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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of Dupilumab on Airway Inflammation Through Assessments of Lung Function, Mucus Plugging and Other Lung Imaging Parameters in Patients with Asthma

    Summary
    EudraCT number
    		 2019-004647-74
    Trial protocol
    		 GB   DK   SE   PT   ES   BG   FR   IT   RO  
    Global end of trial date
    21 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2024
    First version publication date
    28 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS15834
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04400318
    WHO universal trial number (UTN)
    		 U1111-1238-4679
    Sponsors
    Sponsor organisation name
    Sanofi SAG
    Sponsor organisation address
    54-56 Rue la Boétie, Paris, France, 75008
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of dupilumab on lung inflammation and related changes in airway volumes detectable by functional respiratory imaging.
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. During the course of the trail, participants were provided with individual participant cards indicating the nature of the trial the participant 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
    20 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 36
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Saudi Arabia: 4
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    109
    EEA total number of subjects
    64
    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)
    96
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 317 participants were screened from 20 Jun 2020 to 06 Jan 2023 at 72 study sites in 14 countries of which 208 participants were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 109 participants were randomized in a ratio of 2:1 to receive dupilumab 300 milligrams (mg) or matching placebo every 2 weeks (Q2W) for 24 weeks. Randomization was stratified by inhaled corticosteroids (ICS) dose level (medium/high no less than 40% in ‘high ICS’ stratum) and region (Eastern Europe/Rest of the World [ROW]).

    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
    		 Dupilumab 300 mg Q2W
    Arm description
    		 Participants received a loading dose of dupilumab 600 mg as 2 subcutaneous (SC) injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    SAR231893
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was supplied as a 150 milligram per milliliter (mg/mL) solution in prefilled glass syringe to deliver 300 mg in a 2 mL injection. SC injection sites were alternated between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same site was not injected twice during consecutive administrations.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to dupilumab as 2 x 2 milliliter (mL) SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.
    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
    Matching placebo was supplied as an identical formulation to the active formulation without dupilumab, in a prefilled syringe to deliver placebo in a 2 mL injection. SC injection sites were alternated between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same site was not injected twice during consecutive administrations.

    Number of subjects in period 1
    		Dupilumab 300 mg Q2W Placebo
    Started
    72
    37
    Completed
    70
    33
    Not completed
    2
    4
         Consent withdrawn by subject
    1
    1
         Not Related to Coronavirus Disease 2019 Pandemic
    -
    3
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Participants received a loading dose of dupilumab 600 mg as 2 subcutaneous (SC) injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab as 2 x 2 milliliter (mL) SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Reporting group values
    		 Dupilumab 300 mg Q2W Placebo Total
    Number of subjects
    		 72 37 109
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.0 ( 12.81 ) 49.4 ( 12.33 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 46 22 68
        Male
    		 26 15 41
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 8 2 10
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 64 34 98
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)
    Only those participants with data available at baseline are reported.
    Units: milliliter (mL)
        arithmetic mean (standard deviation)
    		 1.90526 ( 0.954024 ) 1.90562 ( 1.161739 ) -

    End points

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    End points reporting groups
    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Participants received a loading dose of dupilumab 600 mg as 2 subcutaneous (SC) injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab as 2 x 2 milliliter (mL) SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Primary: Percentage of Participants who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (ppb) at Week 24

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    End point title
    		 Percentage of Participants who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (ppb) at Week 24
    End point description
    FeNO was analyzed using a NIOX instrument using a flow rate of 50 milliliters per second (mL/s). This assessment was conducted prior to spirometry and following a fast of greater than or equal to (≥1) hour. The test was performed after a wash out period of bronchodilators. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    72
    37
    Units: percentage of participants
        number (not applicable)
    56.9
    10.8
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Odds Ratio, 95% confidence interval (CI) of the odds ratio and p-value between the dupilumab and placebo group based on the Cochran-Mantel-Haenszel (CMH) test adjusted by ICS dose level (medium/high) and region (Eastern Europe/ROW).
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    9.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.13
         upper limit
    		 30.82

    Primary: Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)

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    End point title
    		 Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)
    End point description
    Specific airway volume [(s)iVaw] is the change of volume of the airways (in mL), taking into account the lung volume changes (in liter [L]) as well. It corresponds to the ratio between the airway volume (iVaw) and the lobar volume. This way the airway volumes are normalized across participants and become specific. Untrimmed distal [s]iVaw at TLC was assessed based on 3-dimensional (D) rendering of high-resolution computed tomography (HRCT) scans. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of investigational medicinal product (IMP). The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    68
    34
    Units: percent change
        least squares mean (standard error)
    19.73 ( 8.102 )
    -2.04 ( 11.538 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Statistical analysis description
    The mixed model for repeated measures (MMRM) included study intervention, baseline value, region, ICS dose level, visits, study intervention by visit interaction, and baseline by visit interaction terms all as fixed effects. Region, ICS, study intervention and visits were considered as categorical parameters.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.138
    Method
    		 MMRM
    Parameter type
    		 Least square mean difference
    Point estimate
    21.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.73
         upper limit
    		 51.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    14.022

    Secondary: Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring)

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    End point title
    		 Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring)
    End point description
    The mucus scoring system was derived, with very minor differences, from UCSF mucus score. The mucus score was calculated by counting the number of bronchopulmonary segments which contained 1 or more mucus plug, up to a maximum score of 18 corresponding to the 18 bronchopulmonary segments present in most people. In this system, a mucus plug is defined as a complete occlusion of the airway visible at TLC. Each bronchopulmonary segment is given a score of 1 (mucus plug[s] present) or 0 (mucus plug[s] absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-18. Higher scores indicate worse outcome. Baseline was defined as the last available valid (non-missing) value up to and including the date of first dose of IMP. Results are based on the ITT analysis set. Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    68
    34
    Units: score on a scale
        least squares mean (standard error)
    -3.48 ( 0.463 )
    1.44 ( 0.656 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Statistical analysis description
    MMRM model included study intervention (dupilumab, placebo), baseline value of global lung UCSF mucus scoring, region (Eastern Europe/ROW), ICS dose level (medium/high), visit (up to Week 24), study intervention-by-visit interaction and baseline-by-visit interaction as covariates.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 Least square mean difference
    Point estimate
    -4.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 -3.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.798
    Notes
    [1] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoint is reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only 2 endpoints measures (#4 and #5) were included in this procedure.

    Secondary: Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC

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    End point title
    		 Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC
    End point description
    iRaw is defined as the total pressure drop over an airway, divided by the flow rate through that airway. The specific airway resistance (s)iRaw is derived from iRaw by multiplying the airway resistance with the lobar volume. This way the airway resistances are normalized across participants and become specific. Trimmed distal ([s]iRaw) at TLC was assessed using HRCT scan. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    68
    34
    Units: percent change
        least squares mean (standard error)
    36.85 ( 22.562 )
    90.30 ( 32.541 )
    Statistical analysis title
    		 Dupilumab 300 mg Q2W versus Placebo
    Statistical analysis description
    MMRM model included study intervention (dupilumab, placebo), baseline value of trimmed distal [s]iRaw at TLC, region (Eastern Europe/ROW), ICS dose level (medium/high), visit (up to Week 24), study intervention-by-visit interaction, and baseline-by-visit interaction as covariates.
    Comparison groups
    Dupilumab 300 mg Q2W v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.18
    Method
    		 MMRM
    Parameter type
    		 Least square mean difference
    Point estimate
    -53.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -132.09
         upper limit
    		 25.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    39.562
    Notes
    [2] - A hierarchical testing procedure was used to control the overall type I error. Testing was then performed sequentially in order the endpoint is reported and continued when previous endpoint was statistically significant at two-sided 0.05. Only 2 secondary endpoints (#4 and #5) were included in this procedure.

    Secondary: Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC)

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    End point title
    		 Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC)
    End point description
    (s)iVaw is the change of volume of the airways (mL), taking into account the lung volume changes (in L) as well. It corresponds to the ratio between the airway volume (iVaw) and the lobar volume. Untrimmed distal [s]iVaw at FRC was assessed based on 3D rendering of HRCT scans. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    70
    35
    Units: percent change
        least squares mean (standard error)
    225.91 ( 92.250 )
    -17.07 ( 129.384 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC

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    End point title
    		 Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC
    End point description
    The lung volume was determined from the HRCT scan at TLC, by identifying and grouping the voxels that represent the air in the lungs. The total lung volume along with the volume of each lobe individually was determined which allowed to pick up substantial regional physiological changes of the airways and the lobe volumes. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    68
    34
    Units: percent change
        least squares mean (standard error)
    -0.98 ( 1.691 )
    -3.74 ( 2.401 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone

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    End point title
    		 Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone
    End point description
    The IAD was assessed in the upper and lower lung using HRCT scan. By segmenting the lobes at FRC and TLC for each participant, the participant-specific airflow distribution can be established by assessing lobar and volume expansion. Baseline was defined as the last available valid (non-missing) value up to and including the date of the first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    67
    34
    Units: percentage of IAD
    least squares mean (standard error)
        Upper Lung
    -0.61 ( 0.803 )
    -0.11 ( 1.133 )
        Lower Lung
    0.61 ( 0.803 )
    0.11 ( 1.133 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC

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    End point title
    		 Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC
    End point description
    iRaw is defined as the total pressure drop over an airway, divided by the flow rate through that airway. The specific airway resistance (s)iRaw is derived from iRaw by multiplying the airway resistance with the lobar volume. This way, the airway resistances are normalized across participants and become specific. Trimmed distal [s]iRaw at FRC was assessed using HRCT scan. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    69
    35
    Units: percent change
        least squares mean (standard error)
    98.73 ( 70.143 )
    207.87 ( 98.445 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone

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    End point title
    		 Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone
    End point description
    Blood vessel density can be considered a surrogate for perfusion, hence image-based perfusion (IQ) is calculated by blood vessel density at TLC multiplied by image-based volume at TLC. Image-based ventilation (IV) is calculated by the imaged volume at TLC subtracted from the image-based volume at FRC. The ventilation/perfusion ratio IV/Q is then the ratio IV/IQ. The iV/Q was assessed in the upper and lower lung using HRCT scan at TLC. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    67
    34
    Units: Ratio
    least squares mean (standard error)
        Upper Lung
    1.42 ( 0.538 )
    -0.45 ( 0.758 )
        Lower Lung
    1.75 ( 0.579 )
    -0.91 ( 0.817 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in FeNO

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    End point title
    		 Change From Baseline to Week 24 in FeNO
    End point description
    FeNO was analyzed using a NIOX instrument using a flow rate of 50 mL/s. This assessment was conducted prior to spirometry and following a fast of ≥1 hour. The test was performed after a wash out period of bronchodilators. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    72
    37
    Units: parts per billion
        least squares mean (standard error)
    -35.49 ( 2.440 )
    -12.56 ( 3.444 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    		 Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration. Lung function parameters: pre- and post-bronchodilator FEV1 were measured by spirometry before IMP administration. Spirometry was performed after a wash out period of bronchodilators. Post-BD FEV1 was measured within 30 minutes after short-acting beta-2 agonists (2 to up to 4 puffs of albuterol/salbutamol) administration. Baseline was defined as the last available valid (non-missing) value up to and including the date of the first dose of IMP. The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    72
    37
    Units: liter
    least squares mean (standard error)
        Pre-Bronchodilator FEV1
    0.655 ( 0.0637 )
    0.274 ( 0.0885 )
        Post-Bronchodilator FEV1
    0.468 ( 0.0661 )
    0.151 ( 0.0928 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs)
    End point description
    AE:any untoward medical occurrence in participant/clinical study participant, temporally associated with use of study intervention, whether or not considered related to study intervention. TEAEs:AEs that developed or worsened or became serious during TEAE period, defined as time from first administration of IMP (Day 1) to last administration of IMP+98 days and up to end of study follow-up. Serious adverse events(SAE):AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect, was medically important event. AESI:AE (serious or nonserious) of scientific and medical concern specific to Sponsor’s product or program, for which ongoing monitoring and immediate notification by Investigator to Sponsor is required. The safety analysis set included all randomized participants who received at least 1 injection of IMP.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug (Day 1) up to end of study (up to 36 weeks)
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    72
    37
    Units: participants
        Any TEAE
    31
    21
        Any TESAE
    3
    1
        Any AESI
    1
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7)

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    End point title
    		 Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7)
    End point description
    The ACQ-7 comprises of 7 items: first 5 items assess most common asthma symptoms:1.frequency in past week awoken by asthma during night;2.severity of asthma symptoms in morning; 3.limitation of daily activities due to asthma; 4.shortness of breath due to asthma;5.wheeze; plus questions 6.short-acting bronchodilator use; and 7.FEV1 (pre-bronchodilator use, % and % predicted use).Participants are asked to recall how their asthma has been during previous week,to respond to symptom questions on a 7-point scale (0=no impairment,6=maximum impairment).Clinic staff scores the FEV1% predicted on a 7-point scale.A global score is calculated:questions are equally weighted;overall ACQ-7 score is mean of 7 questions, between 0 (totally controlled) and 6 (severely uncontrolled).Higher score indicates lower asthma control.Baseline=last available valid (non-missing) value up to and including day of first dose of IMP. ITT analysis set.Only participants with data collected at Week 24 are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Dupilumab 300 mg Q2W Placebo
    Number of subjects analysed
    70
    36
    Units: score on a scale
        least squares mean (standard error)
    -1.36 ( 0.101 )
    -0.62 ( 0.143 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug (Day 1) up to end of study (up to 36 weeks)
    Adverse event reporting additional description
    Analysis was performed on safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Dupilumab 300 mg Q2W
    Reporting group description
    		 Participants received a loading dose of dupilumab 600 mg as 2 SC injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab as 2 x 2 mL SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.

    Serious adverse events
    		 Dupilumab 300 mg Q2W Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 37 (2.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Facial Bones Fracture
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Injury
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Eosinophilic Granulomatosis With Polyangiitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 37 (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
    0 / 72 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dupilumab 300 mg Q2W Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 72 (25.00%)
    15 / 37 (40.54%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 72 (6.94%)
    3 / 37 (8.11%)
         occurrences all number
    6
    3
    General disorders and administration site conditions
    Injection Site Reaction
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 37 (2.70%)
         occurrences all number
    10
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Sleep Apnoea Syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    Asthma
         subjects affected / exposed
    4 / 72 (5.56%)
    9 / 37 (24.32%)
         occurrences all number
    4
    11
    Rhinorrhoea
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    Infections and infestations
    Covid-19
         subjects affected / exposed
    7 / 72 (9.72%)
    3 / 37 (8.11%)
         occurrences all number
    7
    3
    Pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2020
    The main reason for this amendment was to meet requirements for Regulatory Agency.
    15 Mar 2021
    The main reasons for this amendment were to introduce some clarifications in the eligibility criteria, to decrease the participant burden and to allow more flexibility for some of the study procedures (e.g., FeNO assessment, complete clinical examination, the sequence of the study procedures). The safety reporting (AESI) were aligned with the updated Investigator’s brochure and contingency measures were incorporated in case of a regional or national emergency. The stratification factor related to regions was changed to Eastern Europe/ROW. In total, no more than 40% participants should be in "Eastern Europe" strata.
    13 Apr 2023
    The main reason for this amendment was evolving interest to evaluate FeNO as an airway inflammatory biomarker related to structural lung changes. Therefore, the primary endpoint FEV1 was proposed to be replaced with the secondary endpoint of FeNO, leading to an overall reduction in sample size. Objectives and Endpoints section was updated. Updates were made to the sample size calculation and hypotheses reflecting the change to the primary endpoint. The efficacy analyses were updated based on changes to the endpoints. Minor grammatical, editorial, and/or administrative changes were made.

    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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