 56.18
    25.88 ± 57.09
        AM: Change at Week 24 (n=299,590,305,588)
    5.55 ± 53.27
    28.71 ± 69.64
    15.43 ± 60.83
    23.74 ± 63.71
        AM: Change at Week 36 (n=289,576,297,564)
    3.24 ± 61.68
    31.19 ± 71.59
    12.57 ± 61.88
    23.93 ± 65.04
        AM: Change at Week 52 (n=270,544,282,529)
    2.85 ± 64.60
    29.86 ± 75.44
    10.99 ± 64.68
    26.67 ± 71.63
        PM: Change at Week 2 (n=313,617,319,629)
    3.33 ± 36.81
    13.80 ± 40.59
    3.87 ± 33.98
    11.35 ± 36.10
        PM: Change at Week 4 (n=312,617,319,623)
    5.01 ± 45.09
    17.94 ± 55.30
    2.73 ± 46.83
    14.90 ± 47.42
        PM: Change at Week 8 (n=308,613,315,610)
    2.82 ± 50.10
    21.06 ± 61.80
    7.68 ± 56.73
    17.26 ± 53.37
        PM: Change at Week 12 (n=306,606,311,605)
    3.24 ± 53.42
    19.75 ± 68.14
    8.52 ± 56.74
    18.70 ± 55.60
        PM: Change at Week 24 (n=299,583,300,585)
    -4.89 ± 55.07
    19.95 ± 71.50
    7.56 ± 63.25
    15.82 ± 61.91
        PM: Change at Week 36 (n=286,570,291,557)
    -6.75 ± 62.44
    21.79 ± 75.00
    2.64 ± 65.21
    14.35 ± 64.66
        PM: Change at Week 52 (n=269,526,268,523)
    -6.43 ± 62.82
    18.77 ± 77.37
    2.83 ± 67.01
    15.58 ± 72.51
    No statistical analyses for this end point

    Secondary: Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Forced Vital Capacity (FVC) at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC is the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liter
    arithmetic mean (standard deviation)
        Change at Week 2 (n=315,610,313,625)
    0.08 ± 0.42
    0.23 ± 0.44
    0.10 ± 0.37
    0.25 ± 0.46
        Change at Week 4 (n=307,613,311,614)
    0.12 ± 0.39
    0.26 ± 0.45
    0.12 ± 0.38
    0.27 ± 0.47
        Change at Week 8 (n=305,604,311,609)
    0.13 ± 0.41
    0.28 ± 0.45
    0.18 ± 0.42
    0.29 ± 0.50
        Change at Week 12 (n=307,611,313,610)
    0.13 ± 0.41
    0.29 ± 0.49
    0.18 ± 0.44
    0.29 ± 0.51
        Change at Week 24 (n=300,599,296,596)
    0.11 ± 0.45
    0.29 ± 0.48
    0.18 ± 0.46
    0.29 ± 0.51
        Change at Week 36 (n=289,590,301,584)
    0.11 ± 0.45
    0.30 ± 0.52
    0.19 ± 0.47
    0.31 ± 0.52
        Change at Week 52 (n=240,477,250,488)
    0.08 ± 0.45
    0.29 ± 0.53
    0.18 ± 0.45
    0.31 ± 0.50
    No statistical analyses for this end point

    Secondary: Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF25-75% is defined as the mean forced expiratory flow between the 25% and 75% of the FVC. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liters/sec
    arithmetic mean (standard deviation)
        Change at Week 2 (n=315,610,313,625)
    0.09 ± 0.40
    0.22 ± 0.47
    0.11 ± 0.44
    0.27 ± 0.48
        Change at Week 4 (n=307,613,311,614)
    0.16 ± 0.45
    0.24 ± 0.48
    0.15 ± 0.44
    0.29 ± 0.48
        Change at Week 8 (n=305,604,311,609)
    0.18 ± 0.45
    0.29 ± 0.52
    0.20 ± 0.49
    0.32 ± 0.51
        Change at Week 12 (n=307,611,313,610)
    0.18 ± 0.46
    0.30 ± 0.53
    0.19 ± 0.50
    0.35 ± 0.53
        Change at Week 24 (n=300,599,296,596)
    0.17 ± 0.47
    0.34 ± 0.57
    0.22 ± 0.56
    0.35 ± 0.54
        Change at Week 36 (n=289,590,301,584)
    0.18 ± 0.49
    0.35 ± 0.59
    0.22 ± 0.49
    0.36 ± 0.56
        Change at Week 52 (n=240,477,250,488)
    0.16 ± 0.50
    0.36 ± 0.63
    0.24 ± 0.55
    0.36 ± 0.55
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Post-Bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52: 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 ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: liter
    arithmetic mean (standard deviation)
        Change at Week 2 (n=310,609,311,617)
    -0.07 ± 0.31
    0.10 ± 0.37
    -0.04 ± 0.33
    0.09 ± 0.34
        Change at Week 4 (n=308,614,311,615)
    -0.02 ± 0.31
    0.10 ± 0.39
    -0.04 ± 0.36
    0.10 ± 0.36
        Change at Week 8 (n=305,607,305,604)
    -0.02 ± 0.31
    0.12 ± 0.40
    0.03 ± 0.35
    0.11 ± 0.37
        Change at Week 12 (n=305,610,313,612)
    -0.02 ± 0.33
    0.12 ± 0.40
    0.01 ± 0.35
    0.11 ± 0.38
        Change at Week 24 (n=302,599,302,601)
    -0.05 ± 0.36
    0.13 ± 0.43
    -0.01 ± 0.40
    0.10 ± 0.39
        Change at Week 36 (n=290,586,302,589)
    -0.03 ± 0.34
    0.12 ± 0.44
    0.01 ± 0.38
    0.11 ± 0.39
        Change at Week 52 (n=239,499,255,494)
    -0.08 ± 0.38
    0.12 ± 0.44
    -0.02 ± 0.39
    0.11 ± 0.40
    No statistical analyses for this end point

    Secondary: Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population

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    End point title
    Annualized Rate of Loss of Asthma Control (LOAC) Event During The 52-Week Treatment Period: ITT Population
    End point description
    LOAC was defined as any of the 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 ICS >=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.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: LOAC per subject-year
        number (confidence interval 95%)
    2.972 (2.573 to 3.432)
    1.853 (1.654 to 2.076)
    2.965 (2.572 to 3.420)
    1.740 (1.554 to 1.947)
    No statistical analyses for this end point

    Secondary: Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

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    End point title
    Time to First Severe Exacerbation Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population
    End point description
    The time to first severe exacerbation was defined as follows: date of the first event - randomization date +1. For subjects who had no event on or before Visit 18 (Week 52) or last contact date, the time was censored at the date of Visit 18 or the last contact date, whichever was earlier. The median time to first severe exacerbation was not estimated; therefore, the probability of severe exacerbation at Weeks 12, 24, 36, and 52, are presented as the descriptive statistics. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: probability of severe exacerbation
    number (confidence interval 95%)
        Probability at Week 12
    0.165 (0.127 to 0.209)
    0.094 (0.073 to 0.119)
    0.193 (0.152 to 0.238)
    0.137 (0.112 to 0.166)
        Probability at Week 24
    0.275 (0.227 to 0.326)
    0.177 (0.148 to 0.208)
    0.297 (0.247 to 0.347)
    0.211 (0.180 to 0.243)
        Probability at Week 36
    0.364 (0.311 to 0.418)
    0.235 (0.203 to 0.270)
    0.376 (0.322 to 0.428)
    0.268 (0.234 to 0.303)
        Probability at Week 52
    0.434 (0.378 to 0.489)
    0.295 (0.259 to 0.331)
    0.437 (0.382 to 0.491)
    0.325 (0.288 to 0.362)
    No statistical analyses for this end point

    Secondary: Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population

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    End point title
    Time to First LOAC Event: Kaplan-Meier Estimates During The 52-Week Treatment Period: ITT Population
    End point description
    The time to first LOAC event was defined as follows: date of the first event - first dose date +1. For subjects who had no event on or before last dose date + 14 days or last contact date, the time was censored at the last dose date + 14 days or the last contact date, whichever was earlier. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: days
        median (confidence interval 95%)
    110.0 (84.00 to 144.00)
    230.0 (187.00 to 276.00)
    102.0 (74.00 to 130.00)
    264.0 (207.00 to 319.00)
    No statistical analyses for this end point

    Secondary: Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population

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    End point title
    Change From Baseline in ACQ-5 Score at Weeks 2, 4, 8, 12, 36, and 52: ITT Population
    End point description
    The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Subjects were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n=304,599,305,615)
    -0.52 ± 0.85
    -0.88 ± 0.91
    -0.58 ± 0.97
    -0.89 ± 0.94
        Change at Week 4 (n=297,599,305,605)
    -0.76 ± 0.90
    -1.07 ± 0.98
    -0.77 ± 1.01
    -1.06 ± 1.01
        Change at Week 8 (n=301,595,310,593)
    -0.94 ± 0.96
    -1.26 ± 1.03
    -1.05 ± 1.04
    -1.24 ± 1.06
        Change at Week 12 (n=303,605,312,603)
    -0.98 ± 1.00
    -1.33 ± 1.03
    -1.09 ± 1.09
    -1.35 ± 1.06
        Change at Week 36 (n=285,583,299,572)
    -1.21 ± 1.01
    -1.50 ± 1.14
    -1.22 ± 1.09
    -1.52 ± 1.09
        Change at Week 52 (n=236,470,245,477)
    -1.07 ± 1.08
    -1.50 ± 1.05
    -1.25 ± 1.05
    -1.50 ± 1.08
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Asthma Control Questionnaire 7-item Version (ACQ-7) Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    The ACQ-7 has 7 questions, the first 5 questions assess the most common asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath and wheeze plus short-acting bronchodilator use, and FEV1 (pre-bronchodilator % predicted). Subjects were asked to recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). Clinic staff scored the FEV1% predicted on a 7-point scale. The questions were equally weighted and the ACQ-7 total score was mean of the scores of all 7 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n=304,599,305,615)
    -0.46 ± 0.70
    -0.79 ± 0.77
    -0.50 ± 0.80
    -0.82 ± 0.81
        Change at Week 4 (n=297,599,305,605)
    -0.65 ± 0.76
    -0.94 ± 0.85
    -0.65 ± 0.85
    -0.97 ± 0.87
        Change at Week 8 (n=301,595,310,593)
    -0.81 ± 0.80
    -1.11 ± 0.90
    -0.90 ± 0.89
    -1.12 ± 0.92
        Change at Week 12 (n=303,605,312,603)
    -0.85 ± 0.83
    -1.17 ± 0.90
    -0.92 ± 0.93
    -1.20 ± 0.92
        Change at Week 24 (n=296,590,297,585)
    -0.89 ± 0.91
    -1.25 ± 0.92
    -1.01 ± 0.96
    -1.22 ± 0.96
        Change at Week 36 (n=285,583,299,572)
    -1.04 ± 0.84
    -1.32 ± 1.01
    -1.05 ± 0.94
    -1.35 ± 0.95
        Change at Week 52 (n=236,470,245,477)
    -0.91 ± 0.92
    -1.32 ± 0.91
    -1.07 ± 0.91
    -1.34 ± 0.93
    No statistical analyses for this end point

    Secondary: Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Morning Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    Morning asthma symptom score was determined using AM (ante meridiem) symptom scoring system which evaluated subject’s overall asthma symptoms experienced during the night. It ranged from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning, no night-time 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n=314,624,321,631)
    -0.07 ± 0.43
    -0.18 ± 0.49
    -0.09 ± 0.49
    -0.15 ± 0.50
        Change at Week 4 (n=313,623,319,627)
    -0.16 ± 0.59
    -0.26 ± 0.59
    -0.16 ± 0.61
    -0.27 ± 0.64
        Change at Week 8 (n=308,620,318,615)
    -0.26 ± 0.64
    -0.40 ± 0.68
    -0.25 ± 0.62
    -0.37 ± 0.70
        Change at Week 12 (n=306,614,315,609)
    -0.30 ± 0.64
    -0.45 ± 0.71
    -0.30 ± 0.69
    -0.44 ± 0.72
        Change at Week 24 (n=302,602,306,592)
    -0.35 ± 0.69
    -0.52 ± 0.76
    -0.36 ± 0.73
    -0.50 ± 0.73
        Change at Week 36 (n=292,583,299,572)
    -0.38 ± 0.69
    -0.54 ± 0.81
    -0.38 ± 0.76
    -0.56 ± 0.77
        Change at Week 52 (n=275,553,286,540)
    -0.41 ± 0.71
    -0.55 ± 0.84
    -0.41 ± 0.78
    -0.60 ± 0.79
    No statistical analyses for this end point

    Secondary: Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Evening Asthma Symptom Score at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    Evening asthma symptom score was determined using PM (post meridiem) symptom scoring system which evaluated subject’s overall asthma symptoms experienced during the day. It ranged 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. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n=313,624,320,631)
    -0.05 ± 0.45
    -0.17 ± 0.48
    -0.06 ± 0.45
    -0.16 ± 0.52
        Change at Week 4 (n=313,623,319,628)
    -0.11 ± 0.59
    -0.27 ± 0.61
    -0.14 ± 0.58
    -0.29 ± 0.64
        Change at Week 8 (n=308,619,318,612)
    -0.24 ± 0.64
    -0.41 ± 0.70
    -0.22 ± 0.63
    -0.40 ± 0.70
        Change at Week 12 (n=307,612,314,606)
    -0.26 ± 0.66
    -0.45 ± 0.72
    -0.30 ± 0.68
    -0.46 ± 0.73
        Change at Week 24 (n=301,596,301,590)
    -0.33 ± 0.72
    -0.52 ± 0.78
    -0.36 ± 0.72
    -0.52 ± 0.73
        Change at Week 36 (n=289,576,292,566)
    -0.39 ± 0.73
    -0.56 ± 0.81
    -0.39 ± 0.75
    -0.56 ± 0.80
        Change at Week 52 (n=274,536,270,535)
    -0.41 ± 0.74
    -0.57 ± 0.84
    -0.42 ± 0.75
    -0.61 ± 0.78
    No statistical analyses for this end point

    Secondary: Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Number of Nocturnal Awakenings Per Night at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    Subjects recorded every morning on awakening the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: number of nocturnal awakenings/night
    arithmetic mean (standard deviation)
        Change at Week 2 (n=314,624,321,631)
    -0.06 ± 0.49
    -0.15 ± 0.55
    -0.04 ± 0.62
    -0.11 ± 0.67
        Change at Week 4 (n=313,623,319,627)
    -0.10 ± 0.61
    -0.19 ± 0.66
    -0.11 ± 0.70
    -0.20 ± 0.67
        Change at Week 8 (n=308,620,318,615)
    -0.18 ± 0.65
    -0.29 ± 0.72
    -0.17 ± 0.62
    -0.24 ± 0.72
        Change at Week 12 (n=306,614,315,609)
    -0.21 ± 0.66
    -0.33 ± 0.75
    -0.18 ± 0.67
    -0.28 ± 0.73
        Change at Week 24 (n=302,602,306,592)
    -0.23 ± 0.78
    -0.36 ± 0.81
    -0.26 ± 0.65
    -0.30 ± 0.73
        Change at Week 36 (n=292,583,299,572)
    -0.25 ± 0.74
    -0.34 ± 0.81
    -0.26 ± 0.71
    -0.36 ± 0.74
        Change at Week 52 (n=275,553,286,540)
    -0.24 ± 0.69
    -0.35 ± 0.88
    -0.26 ± 0.74
    -0.41 ± 0.78
    No statistical analyses for this end point

    Secondary: Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Number of Puffs of Daily Reliever Medication Used Per 24 Hours at Weeks 2, 4, 8, 12, 24, 36, and 52: ITT Population
    End point description
    Subjects might administered salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as needed during the study. The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations were recorded daily by the subjects in an electronic diary/peak expiratory flow (PEF) meter. In the case that Nebulizer solutions were used as an alternative delivery method, the nebulizer dose was converted to number of puffs as per following conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 4, 8, 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: Number of puffs of reliever medication
    arithmetic mean (standard deviation)
        Change at Week 2 (n=313,623,318,630)
    -0.21 ± 1.55
    -0.56 ± 1.96
    -0.10 ± 1.71
    -0.47 ± 1.91
        Change at Week 4 (n=312,622,319,626)
    -0.26 ± 2.19
    -0.68 ± 2.61
    -0.34 ± 3.42
    -0.73 ± 2.42
        Change at Week 8 (n=308,617,314,607)
    -0.50 ± 2.23
    -1.02 ± 2.86
    -0.65 ± 2.96
    -0.94 ± 2.86
        Change at Week 12 (n=306,610,310,603)
    -0.52 ± 2.28
    -1.23 ± 3.03
    -0.89 ± 3.06
    -1.08 ± 2.72
        Change at Week 24 (n=294,588,300,582)
    -0.77 ± 2.60
    -1.27 ± 3.05
    -0.99 ± 3.21
    -1.15 ± 2.83
        Change at Week 36 (n=285,564,287,558)
    -0.99 ± 2.49
    -1.30 ± 2.99
    -1.06 ± 3.57
    -1.23 ± 3.01
        Change at Week 52 (n=270,522,265,521)
    -0.90 ± 2.58
    -1.45 ± 3.33
    -1.12 ± 3.64
    -1.39 ± 2.97
    No statistical analyses for this end point

    Secondary: Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population

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    End point title
    Change From Baseline in AQLQ (S) Self-Administered Global Score at Weeks 12, 36, and 52: ITT Population
    End point description
    The AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that are most important to subjects with asthma. The AQLQ comprises of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item is scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=286,573,308,586)
    0.90 ± 0.97
    1.09 ± 1.03
    0.94 ± 1.01
    1.09 ± 1.09
        Change at Week 36 (n=271,554,295, 548)
    1.05 ± 1.08
    1.26 ± 1.17
    1.08 ± 1.16
    1.33 ± 1.15
        Change at Week 52 (n=224,465,243,459)
    1.00 ± 1.12
    1.28 ± 1.16
    1.02 ± 1.10
    1.34 ± 1.16
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Scores at Weeks 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Scores at Weeks 12, 24, 36, and 52: ITT Population
    End point description
    EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L-VAS records subject’s self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable). Analysis was performed on ITT population. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    317
    631
    321
    633
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Single Index: Change at Week 12(n=280,567,301,576)
    0.07 ± 0.17
    0.09 ± 0.18
    0.08 ± 0.18
    0.09 ± 0.18
        Single Index: Change at Week 24(n=275,552,292,559)
    0.07 ± 0.17
    0.09 ± 0.17
    0.08 ± 0.18
    0.08 ± 0.20
        Single Index: Change at Week 36(n=264,548,290,537)
    0.08 ± 0.19
    0.09 ± 0.20
    0.10 ± 0.18
    0.09 ± 0.20
        Single Index: Change at Week 52(n=220,457,238,448)
    0.07 ± 0.20
    0.10 ± 0.19
    0.08 ± 0.19
    0.10 ± 0.20
        VAS Score: Change at Week 12 (n=280,567,301,576)
    7.69 ± 17.43
    11.10 ± 18.90
    6.39 ± 20.42
    9.80 ± 19.56
        VAS Score: Change at Week 24 (n=275,552,292,559)
    8.33 ± 17.58
    11.44 ± 18.48
    8.59 ± 20.37
    9.21 ± 19.61
        VAS Score: Change at Week 36 (n=264,548,290,537)
    9.70 ± 18.24
    11.61 ± 19.09
    9.31 ± 20.09
    11.41 ± 19.40
        VAS Score: Change at Week 52 (n=220,457,238,448)
    8.35 ± 18.51
    12.98 ± 18.71
    9.52 ± 20.81
    11.90 ± 19.60
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Weeks 12, 24, 36, and 52: ITT Population

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    End point title
    Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Weeks 12, 24, 36, and 52: ITT Population
    End point description
    The HADS is a general scale to detect states of anxiety and depression already used and validated in asthma, which includes HADS-A and HADS-D subscales. The instrument is comprised of 14 items: 7 related to anxiety (HADS-A) and 7 to depression (HADS-D). Each item on the questionnaire is scored from 0-3. The anxiety/depression score is the sum of the scores of the 7 related items; one can score between 0 and 21 for either anxiety or depression. And the total score is the sum of the scores of the 14 items ranging from 0 (no symptoms) to 42 (severe symptoms), with higher scores indicating higher anxiety/depression complains. Analysis was performed on ITT population; 29 participants in Japan who received an incorrectly translated HADS questionnaire were excluded. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    311
    621
    317
    624
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=274,551,297,569)
    -2.11 ± 5.29
    -1.91 ± 5.65
    -1.55 ± 6.11
    -1.98 ± 5.89
        Change at Week 24 (n=270,537,286,552)
    -2.17 ± 5.71
    -1.93 ± 5.97
    -1.73 ± 6.36
    -1.88 ± 6.39
        Change at Week 36 (n=260,535,286,532)
    -2.52 ± 5.89
    -2.02 ± 6.34
    -2.67 ± 6.80
    -2.13 ± 6.67
        Change at Week 52 (n=213,443,234,438)
    -2.00 ± 6.29
    -2.36 ± 6.28
    -1.86 ± 6.79
    -2.17 ± 7.04
    No statistical analyses for this end point

    Secondary: Change From Baseline in 22-Item Sino Nasal Outcome Test (SNOT-22) Score at Weeks 12, 24, 36, and 52: ITT Population With Bilateral Nasal Polyposis/Chronic Rhinosinusitis

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    End point title
    Change From Baseline in 22-Item Sino Nasal Outcome Test (SNOT-22) Score at Weeks 12, 24, 36, and 52: ITT Population With Bilateral Nasal Polyposis/Chronic Rhinosinusitis
    End point description
    The SNOT-22 is a validated measure of health related quality of life in sinonasal disease. It is a 22 item questionnaire with each item assigned a score ranging from 0-5. The total score may range from 0 (no disease) -110 (worst disease), lower scores represent better health related quality of life. Analysis was performed on ITT population with bilateral nasal polyposis/chronic rhinosinusitis. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    63
    126
    70
    123
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=51,113,61,102)
    -6.82 ± 17.19
    -13.55 ± 16.85
    -11.30 ± 16.11
    -16.07 ± 20.54
        Change at Week 24 (n=52,111,58,102)
    -7.21 ± 17.10
    -14.68 ± 18.77
    -9.55 ± 16.04
    -17.41 ± 20.81
        Change at Week 36 (n=49,111,57,100)
    -6.10 ± 19.03
    -15.23 ± 18.20
    -8.51 ± 20.36
    -18.86 ± 21.34
        Change at Week 52 (n=42,89,49,85)
    -6.95 ± 17.10
    -15.78 ± 17.72
    -9.98 ± 18.01
    -19.81 ± 22.39
    No statistical analyses for this end point

    Secondary: Change From Baseline in Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, Ages 12+ (RQLQ[S]+12) Score at Weeks 12, 24, 36, and 52: ITT Population With Comorbid Allergic Rhinitis

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    End point title
    Change From Baseline in Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, Ages 12+ (RQLQ[S]+12) Score at Weeks 12, 24, 36, and 52: ITT Population With Comorbid Allergic Rhinitis
    End point description
    RQLQ(S)+12 is a self-administered questionnaire with standardized activities developed to measure health-related quality of life signs and symptoms that are most problematic in those 12 to 75 years of age, as a result of perennial or seasonal allergic rhinitis. There are 28 items on RQLQ(S) in 7 domains: activities (3 items), sleep (3 items), non-nose/eye symptoms (7 items), practical problems (3 items), nasal symptoms (4 items), eye symptoms (4 items) and emotional (4 items). RQLQ(S)+12 responses are based on 7-point likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). Individual items within RQLQ(S)+12 are equally weighted. The overall score is calculated as the mean score of all items. Higher scores indicated more health-related quality of life impairment (lower scores better). Analysis was performed on ITT population with comorbid allergic rhinitis. Here 'n' signifies number of subjects with available data for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, and 52
    End point values
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    194
    390
    214
    409
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=167,332,192,348)
    -0.50 ± 0.98
    -0.70 ± 0.99
    -0.44 ± 1.05
    -0.64 ± 1.06
        Change at Week 24 (n=164,322,182,342)
    -0.50 ± 0.92
    -0.73 ± 1.09
    -0.54 ± 1.10
    -0.60 ± 1.10
        Change at Week 36 (n=158,323,184,332)
    -0.56 ± 0.96
    -0.78 ± 1.15
    -0.58 ± 1.20
    -0.75 ± 1.12
        Change at Week 52 (n=129,263,149,274)
    -0.41 ± 0.97
    -0.90 ± 1.17
    -0.47 ± 1.33
    -0.76 ± 1.13
    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 64) or entry in the LTS12551 open-label extension study regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment emergent AEs that developed/worsened during ‘treatment-emergent period’ (from first dose of IMP until 98 days after last dose of IMP or entry in the LTS12551 study). Safety population: all subjects who received at least 1 dose or part of a dose of IMP, analyzed according to treatment that subjects actually received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo (for Dupilumab 200 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 2 subjects were excluded, who were randomized to this arm but received single injection of Dupilumab 200 mg q2w and 300 mg q2w, respectively.

    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 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 2 subject were included, who were randomized to Placebo (for Dupilumab 200 mg) arm and Dupilumab 300 mg arm, respectively but both received Dupilumab 200 mg.

    Reporting group title
    Placebo (for Dupilumab 300 mg) q2w
    Reporting group description
    2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.

    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 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines (second or third controller therapy). Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. 1 subject was excluded, who was randomized to this arm but received single injection of Dupilumab 200 mg q2w. 1 subject was included, who was randomized to Placebo (for Dupilumab 200 mg) arm but received Dupilumab 300 mg.

    Serious adverse events
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 313 (8.31%)
    51 / 631 (8.08%)
    28 / 321 (8.72%)
    56 / 632 (8.86%)
         number of deaths (all causes)
    3
    1
    0
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis Superficial
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Of Colon
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaplastic Thyroid Cancer
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 631 (0.32%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear Cell Renal Cell Carcinoma
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysplastic Naevus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangioblastoma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestine Carcinoma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    1 / 321 (0.31%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic Shock
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy Of Partner
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Victim Of Sexual Abuse
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Threatened
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic Pregnancy
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection Site Erythema
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection Site Inflammation
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection Site Oedema
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment Disorder With Depressed Mood
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical Cyst
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian Cyst
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax Traumatic
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-Traumatic Pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Thoracic Procedure Complication
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural Pneumothorax
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    2 / 321 (0.62%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Injury
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 631 (0.32%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Coronary Artery Disease
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Sickle Cell Anaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    10 / 313 (3.19%)
    11 / 631 (1.74%)
    5 / 321 (1.56%)
    7 / 632 (1.11%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 14
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilic Pneumonia Chronic
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal Oedema
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Polyps
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Noninfective Bronchitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Respiratory Depression
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal Detachment
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal Tear
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Volvulus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired Gastric Emptying
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Motility Disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Ulcer
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Strangulated Umbilical Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Infarct
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal Vein Thrombosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    2 / 321 (0.62%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polychondritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Primary Hyperaldosteronism
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    2 / 632 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Capnocytophaga Infection
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis A
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical Device Site Infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    2 / 321 (0.62%)
    4 / 632 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Cellulitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tick-Borne Viral Encephalitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    0 / 321 (0.00%)
    1 / 632 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 631 (0.00%)
    1 / 321 (0.31%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 631 (0.16%)
    0 / 321 (0.00%)
    0 / 632 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (for Dupilumab 200 mg) q2w Dupilumab 200 mg q2w Placebo (for Dupilumab 300 mg) q2w Dupilumab 300 mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    185 / 313 (59.11%)
    363 / 631 (57.53%)
    197 / 321 (61.37%)
    378 / 632 (59.81%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    16 / 313 (5.11%)
    31 / 631 (4.91%)
    16 / 321 (4.98%)
    34 / 632 (5.38%)
         occurrences all number
    17
    34
    16
    42
    Respiratory, thoracic and mediastinal disorders
    Rhinitis Allergic
         subjects affected / exposed
    16 / 313 (5.11%)
    21 / 631 (3.33%)
    15 / 321 (4.67%)
    18 / 632 (2.85%)
         occurrences all number
    22
    22
    16
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 313 (8.31%)
    47 / 631 (7.45%)
    25 / 321 (7.79%)
    40 / 632 (6.33%)
         occurrences all number
    34
    71
    37
    83
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    13 / 313 (4.15%)
    76 / 631 (12.04%)
    22 / 321 (6.85%)
    98 / 632 (15.51%)
         occurrences all number
    30
    329
    96
    353
    Injection Site Oedema
         subjects affected / exposed
    2 / 313 (0.64%)
    23 / 631 (3.65%)
    5 / 321 (1.56%)
    40 / 632 (6.33%)
         occurrences all number
    3
    65
    9
    119
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    16 / 313 (5.11%)
    30 / 631 (4.75%)
    7 / 321 (2.18%)
    25 / 632 (3.96%)
         occurrences all number
    16
    35
    8
    28
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    47 / 313 (15.02%)
    73 / 631 (11.57%)
    43 / 321 (13.40%)
    70 / 632 (11.08%)
         occurrences all number
    72
    98
    70
    104
    Influenza
         subjects affected / exposed
    29 / 313 (9.27%)
    36 / 631 (5.71%)
    22 / 321 (6.85%)
    38 / 632 (6.01%)
         occurrences all number
    35
    41
    28
    44
    Sinusitis
         subjects affected / exposed
    27 / 313 (8.63%)
    36 / 631 (5.71%)
    29 / 321 (9.03%)
    26 / 632 (4.11%)
         occurrences all number
    40
    43
    35
    34
    Upper Respiratory Tract Infection
         subjects affected / exposed
    37 / 313 (11.82%)
    70 / 631 (11.09%)
    48 / 321 (14.95%)
    77 / 632 (12.18%)
         occurrences all number
    57
    111
    77
    110
    Urinary Tract Infection
         subjects affected / exposed
    17 / 313 (5.43%)
    17 / 631 (2.69%)
    12 / 321 (3.74%)
    20 / 632 (3.16%)
         occurrences all number
    25
    20
    12
    22
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    60 / 313 (19.17%)
    121 / 631 (19.18%)
    64 / 321 (19.94%)
    112 / 632 (17.72%)
         occurrences all number
    76
    166
    104
    154

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2015
    It included following changes: - Stratification on ICS dose (medium/high) was added; - Number of randomization strata for age, eosinophil count was reduced.
    21 Sep 2015
    It included following changes: - The biomarkers were splitted into 3 subgroups; - The vaccine category considered for evaluation were limited; - Clinical handling of subjects with missed dose(s) of investigational medicinal product (IMP) was clarified; - Hepatitis/human immunodeficiency virus (HIV)/anti-nuclear antibody (ANA) test at Visit 17 was added for subjects who plan to participate in the open label extension (OLE) study; - hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test was added for subjects believed to be false positive for (hepatitis C virus) HBc antibody (Ab) or if the HBV serological status was unclear and HCV ribonucleic acid (RNA) was added for subjects believed to be false positive for HCV Ab at Visits 1 & 17; - The eligibility criteria regarding IMP compliance was deleted for OLE study; - Exclusion criteria regarding hepatitis and tuberculosis was modified; - Exclusion criteria regarding washout period of live attenuated vaccinations was modified; - Exclusion criteria on birth control for male subjects with a female partner of childbearing potential was modified; - Lactate dehydrogenase & differentiation in conjugated and non-conjugated bilirubin was added in case of total bilirubin above normal into serum chemistry panel; - Post-bronchodilator FEV1 at Visit 2 was added; - Spirometry operation requirement was clarified; - Table of handling procedures for dupilumab and anti-drug antibody (ADA) was removed; - Difference between withdrawal from IMP and withdrawal from the study and how this should be documented was clarified; - Local amendments 1 and 3 were incorporated into global protocol; - Lower limit of pre-bronchodilator FEV1 was removed in inclusion criteria for all subjects and the upper limit of pre-bronchodilator FEV1 was revised in inclusion criteria for adolescents to decrease screening failure rate and to adapt the criterion to adolescent values of pre-bronchodilator FEV1.
    09 Aug 2016
    It included following changes: Criteria for adverse event of special interest (AESI) was changed; - Study procedures were simplified for subjects who permanently discontinued the study; - Sampling times of ADA was changed, ADA response definitions were added; - Sample size and planned database lock date was modified; - Loading dose analysis was added; - The recognized controller classes were clarified; - Temporary and permanent treatment discontinuation criteria were clarified; - Hepatitis serology testing and interpretation of the results in context of eligibility criteria were clarified - Chest X-Ray or MRI (MRI for Germany only) at Visit 17 was introduced for subjects who plan to participate in the OLE study and if available chest imaging was over 12 months from entry into the open label extension study; - Height measurement was added for adolescents at each site visit for accurate calculation of spirometry parameters when doing spirometry; - Local amendments 5 and 6 were incorporated into global protocol.
    26 May 2017
    It included following changes: - Wording referring to the sample size was modified.

    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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