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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel-group, 52-week pivotal study to assess the efficacy, safety, and tolerability of dupilumab in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) with type 2 inflammation (NOTUS)

    Summary
    EudraCT number
    		 2018-001954-91
    Trial protocol
    		 DE   LV   NL   LT   BG   GB   FR   PT   PL   ES   GR   BE   HU   CZ   SK   RO  
    Global end of trial date
    27 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2025
    First version publication date
    06 Apr 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC15805
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04456673
    WHO universal trial number (UTN)
    		 U1111-1211-8837
    Sponsors
    Sponsor organisation name
    Sanofi-Aventis Recherche & Développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of dupilumab 300 milligrams (mg) every 2 weeks (q2w) in participants with moderate or severe COPD as measured by annualized rate of acute moderate or severe COPD exacerbation (AECOPD).
    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 trial, 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
    06 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 125
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Bulgaria: 130
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 53
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Czechia: 26
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Greece: 40
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    Latvia: 24
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Mexico: 48
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Peru: 37
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    Serbia: 20
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    South Africa: 23
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 79
    Worldwide total number of subjects
    935
    EEA total number of subjects
    415
    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)
    409
    From 65 to 84 years
    525
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 329 centers in 29 countries. A total of 2769 participants were screened between 06 July 2020 to 19 April 2023, of which 1834 participants were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 935 participants were randomized in a 1:1 ratio to receive either dupilumab 300 mg q2w or matching placebo. Randomization was stratified by country, inhaled corticosteroid (ICS) dose (high-dose ICS [yes/no]) at baseline, and smoking status at screening (current smokers or not).

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks.
    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
    Placebo for dupilumab was provided in identically matched glass pre-filled syringe to deliver 2 mL which matched dupilumab 300 mg. 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 injections.

    Arm title
    		 Dupilumab 300 mg q2w
    Arm description
    		 Participants received dupilumab 300 mg SC injection q2w up to 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    SAR231893, Dupixent®, REGN668
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was supplied as 150 milligram per milliliter (mg/mL) solution in a pre-filled glass syringe to deliver 300 mg in 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 injections.

    Number of subjects in period 1
    		Placebo Dupilumab 300 mg q2w
    Started
    465
    470
    Randomized and treated
    465
    468
    Safety Population
    464
    469
    Completed
    422
    428
    Not completed
    43
    42
         Consent withdrawn by subject
    31
    23
         Adverse event, non-fatal
    7
    14
         Not related to Coronavirus Disease-2019 (COVID-19)
    4
    5
         Poor compliance to protocol
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Participants received dupilumab 300 mg SC injection q2w up to 52 weeks.

    Reporting group values
    		 Placebo Dupilumab 300 mg q2w Total
    Number of subjects
    		 465 470 935
    Age categorical
    Units: Subjects
        From 18 - 64 years
    		 213 196 409
        From 65 - 84 years
    		 251 274 525
        85 years and over
    		 1 0 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.9 ( 8.5 ) 65.2 ( 8.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 153 150 303
        Male
    		 312 320 632
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 26 22 48
        Asian
    		 3 7 10
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 8 4 12
        White
    		 416 422 838
        More than one race
    		 8 12 20
        Unknown or Not Reported
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks.

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Participants received dupilumab 300 mg SC injection q2w up to 52 weeks.

    Primary: Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-week Treatment Period

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    End point title
    		 Annualized Rate of Moderate or Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Over the 52-week Treatment Period
    End point description
    Moderate exacerbations were recorded by the Investigator and defined as AECOPD event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were also recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for >24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period. The Intent-to-treat (ITT) population included all randomized participants analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    465
    470
    Units: Exacerbation per participant-year
        number (confidence interval 95%)
    1.295 (1.048 to 1.600)
    0.859 (0.699 to 1.057)
    Statistical analysis title
    		 Placebo versus Dupilumab 300 mg q2w
    Statistical analysis description
    Derived using negative binomial model with the total number of the events occurring during the 52-week treatment period as the response variable, and treatment group, region (pooled country), ICS dose, smoking status at screening, baseline disease severity, and number of moderate or severe COPD exacerbation events within one year prior to the study as covariates, and log-transformed treatment duration as an offset variable.
    Comparison groups
    Dupilumab 300 mg q2w v Placebo
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0002
    Method
    		 Negative binomial model
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.435
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.682
         upper limit
    		 -0.188
    Notes
    [1] - A hierarchical testing procedure was used to control type I error and handle primary and first 4 secondary endpoints (reported sequentially) analyses at a 2-sided significance level of 0.05.

    Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) to Week 12

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    End point title
    		 Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) to Week 12
    End point description
    The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment. The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization. Only those participants with data collected are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    461
    464
    Units: Liters
        least squares mean (standard error)
    0.057 ( 0.017 )
    0.139 ( 0.017 )
    Statistical analysis title
    		 Placebo versus Dupilumab 300 mg q2w
    Statistical analysis description
    Derived from mixed-effect model with repeated measures (MMRM) model with the change from baseline in pre-bronchodilator FEV1 up to Week 12 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-bronchodilator FEV1, and FEV1 baseline-by-visit interaction as covariates.
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    925
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0001
    Method
    		 MMRM model
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.124
    Notes
    [2] - A hierarchical testing procedure was used to control type I error and handle primary and first 4 secondary endpoints (reported sequentially) analyses at a 2-sided significance level of 0.05.

    Secondary: Change From Baseline in Saint George’s Respiratory Questionnaire (SGRQ) Total Score to Week 52

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    End point title
    		 Change From Baseline in Saint George’s Respiratory Questionnaire (SGRQ) Total Score to Week 52
    End point description
    SGRQ measures and quantify health status in adult participants with chronic airflow limitation and rated on electronic diary. Scores by dimension were calculated for 3 domains:symptoms (respiratory symptoms: frequency and severity), activity (activities that cause or are limited by breathlessness) and impacts (social functioning and psychological disturbances due to airway disease). Each question's response had a unique empirically derived weight; lowest possible weight: 0 and highest: 100. Total score: summing all positive responses. Total and domain score derived from relevant items and converted to a score of 0 to 100; higher score indicating worse health status/health related quality of life. Baseline: last available value up to randomization but prior to first dose of study treatment. ITT population with opportunity to reach Week 52: participants who had an opportunity to reach Week 52 assessments. Only those participants with data collected are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    342
    350
    Units: score on a scale
        least squares mean (standard error)
    -6.444 ( 0.922 )
    -9.816 ( 0.920 )
    Statistical analysis title
    		 Placebo versus Dupilumab 300 mg q2w
    Statistical analysis description
    Derived from MMRM model with the change from baseline in SGRQ total score up to Week 52 as response variables, and treatment group, region (pooled country), ICS dose, smoking status at screening, treatment-by-visit interaction, baseline SGRQ total score, and SGRQ baseline-by-visit interaction as covariates.
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0068
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.371
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.811
         upper limit
    		 -0.931
    Notes
    [3] - A hierarchical testing procedure was used to control type I error and handle primary and first 4 secondary endpoints (reported sequentially) analyses at a 2-sided significance level of 0.05.

    Secondary: Percentage of Participants With Saint George’s Respiratory Questionnaire Improvement ≥4 Points at Week 52

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    End point title
    		 Percentage of Participants With Saint George’s Respiratory Questionnaire Improvement ≥4 Points at Week 52
    End point description
    A responder was defined as a participant with improvement from baseline in SGRQ total score at Week 52 by ≥4 points. Percentage of participants who achieved a clinically meaningful response in SGRQ total score (improvement by ≥4 points)/responders are reported. SGRQ is 50-item self-administered questionnaire. Scores by dimension were calculated for 3 domains:symptoms(respiratory symptoms: frequency and severity), activity(activities that cause or are limited by breathlessness) and impacts(social functioning and psychological disturbances due to airway disease). Each question's response had unique empirically derived weight where lowest possible weight was 0 and highest was 100. Total score was obtained by summing all positive responses. Total and domain score was derived from relevant items and converted to a score of 0 to 100; higher score indicating worse health status/health related quality of life. Analysis was performed in ITT population with an opportunity to reach Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    359
    362
    Units: Percentage of participants
        number (not applicable)
    46.5
    51.4
    Statistical analysis title
    		 Placebo versus Dupilumab 300 mg q2w
    Statistical analysis description
    Derived from logistic regression model which includes treatment group, region (pooled country), ICS dose, smoking status at screening, and baseline SGRQ total score as covariates.
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    721
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.3329
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.164
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.856
         upper limit
    		 1.581
    Notes
    [4] - A hierarchical testing procedure was used to control type I error and handle primary and first 4 secondary endpoints (reported sequentially) analyses at a 2-sided significance level of 0.05.

    Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Week 52

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    End point title
    		 Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Week 52
    End point description
    The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment. The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for the continuous and proportion type endpoints at Week 52. Only those participants with data collected are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    356
    359
    Units: Liters
        least squares mean (standard error)
    0.054 ( 0.020 )
    0.115 ( 0.021 )
    Statistical analysis title
    		 Placebo versus Dupilumab 300 mg q2w
    Statistical analysis description
    Derived from MMRM model with the change from baseline in pre-bronchodilator FEV1 up to Week 52 as response variables, and treatment group, age, sex, height, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline pre-bronchodilator FEV1, and FEV1 baseline-by-visit interaction as covariates.
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    715
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0182
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.062
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.011
         upper limit
    		 0.113
    Notes
    [5] - A hierarchical testing procedure was used to control type I error and handle primary and first 4 secondary endpoints (reported sequentially) analyses at a 2-sided significance level of 0.05.

    Secondary: Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 24, 36, and 44

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    End point title
    		 Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 24, 36, and 44
    End point description
    The FEV1 was defined as the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment. The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 8, 24, 36 and 44
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    356
    359
    Units: Liters
    least squares mean (standard error)
        Week 2
    0.072 ( 0.018 )
    0.108 ( 0.018 )
        Week 4
    0.077 ( 0.018 )
    0.132 ( 0.019 )
        Week 8
    0.069 ( 0.019 )
    0.133 ( 0.020 )
        Week 24
    0.064 ( 0.020 )
    0.154 ( 0.021 )
        Week 36
    0.068 ( 0.021 )
    0.117 ( 0.021 )
        Week 44
    0.065 ( 0.020 )
    0.154 ( 0.021 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 12, 24, 36, and 52

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    End point title
    		 Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in 1 Second to Weeks 2, 4, 8, 12, 24, 36, and 52
    End point description
    The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 referred to the spirometry performed consistent with the mechanism of action of reliever (30 minutes for albuterol or another short-acting beta agonists). Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment. The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    356
    358
    Units: Liters
    least squares mean (standard error)
        Week 2
    0.082 ( 0.018 )
    0.101 ( 0.018 )
        Week 4
    0.098 ( 0.018 )
    0.126 ( 0.018 )
        Week 8
    0.083 ( 0.019 )
    0.147 ( 0.020 )
        Week 12
    0.064 ( 0.020 )
    0.136 ( 0.020 )
        Week 24
    0.081 ( 0.020 )
    0.152 ( 0.020 )
        Week 36
    0.070 ( 0.020 )
    0.131 ( 0.021 )
        Week 52
    0.059 ( 0.020 )
    0.127 ( 0.021 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Forced Expiratory Flow (FEF) 25 to 75 Percent (%) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52

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    End point title
    		 Change From Baseline in Forced Expiratory Flow (FEF) 25 to 75 Percent (%) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52
    End point description
    FEF is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the FEF at 25% to 75% of forced vital capacity (FVC), where FVC was defined as the volume of air that can be forcibly blown out after full inspiration in the upright position. Spirometry was performed after a wash out period of bronchodilators according to their action duration. Baseline was defined as the last available value up to randomization but prior to the first dose of study treatment. The ITT population with an opportunity to reach Week 52 included participants who had an opportunity to reach Week 52 assessments and were analyzed for all weeks up to Week 52. Only those participants with data collected at specified timepoints are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 44 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    356
    359
    Units: Liters per second
    least squares mean (standard error)
        Week 2
    0.057 ( 0.018 )
    0.103 ( 0.018 )
        Week 4
    0.056 ( 0.018 )
    0.114 ( 0.018 )
        Week 8
    0.059 ( 0.019 )
    0.134 ( 0.019 )
        Week 12
    0.066 ( 0.021 )
    0.137 ( 0.021 )
        Week 24
    0.051 ( 0.019 )
    0.147 ( 0.020 )
        Week 36
    0.073 ( 0.021 )
    0.128 ( 0.022 )
        Week 44
    0.053 ( 0.021 )
    0.154 ( 0.021 )
        Week 52
    0.065 ( 0.020 )
    0.122 ( 0.020 )
    No statistical analyses for this end point

    Secondary: Annualized Rate of Severe Chronic Obstructive Pulmonary Disease Exacerbations Over the 52-week Treatment Period

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    End point title
    		 Annualized Rate of Severe Chronic Obstructive Pulmonary Disease Exacerbations Over the 52-week Treatment Period
    End point description
    Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for >24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Annualized event rate was the total number of events that occurred during the 52-week treatment period divided by the total number of participant-years followed in the 52-week treatment period. The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    465
    470
    Units: Exacerbation per participant-year
        number (confidence interval 95%)
    0.124 (0.072 to 0.215)
    0.070 (0.039 to 0.123)
    No statistical analyses for this end point

    Secondary: Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease Exacerbation Event During the 52-week Treatment Period

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    End point title
    		 Time to First Moderate or Severe Chronic Obstructive Pulmonary Disease Exacerbation Event During the 52-week Treatment Period
    End point description
    The time to first moderate or severe exacerbation was defined as date of the first event minus randomization date +1. Moderate exacerbations were recorded by the Investigator and defined as AECOPD event that required either systemic corticosteroids (such as intramuscular, intravenous, or oral) and/or antibiotics. Severe exacerbations were recorded by the Investigator and defined as AECOPD event that required hospitalization or observation for >24 hours in an emergency department/urgent care facility or resulted in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. Median time as well as 95% confidence interval was calculated using Kaplan-Meier estimates. The ITT population included all randomized participants analyzed according to the treatment group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to Weeks 12, 24, 36 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    465
    470
    Units: Weeks
    median (confidence interval 95%)
        Week 12
    0.172 (0.139 to 0.207)
    0.108 (0.081 to 0.138)
        Week 24
    0.265 (0.225 to 0.306)
    0.206 (0.170 to 0.244)
        Week 36
    0.342 (0.298 to 0.387)
    0.292 (0.250 to 0.335)
        Week 52
    0.424 (0.375 to 0.471)
    0.361 (0.315 to 0.407)
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed or worsened or became serious during TE period (between the first administration of study treatment to the last administration of the study treatment + 98 days). The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    464
    469
    Units: Participants
        Any TEAE
    330
    322
        Any TESAE
    79
    65
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Hematology

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    End point title
    		 Percentage of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Hematology
    End point description
    Blood samples were collected to determine PCSA in hematology. PCSA values were defined as abnormal values considered medically important by Sponsor according to pre-defined criteria/thresholds based on literature review and defined by Sponsor for clinical laboratory tests. Criteria for PCSA: Hemoglobin (Hb): ≤115 grams per liter (g/L) (Male[M]); ≤95 g/L (Female[F]), ≥185 g/L (M); ≥165 g/L (F), Decrease from baseline ≥20 g/L; Hematocrit: ≤0.37 volume per volume (v/v) (M); ≤0.32 v/v (F), ≥0.55 v/v (M); ≥0.5 v/v (F); Erythrocyte Count: ≥6 Tera/L; Platelet count: <100 Giga/L, ≥700 Giga/L; Leukocytes: <3 Giga/L (Non-Black [NB]); <2 Giga/L (Black [B]), ≥16 Giga/L; Neutrophils: <1.5 Giga/L (NB); <1 Giga/L (B); Lymphocytes: >4 Giga/L; Monocytes: >0.7 Giga/L; Basophils: >0.1 Giga/L; Eosinophils: >0.5 Giga/L or >upper limit of normal (ULN) (if ULN ≥0.5 Giga/L). Safety population. n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    459
    464
    Units: Percentage of participants
    number (not applicable)
        Hb: ≤115 g/​L (M); ≤95 g/​L (F) (n=459,464)
    6.1
    5.0
        Hb: ≥185 g/L (M); ≥165 g/L (F) (n=459,464)
    3.7
    4.7
        Hb: Decrease from baseline ≥20 g/L (n=459,464)
    9.8
    11.4
        Hematocrit:≤0.37 v/v(M);≤0.32 v/v(F)(n=459,464)
    6.1
    5.0
        Hematocrit:≥0.55 v/v(M);≥0.5 v/v(F)(n=459,464)
    23.1
    26.5
        Erythrocyte Count: ≥6 Tera/L (n=459,464)
    4.4
    6.0
        Platelet count: <100 Giga/L (n=459,464)
    0.2
    0.6
        Platelet count: ≥700 Giga/L (n=459,464)
    0.7
    0.4
        Leukocytes:<3 Giga/L(NB);<2 Giga/L(B)(n=459,464)
    0.7
    0.6
        Leukocytes: ≥16 Giga/L (n=459,464)
    5.2
    4.1
        Neutrophils:<1.5Giga/L(NB);<1 Giga/L(B)(n=447,456)
    2.7
    1.5
        Lymphocytes: >4 Giga/L (n=459,464)
    5.9
    8.2
        Monocytes: >0.7 Giga/L (n=459,464)
    65.8
    64.9
        Basophils: >0.1 Giga/L (n=459,464)
    28.1
    29.5
        Eosinophils: >0.5 Giga/L or >ULN (n=458,464)
    15.3
    21.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Potentially Clinically Significant Abnormalities in Clinical Chemistry

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    End point title
    		 Percentage of Participants With Potentially Clinically Significant Abnormalities in Clinical Chemistry
    End point description
    PCSA criteria: Sodium: ≤129 millimoles (mmol)/L, ≥160 mmol/L; Potassium: <3 mmol/L, ≥5.5 mmol/L; Chloride: <80 mmol/L, >115 mmol/L; Glucose: ≤3.9 mmol/L and <lower limit of normal (LLN), ≥11.1 mmol/L (unfasted [UF]); ≥7 mmol/L (fasted [F]);Total cholesterol: ≥7.74 mmol/L; Creatinine kinase: >3 ULN, >10 ULN; Creatinine: ≥150 micromoles (µmol)/L (adults), ≥30% change from baseline (CFB), ≥100% CFB, Creatinine Clearance (CG): ≥60 - <90 milliliter per minute (mL/min), ≥30 - <60 mL/min, ≥15 - <30 mL/min, <15 mL/min; Urea nitrogen: ≥17 mmol/L; Uric acid: <120 μmol/L, >408 μmol/L; Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST): >3 ULN, >5 ULN, >10 ULN; Alkaline phosphatase (ALP): >1.5 ULN; Total bilirubin (TB): >1.5 ULN, >2 ULN; ALT and TB: ALT >3 ULN and Bilirubin (B) > 2 ULN; Direct bilirubin (DB) and TB: DB >35% B and B >1.5 ULN; Albumin: ≤25 g/L. Safety population. n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    459
    464
    Units: Percentage of participants
    number (not applicable)
        Sodium: ≤129 mmol/L (n=459,464)
    1.7
    1.9
        Sodium: ≥160 mmol/L (n=459,464)
    0
    0.2
        Potassium: <3 mmol/L (n=459,464)
    0.4
    0.4
        Potassium: ≥5.5 mmol/L (n=459,464)
    11.3
    10.8
        Chloride: <80 mmol/L (n=459,464)
    0
    0.2
        Chloride: >115 mmol/L (n=459,464)
    0
    0.2
        Glucose: ≤3.9 mmol/L and <LLN (n=459,464)
    7.0
    6.5
        Glucose:≥11.1 mmol/L(UF); ≥7 mmol/L(F) (n=459,464)
    7.6
    8.8
        Total cholesterol: ≥7.74 mmol/L (n=459,464)
    6.1
    4.3
        Creatinine kinase: >3 ULN (n=459,464)
    2.2
    3.9
        Creatinine kinase: >10 ULN (n=459,464)
    0
    0
        Creatinine: ≥150 µmol/L (n=459,464)
    2.6
    3.0
        Creatinine: ≥30% CFB (n=459,464)
    20.3
    19.2
        Creatinine: ≥100% CFB (n=459,464)
    0.7
    2.4
        CG: ≥60 - <90 mL/min (n=459,464)
    36.4
    39.0
        CG: ≥30 - <60 mL/min (n=459,464)
    18.5
    16.8
        CG: ≥15 - <30 mL/min (n=459,464)
    0
    0.9
        CG: <15 mL/min (n=459,464)
    0.2
    0.4
        Urea nitrogen: ≥17 mmol/L
    0.2
    0.4
        Uric acid: <120 μmol/L (n=459,464)
    0
    0.4
        Uric acid: >408 μmol/L (n=459,464)
    37.7
    39.7
        ALT: >3 ULN (n=459,464)
    1.5
    0.4
        ALT: >5 ULN (n=459,464)
    0.2
    0
        ALT: >10 ULN (n=459,464)
    0
    0
        AST: >3 ULN (n=459,464)
    0.2
    0.4
        AST: >5 ULN (n=459,464)
    0
    0.2
        AST: >10 ULN (n=459,464)
    0
    0
        ALP: >1.5 ULN (n=459,464)
    3.9
    2.8
        TB: >1.5 ULN (n=459,464)
    0.9
    2.2
        TB: >2 ULN (n=459,464)
    0.2
    0
        ALT and TB: ALT >3 ULN and B> 2 ULN (n=459,464)
    0.2
    0
        DB and TB: DB >35% B and B >1.5 ULN (n=22,36)
    4.5
    5.6
        Albumin: ≤25 g/L (n=459,464)
    0.2
    0.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Abnormal Results for Urine Protein in Urinalysis

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    End point title
    		 Percentage of Participants With Abnormal Results for Urine Protein in Urinalysis
    End point description
    Urine dipstick samples were collected to determine the significant abnormalities in urine protein. The Safety population included all participants who actually received at least 1 dose or partial of a dose of the study treatment, analyzed according to the treatment participants actually received. Only those participants with data collected are reported. Here, n=number of participants with data collected for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 4, 8, 12, 24, 36, 52 and 64
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    462
    469
    Units: Percentage of participants
    number (not applicable)
        Baseline (Day 1) (n=462,469)
    5.0
    6.2
        Week 4 (n=452,456)
    4.1
    4.9
        Week 8 (n=443,452)
    3.7
    5.3
        Week 12 (n=440,450)
    4.5
    6.4
        Week 24 (n=444,447)
    3.9
    4.5
        Week 36 (n=434,436)
    3.9
    4.5
        Week 52 (n=421,422)
    5.0
    6.6
        Week 64 (n=384,403)
    4.5
    5.5
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab

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    End point title
    		 Number of Participants With Anti-Drug Antibodies (ADA) to Dupilumab
    End point description
    Plasma samples were collected to evaluate antibodies to dupilumab. Pre-existing immunoreactivity is defined as 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. Treatment-emergent response is defined as a positive response in the ADA assay post first dose, when baseline results are negative or missing. Treatment-boosted response is defined as an ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over baseline titer levels, when baseline results are positive. The ADA population included all participants in the safety population who had at least 1 reportable ADA result after first dose of the study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    452
    461
    Units: Participants
        Pre-existing immunoreactivity
    6
    4
        Treatment-emergent ADA response
    11
    47
        Treatment-boosted ADA response
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs, SAEs, all-cause mortality (deaths) were collected from the first dose of study treatment (Day 1) up to the last dose of the study treatment + 98 days, up to 506 days.
    Adverse event reporting additional description
    Analysis was performed on the Safety population. 1 participant was exposed to different treatment other than planned (was allocated to placebo arm but inadvertently received dupilumab 300 mg q2w on Day 113). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Participants received dupilumab 300 mg SC injection q2w up to 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks.

    Serious adverse events
    		 Dupilumab 300 mg q2w Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 469 (13.86%)
    79 / 464 (17.03%)
         number of deaths (all causes)
    14
    8
         number of deaths resulting from adverse events
    13
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Of Colon
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Myelomonocytic Leukaemia
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary Thyroid Cancer
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Lung
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity Necrosis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Vascular Disorder
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden Death
         subjects affected / exposed
    2 / 469 (0.43%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    2 / 2
    2 / 2
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    25 / 469 (5.33%)
    40 / 464 (8.62%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 47
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Tibia Fracture
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal Burn
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella Fracture
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Unstable
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    2 / 469 (0.43%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ventricular Arrhythmia
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postinfarction Angina
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral Valve Incompetence
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor Pulmonale
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular Disorder
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Lacunar Stroke
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebral Infarction
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune Haemolytic Anaemia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical Fistula
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Stenosis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Stenosis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Soft Tissue Necrosis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal Abscess
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Colitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    3 / 469 (0.64%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Covid-19 Pneumonia
         subjects affected / exposed
    6 / 469 (1.28%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective Exacerbation Of Chronic Obstructive Airways Disease
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection Bacterial
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Candidiasis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal Candidiasis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 469 (1.92%)
    5 / 464 (1.08%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Pneumonia Klebsiella
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia Pneumococcal
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pseudomonal
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspected Covid-19
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    2 / 469 (0.43%)
    2 / 464 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 464 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 464 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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
    125 / 469 (26.65%)
    120 / 464 (25.86%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    31 / 469 (6.61%)
    33 / 464 (7.11%)
         occurrences all number
    34
    35
    Nervous system disorders
    Headache
         subjects affected / exposed
    37 / 469 (7.89%)
    29 / 464 (6.25%)
         occurrences all number
    72
    46
    Infections and infestations
    Covid-19
         subjects affected / exposed
    45 / 469 (9.59%)
    36 / 464 (7.76%)
         occurrences all number
    45
    38
    Nasopharyngitis
         subjects affected / exposed
    32 / 469 (6.82%)
    28 / 464 (6.03%)
         occurrences all number
    39
    31

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2020
    To decrease the study burden on participants, to minimize COVID-19 pandemic-related risks in this vulnerable and elderly population of COPD participants, and to update the adverse event of special interest with the updated Sponsor safety information related to eye disorders.
    16 Dec 2021
    To provide flexibility for participant enrollment criteria while maintaining the favorable benefit risk profile and scientific objectives of the study.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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