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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Severe Steroid Dependent Asthma

    Summary
    EudraCT number
    2015-001573-40
    Trial protocol
    NL   ES   BE   PL   HU  
    Global end of trial date
    13 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    18 May 2018
    First version publication date
    28 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13691
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02528214
    WHO universal trial number (UTN)
    U1111-1170-7152
    Other trial identifiers
    Study Name: LIBERTY ASTHMA VENTURE
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of dupilumab, compared with placebo, for reducing the use of maintenance oral corticosteroids (OCS) in subjects with severe steroid-dependent 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
    Oral corticosteroids (OCS [(prednisone or prednisolone]) therapy and stable high dose of inhaled corticosteroid (ICS) in combination with a second or third controller medication for at least 1 month prior to screening and continued throughout the study. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Oct 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
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Argentina: 17
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    210
    EEA total number of subjects
    92
    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)
    3
    Adults (18-64 years)
    179
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 68 centers in 17 countries. A total of 390 subjects were screened between October 2015 & April 2017, of which, 210 subjects were randomized & treated. 180 subjects were screen failure mainly due to exclusion criteria met & inclusion criteria not met. Assignment was done by Interactive Voice/Web Response System(IVRS/IWRS).

    Pre-assignment
    Screening details
    The screening period included an OCS optimization phase(up to 10 weeks)where subjects using OCS other than prednisone/prednisolone switched to these OCS. At the end of period, subjects were randomized in 1:1 ratio for dupilumab & placebo. Randomization was stratified by optimized OCS dose(=<10mg/day & >10mg/day) at randomization visit & by country.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo q2w
    Arm description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1, followed by a single injection every 2 weeks (q2w) for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo (for Dupilumab)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (2 ml) in the abdomen or 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, followed by a single 300 mg injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.
    Arm type
    Experimental

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

    Number of subjects in period 1
    Placebo q2w Dupilumab 300 mg q2w
    Started
    107
    103
    Treated
    107
    103
    Completed
    102
    101
    Not completed
    5
    2
         Adverse event
             4
             1
         Other than specified above
             1
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1, followed by a single injection every 2 weeks (q2w) for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.

    Reporting group values
    Placebo q2w Dupilumab 300 mg q2w Total
    Number of subjects
    107 103 210
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    2 1 3
        Adults (18-64 years)
    88 91 179
        From 65-84 years
    17 11 28
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.7 ± 12.8 51.9 ± 12.5 -
    Gender categorical
    Units: Subjects
        Female
    65 62 127
        Male
    42 41 83
    Race
    Units: Subjects
        Caucasian/White
    100 97 197
        Black/of African descent
    1 4 5
        Asian/Oriental
    2 0 2
        American Indian or Alaska Native
    2 0 2
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Other
    2 1 3
    Ethnicity
    Units: Subjects
        Hispanic
    22 23 45
        Not Hispanic
    85 80 165
    Baseline Blood Eosinophil Count
    Units: Subjects
        <0.15 Giga/L
    38 22 60
        >=0.15 - <0.3 Giga/L
    28 33 61
        >=0.3 Giga/L
    41 48 89
    Baseline Optimized Daily OCS Dose
    During screening period and before randomization, dose of OCS was adjusted in each subject to achieve the lowest OCS dose, also known as the optimized dose, required for management of the subject’s asthma. Subjects using OCS medications other than prednisone or prednisolone were switched to either of these corticosteroids at a dose clinically comparable to their current stable OCS dose. To optimize the OCS dose, investigators were instructed to adjust the OCS dose weekly according to a pre-specified titration schedule, based on changes in subject’s asthma control, and their clinical judgment.
    Units: mg/day
        arithmetic mean (standard deviation)
    11.75 ± 6.31 10.75 ± 5.90 -
    Daily OCS Dose at Visit 1 (i.e. preoptimization)
    Units: mg/day
        arithmetic mean (standard deviation)
    11.83 ± 6.02 11.79 ± 6.40 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    2 subcutaneous injections of Placebo (for Dupilumab) as a loading dose on Day 1, followed by a single injection every 2 weeks (q2w) for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1, followed by a single 300 mg injection q2w for 24 weeks in combination with OCS - (prednisone or prednisolone) and stable ICS. OCS dose was reduced according to a predetermined titration schedule every 4 weeks until week 20.

    Primary: Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control

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    End point title
    Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control
    End point description
    Percentage reduction of OCS dose was calculated from observed data as (optimized OCS dose at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. Analysis was performed on intent-to- treat (ITT) population which included randomized population analyzed according to the treatment group allocated by randomization regardless of whether the treatment kit was used or not. Here "n" = subjects with available data for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: mg/day
    arithmetic mean (standard deviation)
        Baseline (n= 107, 103)
    11.75 ± 6.31
    10.75 ± 5.90
        Week 24 (n= 106, 101)
    6.32 ± 6.75
    3.13 ± 5.44
        Percent reduction at Week 24 (n= 106, 101)
    45.28 ± 50.73
    73.85 ± 39.78
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    The endpoint was analyzed using analysis of covariance (ANCOVA) model which included percentage reduction of OCS dose at Week 24 as the response variable, and treatment group, baseline eosinophil level, optimized OCS dose at baseline, region as covariates. Missing data was imputed using a pattern mixture model by multiple imputation approach.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    28.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    15.81
         upper limit
    40.67
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoints are reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only the primary and the first 4 secondary endpoints were included in the procedure.
    [2] - Threshold for significance at two-sided 0.05 level. LS mean difference represents reduction difference i.e. dupilumab - placebo.

    Secondary: Percentage of Subjects Achieving >= 50% Reduction in Oral Corticosteroids dose at Week 24 While Maintaining Asthma Control

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    End point title
    Percentage of Subjects Achieving >= 50% Reduction in Oral Corticosteroids dose at Week 24 While Maintaining Asthma Control
    End point description
    Subjects were classified according to the binary status of whether or not the 50% OCS dose reduction criterion was achieved at week 24. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: percentage of subjects
        number (not applicable)
    53.3
    79.6
    Statistical analysis title
    Dupilumab 300 mg q2w vs. Placebo q2w
    Statistical analysis description
    The endpoint was analyzed using a logistic regression model. The model included the binary status of whether or not a subject achieved the 50% OCS dose reduction criterion as the response variable, and treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.06
         upper limit
    7.67
    Notes
    [3] - Testing was performed according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
    [4] - Threshold for significance at 0.05.

    Secondary: Percentage of Subjects Achieving a Reduction in Oral Corticosteroids dose to <5 mg/day at Week 24 While Maintaining Asthma Control

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    End point title
    Percentage of Subjects Achieving a Reduction in Oral Corticosteroids dose to <5 mg/day at Week 24 While Maintaining Asthma Control
    End point description
    Subjects were classified according to the binary status of whether or not the reduction of OCS dose to <5 mg/day was achieved at week 24. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: percentage of subjects
        number (not applicable)
    37.4
    71.8
    Statistical analysis title
    Dupilumab 300 mg q2w vs. Placebo q2w
    Statistical analysis description
    The endpoint was analyzed using a logistic regression model. The model included the binary status of whether or not a subject achieved a reduction of OCS dose to <5 mg/day at Week 24 as the response variable, treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    < 0.0001 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.39
         upper limit
    8.39
    Notes
    [5] - Testing was performed according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
    [6] - Threshold for significance at 0.05.

    Secondary: Percentage of Subjects Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control

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    End point title
    Percentage of Subjects Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control
    End point description
    For all subjects except those with baseline OCS dose at 35 mg/day, the maximum possible reduction corresponds to reduction to 0 mg/day (no longer requiring OCS). For subjects starting with 35 mg/day at baseline, the maximum possible reduction is 32.5 mg/day (i.e., minimum dose per protocol is 2.5 mg). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: percentage of subjects
        number (not applicable)
    29.9
    52.4
    Statistical analysis title
    Dupilumab 300 mg q2w vs. Placebo q2w
    Statistical analysis description
    The endpoint was analyzed using a logistic regression model. The model included binary status of whether or not a subject achieved their maximum possible reduction of OCS dose per protocol at Week 24 as the response variable, treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed by using a pattern mixture model by multiple imputation approach.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.0024 [8]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    4.73
    Notes
    [7] - Testing was performed according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
    [8] - Threshold for significance at 0.05.

    Secondary: Percentage of Subjects Who No Longer Require Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

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    End point title
    Percentage of Subjects Who No Longer Require Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control
    End point description
    Subjects were classified according to the binary status of whether or not the subject still requires OCS at week 24 while maintaining asthma control. Analysis was performed on ITT population with baseline OCS dose less than or equal to 30 mg/day. Here, Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    106
    103
    Units: percentage of subjects
        number (not applicable)
    29.2
    52.4
    Statistical analysis title
    Dupilumab 300 mg q2w vs. Placebo q2w
    Statistical analysis description
    The endpoint was analyzed using a logistic regression model. The model included the binary status of whether or not a subject no longer required OCS at Week 24 as the response variable, and treatment groups, optimized OCS dose at baseline, regions, and baseline eosinophil level subgroups as covariates. Missing data was imputed using a pattern mixture model by multiple imputation approach.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo q2w
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.0015 [10]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.47
         upper limit
    5.1
    Notes
    [9] - Testing was performed according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant).
    [10] - Threshold for significance at 0.05.

    Secondary: Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control

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    End point title
    Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control
    End point description
    Analysis was performed on ITT population but not included in the hierarchical testing procedure. Here, "n"= subjects with available data for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: mg/day
    arithmetic mean (standard deviation)
        Baseline (n= 107, 103)
    11.75 ± 6.31
    10.75 ± 5.90
        Week 24 (n= 106, 101)
    6.32 ± 6.75
    3.13 ± 5.44
        Absolute reduction at Week 24 (n= 106, 101)
    5.45 ± 6.80
    7.66 ± 6.10
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24

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    End point title
    Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24
    End point description
    The ACQ-5 has 5 questions, reflecting top-scoring 5 asthma symptoms: woken at night by symptoms, wake in mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Subjects were asked to recall how their asthma had been during previous week and to respond to each of 5 symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of 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= subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and at Weeks 2, 4, 8, 12, 16, 20, and 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 2 (n= 102, 95)
    -0.18 ± 0.67
    -0.49 ± 0.86
        Change at Week 4 (n= 103, 93)
    -0.36 ± 0.81
    -0.61 ± 1.01
        Change at Week 8 (n= 104, 96)
    -0.39 ± 1.13
    -0.68 ± 1.06
        Change at Week 12 (n= 101, 96)
    -0.54 ± 1.17
    -0.92 ± 1.09
        Change at Week 16 (n= 104, 95)
    -0.57 ± 1.05
    -0.87 ± 1.18
        Change at Week 20 (n= 102, 97)
    -0.53 ± 1.09
    -0.83 ± 1.19
        Change at Week 24 (n= 99, 96)
    -0.57 ± 1.19
    -0.94 ± 1.22
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12 and Week 24

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    End point title
    Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12 and Week 24
    End point description
    AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that were most important to subjects with asthma. AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item was scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire were 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= subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (105, 98)
    0.56 ± 1.08
    0.78 ± 1.09
        Change at Week 24 (100, 98)
    0.56 ± 0.97
    0.94 ± 1.17
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Scores at Week 12 and Week 24

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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 Week 12 and Week 24
    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. 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”=subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: score on a scale
    arithmetic mean (standard deviation)
        Single Index: Change at Week 12 (n= 105, 98)
    0.04 ± 0.20
    0.03 ± 0.17
        Single Index: Change at Week 24 (n= 100, 98)
    0.05 ± 0.18
    0.05 ± 0.18
        VAS Score: Change at Week 12 (n=105,98)
    5.99 ± 16.85
    9.34 ± 18.20
        VAS Score: Change at Week 24 (n=100,98)
    4.16 ± 16.74
    11.06 ± 17.60
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 12 and Week 24

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    End point title
    Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 12 and Week 24
    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. 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. Here "n" signifies number of subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    107
    103
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n=105, 98)
    -0.75 ± 5.50
    -2.13 ± 5.32
        Change at Week 24 (n= 100, 98)
    -0.99 ± 5.36
    -2.53 ± 5.98
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Sino Nasal Outcome Test-22 (SNOT-22) Global Score at Week 12 and Week 24

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    End point title
    Change From Baseline in Sino Nasal Outcome Test-22 (SNOT-22) Global Score at Week 12 and Week 24
    End point description
    The SNOT-22 is a validated measure of health related quality of life in sino nasal 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" = subjects with available data for specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Placebo q2w Dupilumab 300 mg q2w
    Number of subjects analysed
    41
    31
    Units: score on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 38, 29)
    -3.79 ± 21.34
    -12.45 ± 17.10
        Change at Week 24 (n= 37, 27)
    -2.46 ± 19.11
    -14.56 ± 15.89
    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 36) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs were treatment emergent AEs developed/worsened occurred during 'treatment-emergent period'(from first dose of study drug injection up to end of 12 weeks post-treatment period) or entry in the LTS12551 study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo q2w
    Reporting group description
    Subjects who received Placebo (for Dupilumab) in combination with OCS and stable ICS (mean exposure of 24 weeks).

    Reporting group title
    Dupilumab 300mg q2w
    Reporting group description
    Subjects who received Dupilumab 300 mg q2w in combination with OCS and stable ICS (mean exposure of 24 weeks).

    Serious adverse events
    Placebo q2w Dupilumab 300mg q2w
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 107 (5.61%)
    9 / 103 (8.74%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Acetabulum Fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign Body Aspiration
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 107 (2.80%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic Crisis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo q2w Dupilumab 300mg q2w
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 107 (28.04%)
    29 / 103 (28.16%)
    Investigations
    Eosinophil Count Increased
         subjects affected / exposed
    0 / 107 (0.00%)
    7 / 103 (6.80%)
         occurrences all number
    0
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 107 (5.61%)
    7 / 103 (6.80%)
         occurrences all number
    7
    7
    Sinusitis
         subjects affected / exposed
    4 / 107 (3.74%)
    7 / 103 (6.80%)
         occurrences all number
    5
    9
    Influenza
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 103 (2.91%)
         occurrences all number
    6
    3
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 107 (17.76%)
    9 / 103 (8.74%)
         occurrences all number
    23
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2016
    Following changes were made: - Added instructions to allow the investigator to stop the downward titration of OCS in case of a safety concern; - Modified the forced expiratory volume in 1 second (FEV1) inclusion criteria for screening period and prior to randomization; - Deleted the exclusion criteria on birth control for male subjects with a female partner of childbearing potential; - Modification of the definition of the adverse events of special interest (AESIs) for infections, opportunistic infections, and the reporting requirements for systemic allergic reactions related to IMP and requiring treatment; - Updated the list of controller medications; - Modified the criteria for temporary treatment discontinuation to include infection and infestation that do not respond to medical treatment and updated the list of criteria for permanent treatment discontinuation to be consistent with changes to AESI criteria; - Provided clarification of hepatitis serology testing and interpretation of the results in context of eligibility criteria; - Added chest X-Ray or magnetic resonance imaging (MRI) at Visit 10 for subjects who planned to roll over into a long term study.
    25 Jan 2017
    Following changes were made: Increased the number of subjects to be enrolled from 150 to 180.

    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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