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    Clinical Trial Results:
    An Exploratory, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Dupilumab on Airway Inflammation of Adults With Persistent Asthma

    Summary
    EudraCT number
    2015-001572-22
    Trial protocol
    DE   GB   SE   DK  
    Global end of trial date
    03 Jan 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Feb 2019
    First version publication date
    04 Jan 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Data and description for endpoint #8 (Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12) was updated

    Trial information

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    Trial identification
    Sponsor protocol code
    PDY14192
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02573233
    WHO universal trial number (UTN)
    U1111-1170-7168
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of dupilumab, compared to placebo, on airway inflammation in subjects with persistent asthma
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    42
    EEA total number of subjects
    15
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    42
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 16 sites in 6 countries . A total of 133 subjects were screened between January 2016 and January 2018. Of which, 42 subjects were randomized. 91 subjects were screen failures mainly due to exclusion criteria met and inclusion criteria not met.

    Pre-assignment
    Screening details
    Subjects were randomized in 1:1 ratio to receive dupilumab 300 mg every 2 weeks (q2w) and placebo q2w by using Interactive Voice/Web Response System (IVRS). Randomization was stratified by inhaled corticosteroids (ICS) dose (medium and high) and region (North America and Europe).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (2 mL) in abdomen (avoiding navel and waist areas), the upper thighs or the upper arms.

    Arm title
    Dupilumab
    Arm description
    Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.
    Arm type
    Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    REGN668
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection (2 mL) in abdomen (avoiding navel and waist areas), the upper thighs or the upper arms.

    Number of subjects in period 1
    Placebo Dupilumab
    Started
    22
    20
    Completed
    22
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Reporting group title
    Dupilumab
    Reporting group description
    Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Reporting group values
    Placebo Dupilumab Total
    Number of subjects
    22 20 42
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.0 ± 10.3 45.5 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    8 13 21
        Male
    14 7 21
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1 2
        Not Hispanic or Latino
    21 19 40
        Unknown or Not Reported
    0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 1 1
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    3 3 6
        White
    19 16 35
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Baseline Eosinophils Count in Bronchial Tissue
    Inflammatory cells i.e. eosinophils were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Data is reported for 40 subjects (Placebo: 21 subjects and Dupilumab: 19 subjects).
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    12.97 (9.91 to 21.24) 34.96 (10.07 to 263.75) -
    Baseline Mast Cells Count (Chymase Positive) in Bronchial Tissue
    Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    74.36 ± 58.63 79.17 ± 68.07 -
    Baseline Mast Cells Count (Tryptase Positive) in Bronchial Tissue
    Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Data is reported for 41 subjects (Placebo: 22 subjects and Dupilumab: 19 subjects).
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    80.10 ± 64.92 105.53 ± 104.68 -
    Baseline Total T-Lymphocytes Count in Bronchial Tissue
    T-Lymphocytes i.e. CD3 positive cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Data is reported for 41 subjects (Placebo: 22 subjects and Dupilumab: 19 subjects).
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    301.09 (121.01 to 500.43) 153.33 (83.81 to 192.40) -
    Baseline T-Helper Lymphocytes Count in Bronchial Tissue
    T-helper i.e. CD4 positive lymphocytes were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Data is reported for 41 subjects (Placebo: 22 subjects and Dupilumab: 19 subjects).
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    237.10 (190.17 to 511.48) 200.85 (102.49 to 398.08) -
    Baseline Mucin-Stained Area in Bronchial Tissue
    Mucin was identified by staining with Alcian-blue periodic acid-Schiff and/or immunostaining for MUC5AC and then the mucin-positive area was measured and expressed per square millimeter. Data is reported for 41 subjects (Placebo: 22 subjects and Dupilumab: 19 subjects).
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    561.12 ± 289.00 520.57 ± 511.69 -
    Baseline Fractional exhaled nitric oxide (FeNO)
    FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyser using a flow rate of 50 mL/s, and reported in ppb.
    Units: parts per billion (ppb)
        arithmetic mean (standard deviation)
    41.2 ± 31.5 36.4 ± 22.8 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Reporting group title
    Dupilumab
    Reporting group description
    Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Primary: Change From Baseline in Eosinophils Cells Count in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in Eosinophils Cells Count in the Bronchial Submucosa at Week 12
    End point description
    Inflammatory cells i.e. eosinophils were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Analysis was performed on pharmacodynamic (PD) population which consisted of all randomized subjects who underwent baseline and Week 12/end of treatment (EOT) bronchoscopies and have adequate biopsies for analysis at both baseline and EOT. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    20
    17
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    5.80 (-9.18 to 33.41)
    -6.04 (-174.71 to 19.41)
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84 [1]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [1] - Threshold for significance at 0.05 level.

    Primary: Change From Baseline in Mast Cells Count (Chymase Positive) in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in Mast Cells Count (Chymase Positive) in the Bronchial Submucosa at Week 12
    End point description
    Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Analysis was performed on PD population. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    20
    17
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    -14.80 ± 76.52
    1.76 ± 62.41
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a linear fixed-effect model with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4795 [2]
    Method
    Linear fixed-effect model
    Parameter type
    LS Mean Difference
    Point estimate
    13.89
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -19
         upper limit
    46.78
    Notes
    [2] - Threshold for significance at 0.05 level.

    Primary: Change From Baseline in Mast Cells Count (Tryptase Positive) in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in Mast Cells Count (Tryptase Positive) in the Bronchial Submucosa at Week 12
    End point description
    Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Analysis was performed on PD population. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    21
    17
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    2.37 ± 90.20
    -20.89 ± 59.09
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a linear fixed-effect model with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4494 [3]
    Method
    Linear fixed-effect model
    Parameter type
    LS mean difference
    Point estimate
    -18.98
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -60.92
         upper limit
    22.97
    Notes
    [3] - Threshold for significance at 0.05 level.

    Primary: Change From Baseline in T-Lymphocytes Count in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in T-Lymphocytes Count in the Bronchial Submucosa at Week 12
    End point description
    T-Lymphocytes i.e. CD3 positive cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Analysis was performed on PD population. Here, number of subjects analysed = subjects with available data for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    20
    16
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    -36.70 (-200.25 to 267.51)
    34.21 (-95.08 to 232.99)
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region.
    Comparison groups
    Placebo v Dupilumab
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6865 [4]
    Method
    Rank Ancova
    Confidence interval
    Notes
    [4] - Threshold for significance at 0.05 level.

    Primary: Change From Baseline in T-Helper Lymphocytes Count in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in T-Helper Lymphocytes Count in the Bronchial Submucosa at Week 12
    End point description
    T-helper i.e. CD4 positive lymphocytes were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. Analysis was performed on PD population. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    20
    16
    Units: cells/mm^2
        median (inter-quartile range (Q1-Q3))
    7.26 (-179.43 to 224.96)
    62.34 (-100.62 to 159.09)
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7588 [5]
    Method
    Rank ANCOVA
    Confidence interval
    Notes
    [5] - Threshold for significance at 0.05 level.

    Primary: Change From Baseline in Mucin-Stained Area in the Bronchial Submucosa at Week 12

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    End point title
    Change From Baseline in Mucin-Stained Area in the Bronchial Submucosa at Week 12
    End point description
    Mucin was identified by staining with Alcian-blue periodic acid-Schiff and/or immunostaining for MUC5AC and then the mucin-positive area was measured and expressed per square millimeter. Analysis was performed on PD population. Here, number of subjects analysed = subjects with available data for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    20
    16
    Units: cells/mm^2
        arithmetic mean (standard deviation)
    64.09 ± 391.96
    -142.74 ± 477.89
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using linear fixed-effect model on log-transformed data, with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate.
    Comparison groups
    Placebo v Dupilumab
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0336 [6]
    Method
    Linear fixed-effect model
    Parameter type
    LS Mean Difference
    Point estimate
    -235.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -414.19
         upper limit
    -55.84
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 12

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    End point title
    Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 12
    End point description
    FeNO is a surrogate marker for airway inflammation. FeNO was analysed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb. Analysis was performed on secondary PD population which consisted of all randomized and treated subjects. Here, number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    21
    18
    Units: ppb
        arithmetic mean (standard deviation)
    3.9 ± 22.8
    -15.1 ± 18.3
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a Mixed-effect Model with Repeated Measures (MMRM) with treatment, treatment-by-visit interaction, region, and ICS dose level as fixed effects, and baseline biomarker-by-visit interaction as fixed covariate, and assuming an unstructured covariance structure separately by treatment group.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012 [7]
    Method
    MMRM
    Parameter type
    LS Mean Difference
    Point estimate
    -22.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -32.9
         upper limit
    -11.9
    Notes
    [7] - Threshold for significance at 0.05 level.

    Secondary: Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12

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    End point title
    Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12
    End point description
    FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s, and reported in ppb. The average change in FeNO from baseline to Week 6 through Week 12 was calculated as follows: For each participant the change in FeNO from Baseline to Week 6, Week 8, Week 10 and Week 12 was calculated (value at Week X - value at baseline). Subsequently the weekly mean of these 4"change from baseline" values was determined (Weeks 6, 8, 10 and 12). Using these weekly mean values the overall arithmetic mean and standard deviation of the average change in FeNO from baseline to Week 6 through Week 12 was calculated.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6 through Week 12
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    22
    20
    Units: ppb
        arithmetic mean (standard deviation)
    3.5 ± 18
    -16 ± 18
    Statistical analysis title
    Dupilumab vs. Placebo
    Statistical analysis description
    Analysis was performed using a Mixed-effect model with Repeated Measures with treatment (MRMM) with treatment, treatment-by-visit interaction, region, and ICS dose level as fixed effects, and baseline biomarker-by-visit interaction as fixed covariate, and assuming an unstructured covariance structure separately by treatment group.
    Comparison groups
    Dupilumab v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005 [8]
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -22
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -31.3
         upper limit
    -12.8
    Notes
    [8] - Threshold for significance at 0.05 level.

    Secondary: Number of Subjects With Antidrug Antibodies (ADA)

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    End point title
    Number of Subjects With Antidrug Antibodies (ADA)
    End point description
    Anti-drug antibodies were detected using a validated immunoassay. Incidence of ADA were classified as following: 1) Pre-existing immunoreactivity - an ADA positive response in the assay at baseline with all post treatment ADA results negative or an ADA positive response at baseline with all post treatment ADA responses less than 4-fold over baseline titer levels. 2) Treatment-emergent ADA: an ADA positive response in the assay post first dose, when baseline results were negative or missing. 3) Treatment-boosted ADA: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive. Analysis was performed on ADA population which consisted of all subjects with at least one qualified ADA result in the ADA assay following the first dose of the study medication.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 24 weeks
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    21
    19
    Units: subjects
    number (not applicable)
        With pre-existing immunoreactivity
    1
    0
        With treatment-emergent ADA
    0
    1
        With treatment-boosted ADA
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) Assessment: Serum Functional Dupilumab Concentration

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    End point title
    Pharmacokinetics (PK) Assessment: Serum Functional Dupilumab Concentration [9]
    End point description
    Serum functional dupilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method. Analysis was performed on PK population which consisted of all subjects with at least one non-missing and eligible post-baseline dupilumab serum concentration data. Here, "n" represents number of subjects with available data for specified time points. Data for this endpoint were not planned to be analysed for placebo arm.
    End point type
    Secondary
    End point timeframe
    Week 0, Week 2, 6, 8, 12, 18, End of study (Week 24)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint were not planned to be analysed for placebo arm.
    End point values
    Dupilumab
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 0 (n= 20)
    0.00 ± 0.00
        Week 2 (n= 20)
    52675.00 ± 23107.55
        Week 6 (n= 20)
    59969.00 ± 27422.27
        Week 8 (n= 20)
    61097.95 ± 29775.23
        Week 12 (n= 20)
    67387.00 ± 32800.44
        Week 18 (n= 6)
    20728.17 ± 17718.93
        Week 24 (n= 5)
    1851.20 ± 2796.78
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
    End point description
    Adverse event (AE) was defined as any untoward medical occurrence in a subject who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during the interval between the first administration of study medication and the end of the 12 week Post-treatment Period. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs. Analysis was performed on safety population which consisted of all subjects randomized and exposed to study medication, regardless of the amount of treatment administered.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    Placebo Dupilumab
    Number of subjects analysed
    22
    20
    Units: subjects
    number (not applicable)
        Any TEAE
    17
    15
        Any treatment emergent SAE
    0
    1
        Any TEAE leading to death
    0
    0
        Any TEAE leading to permanent discontinuation
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were collected from signature of the informed consent form up to the end of study (i.e. up to the end of Post-treatment period [Week 24]) regardless of seriousness or relationship to investigational medicinal product (IMP).
    Adverse event reporting additional description
    Reported AEs and deaths are treatment emergent AEs that developed/worsened and deaths that occurred during ‘treatment-emergent period’ (from first dose of investigational product injection up to the end of Post-treatment period [Week 24]). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Reporting group title
    Dupilumab
    Reporting group description
    Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication.

    Serious adverse events
    Placebo Dupilumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Dupilumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 22 (50.00%)
    14 / 20 (70.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    Road Traffic Accident
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Accidental Overdose
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
         occurrences all number
    1
    2
    Cough
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Wheezing
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 20 (25.00%)
         occurrences all number
    9
    11
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 20 (15.00%)
         occurrences all number
    8
    8
    Injection Site Inflammation
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    3
    3
    Injection Site Pruritus
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 20 (10.00%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 22 (18.18%)
    2 / 20 (10.00%)
         occurrences all number
    6
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 20 (15.00%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2016
    Following changes were made: - Virus serology and anti-drug antibody sampling times moved for subjects entering the long-term extension study - Chest imaging added for subjects entering the long-term extension study - Virus serology testing modified to align with exclusion criteria for the other dupilumab clinical trials in asthma and allow more low risk subjects to be enrolled - Peak Expiratory Flow measurements operational requirements clarified - Prednisolone added as an equivalent alternative treatment to prednisone after the bronchoscopy procedure - Anti-drug antibody sampling times, follow-up and terminology modified for harmonization across the clinical program - Previous local protocol amendments for Germany and UK incorporated to simplify documentation for these countries - Exclusion criterion related to infections simplified to allow inclusion of low risk subjects with common non-threatening conditions
    23 Nov 2016
    Following changes were made: -Clinical Study Director changed - Non-investigational product list updated - Clarified the screening period extension as a one-time window - Clarified the timing of performing spirometry during all visits - Language regarding steering committee removed - Changes made to inclusion/exclusion criteria - Permanent discontinuation criteria clarified - List of exploratory biomarkers modified - Anti-drug antibody sampling time modified to detect early ADA responses

    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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