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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

    Summary
    EudraCT number
    		 2018-001953-28
    Trial protocol
    		 DE   SE   DK   FI   CZ   HU   PL   SK   BG   IT   RO  
    Global end of trial date
    02 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2024
    First version publication date
    27 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15804
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03930732
    WHO universal trial number (UTN)
    		 U1111-1211-8804
    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
    31 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2023
    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) administered every 2 weeks (q2w) in participants with acute moderate or severe chronic obstructive pulmonary disease (COPD) as measured by annualized rate of acute moderate or severe COPD exacerbation (AECOPD).
    Protection of trial subjects
    Subjects 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 subject and considering the local culture. During the course of the trail, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2019
    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: 76
    Country: Number of subjects enrolled
    Bulgaria: 49
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Chile: 99
    Country: Number of subjects enrolled
    China: 107
    Country: Number of subjects enrolled
    Czechia: 31
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Israel: 31
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 5
    Country: Number of subjects enrolled
    Mexico: 50
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    Slovakia: 23
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Turkey: 15
    Country: Number of subjects enrolled
    Ukraine: 60
    Country: Number of subjects enrolled
    United States: 104
    Worldwide total number of subjects
    939
    EEA total number of subjects
    306
    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)
    393
    From 65 to 84 years
    546
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 275 centers in 24 countries. A total of 2599 participants were screened from 09 May 2019 to 12 Jan 2022, of which 1660 were screen failures due to not meeting eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 939 participants were randomized in a 1:1 ratio to receive either dupilumab 300 mg q2w or matching placebo for 52 weeks.

    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, Monitor, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, end of treatment [EOT] visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
    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 was administered in identically matched glass pre-filled syringe to deliver 2 milliliter (mL) which matched dupilumab 300 mg q2w up to 52 weeks. SC injection sites 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 visits.

    Arm title
    		 Dupilumab 300 mg q2w
    Arm description
    		 Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dupilumab
    Investigational medicinal product code
    Other name
    SAR231893/REGN668, Dupixent
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dupilumab was administered for SC administration and supplied as 150 mg/mL solution in 2.25 mL prefilled glass syringes to deliver 300 mg in 2.0 mL q2w up to 52 weeks. SC injection sites 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 visits.

    Number of subjects in period 1
    		Placebo Dupilumab 300 mg q2w
    Started
    471
    468
    Completed
    434
    440
    Not completed
    37
    28
         Consent withdrawn by subject
    23
    11
         Other, not related to Coronavirus Disease-2019
    5
    8
         Adverse event, non-fatal
    9
    7
         Poor compliance to protocol
    -
    1
         Other, related to Coronavirus Disease-2019
    -
    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 as subcutaneous (SC) injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, end of treatment [EOT] visit occurred 2 weeks after last administration of treatment i.e., at Week 52).

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).

    Reporting group values
    		 Placebo Dupilumab 300 mg q2w Total
    Number of subjects
    		 471 468 939
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.2 ± 8.1 65.0 ± 8.0 -
    Gender categorical
    Units: Subjects
        Female
    		 149 170 319
        Male
    		 322 298 620
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 4 3 7
        Asian
    		 67 67 134
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 2 3 5
        White
    		 397 393 790
        More than one race
    		 0 2 2
        Unknown or Not Reported
    		 0 0 0

    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 as subcutaneous (SC) injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, end of treatment [EOT] visit occurred 2 weeks after last administration of treatment i.e., at Week 52).

    Reporting group title
    Dupilumab 300 mg q2w
    Reporting group description
    		 Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).

    Subject analysis set title
    Dupilumab 300 mg q2w-Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52). One participant was exposed to different treatment other than planned (was randomized to placebo arm but received dupilumab on Day 40). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.

    Primary: Annualized Rate of Moderate or Severe COPD Exacerbations Over the 52-Week Treatment Period

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    End point title
    		 Annualized Rate of Moderate or Severe COPD Exacerbations Over the 52-Week Treatment Period
    End point description
    Moderate exacerbations were recorded by the Investigator and defined as AECOPD 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party. The intent-to-treat (ITT) population consisted of the randomized population 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
    471
    468
    Units: exacerbation per participant-year
        number (confidence interval 95%)
    1.01 (0.931 to 1.301)
    0.776 (0.645 to 0.934)
    Statistical analysis title
    		 Annualized rate-COPD exacerbations over 52 weeks
    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), inhaled corticosteroid (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
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    939
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0005
    Method
    		 Negative binomial model
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.324
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.508
         upper limit
    		 -0.14
    Notes
    [1] - A hierarchical testing procedure was used to control type I error and handle primary and a few secondary endpoint analyses at a 2-sided significance level of 0.049. Testing was then performed sequentially in the order the endpoints are reported (till OM 9). The hierarchical testing sequence continued only when the previous endpoint was statistically significant at 0.049 level. Parameter estimate derived using delta method.

    Secondary: Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in one Second (FEV1) at Week 12

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    End point title
    		 Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in one Second (FEV1) at Week 12
    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. Spirometry was performed after a wash out period of bronchodilators according to their action duration. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 12
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    469
    466
    Units: liters
        least squares mean (standard error)
    0.077 ± 0.018
    0.160 ± 0.018
    Statistical analysis title
    		 Change from Baseline in Pre-BD FEV1 at Week 12
    Statistical analysis description
    Derived from mixed-effect model with repeated measures (MMRM) model with the change from baseline in pre-BD 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-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 MMRM model
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.125
    Notes
    [2] - Threshold for significance at 0.049 level.

    Secondary: Change From Baseline in Pre-BD FEV1 at Week 52

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    End point title
    		 Change From Baseline in Pre-BD FEV1 at Week 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. Spirometry was performed after a wash out period of bronchodilators according to their action duration. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    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
    469
    466
    Units: liters
        least squares mean (standard error)
    0.070 ± 0.019
    0.153 ± 0.019
    Statistical analysis title
    		 Change from Baseline in Pre-BD FEV1 at Week 52
    Statistical analysis description
    Derived from MMRM model with the change from baseline in pre-BD 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-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    935
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [3]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.038
         upper limit
    		 0.128
    Notes
    [3] - Threshold for significance at 0.049 level.

    Secondary: Change From Baseline in Pre-BD FEV1 at Week 12 in Subgroup of Participants With Baseline Fractional Exhaled Nitric Oxide (FeNO) >=20 Parts per Billion (Ppb)

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    End point title
    		 Change From Baseline in Pre-BD FEV1 at Week 12 in Subgroup of Participants With Baseline Fractional Exhaled Nitric Oxide (FeNO) >=20 Parts per Billion (Ppb)
    End point description
    FeNO is a demonstrated biomarker of type 2 airway inflammation in respiratory diseases. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 milliliter per second (mL/s) and reported in ppb. This assessment was conducted prior to spirometry and following a fast of at least 1 hour. The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 12
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    186
    193
    Units: liters
        least squares mean (standard error)
    0.108 ± 0.035
    0.232 ± 0.034
    Statistical analysis title
    		 Change from baseline-subgroup FeNO>=20 ppb:Week 12
    Statistical analysis description
    Derived from MMRM model with the change from baseline in pre-BD 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-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022 [4]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.124
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.045
         upper limit
    		 0.203
    Notes
    [4] - Threshold for significance at 0.049 level.

    Secondary: Change From Baseline in Pre-BD FEV1 at Week 52 in Subgroup of Participants With Baseline FeNO >=20 Ppb

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    End point title
    		 Change From Baseline in Pre-BD FEV1 at Week 52 in Subgroup of Participants With Baseline FeNO >=20 Ppb
    End point description
    FeNO is a demonstrated biomarker of type 2 airway inflammation in respiratory diseases. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s and reported in ppb. This assessment was conducted prior to spirometry and following a fast of at least 1 hour. The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included. Only those participants with data available were analyzed.
    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
    186
    193
    Units: liters
        least squares mean (standard error)
    0.120 ± 0.037
    0.247 ± 0.036
    Statistical analysis title
    		 Change from baseline-subgroup FeNO>=20 ppb:Week 52
    Statistical analysis description
    Derived from MMRM model with the change from baseline in pre-BD 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-BD FEV1, and FEV1 baseline-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0034 [5]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.127
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.042
         upper limit
    		 0.212
    Notes
    [5] - Threshold for significance at 0.049 level.

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

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    End point title
    		 Change From Baseline in Saint (St.) George’s Respiratory Questionnaire (SGRQ) Total Score at Week 52
    End point description
    The SGRQ was a 50-item self-administered questionnaire designed to measure 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, activity and impacts (psycho-social) as well as a total score. Global and domain scores range from 0 to 100, with 100 representing the worst possible health status and 0 indicating the best possible health status. Higher score indicates worse health status/heath related quality of life. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    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
    456
    456
    Units: score on a scale
        least squares mean (standard error)
    -6.369 ± 0.816
    -9.732 ± 0.810
    Statistical analysis title
    		 Change from baseline in SGRQ total score: Week 52
    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. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    912
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017 [6]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.363
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.459
         upper limit
    		 -1.266
    Notes
    [6] - Threshold for significance at 0.049 level.

    Secondary: Percentage of Participants With SGRQ Improvement >=4 Points at Week 52

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    End point title
    		 Percentage of Participants With SGRQ 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. Participants with improvement <4 points or with missing values were considered as non-responders. The percentage (%) of participants (pts) who achieved a clinically meaningful response in SGRQ total score (reduction [improvement] by >=4 points)/responders are reported. The ITT population consisted of the randomized population 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
    471
    468
    Units: percentage of participants
        number (not applicable)
    43.1
    51.5
    Statistical analysis title
    		 % of pts-SGRQ Improvement >=4 points: Week 52
    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. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    939
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0089 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.439
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.096
         upper limit
    		 1.89
    Notes
    [7] - Threshold for significance at 0.049 level.

    Secondary: Change From Baseline in Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) RS-Total Score at Week 52

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    End point title
    		 Change From Baseline in Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) RS-Total Score at Week 52
    End point description
    The E-RS in COPD scale was a part of the exacerbations of chronic pulmonary disease tool (EXACT). It was a derivative instrument used to measure the effect of treatment on the severity of respiratory symptoms in stable COPD. E-RS: COPD RS-Total Score was derived based on weekly averages of daily assessed 11 respiratory symptom items contained in the 14-item EXACT questionnaire. The RS-Total Score represented overall respiratory symptom severity, ranged from 0 to 40. Summation procedure was used to derive the three daily domain scores: 1). RS-Breathlessness (range 0–17), 2) RS-Cough and Sputum (score range 0–11), 3) RS-Chest Symptoms (score range 0–12). The higher the score, more severe were the symptoms. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    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
    467
    461
    Units: score on a scale
        least squares mean (standard error)
    -1.558 ± 0.256
    -2.694 ± 0.257
    Statistical analysis title
    		 Change from Baseline: E-RS: COPD RS Total Score
    Statistical analysis description
    Derived from MMRM model with the change from baseline in E-RS: COPD RS-Total Score to Week 52 as response variables, and treatment group, region (pooled country), ICS dose, smoking status at screening, visit, treatment-by-visit interaction, baseline E-RS: COPD RS-Total Score, and baseline E-RS: COPD RS-Total Score-by-visit interaction as covariates. Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
    Comparison groups
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    928
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012 [8]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.823
         upper limit
    		 -0.45
    Notes
    [8] - Threshold for significance at 0.049 level.

    Secondary: Annualized Rate of Moderate or Severe COPD Exacerbation Over the 52-Week Treatment Period in Subgroup of Participants With Baseline FeNO >=20 Ppb

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    End point title
    		 Annualized Rate of Moderate or Severe COPD Exacerbation Over the 52-Week Treatment Period in Subgroup of Participants With Baseline FeNO >=20 Ppb
    End point description
    Moderate exacerbations were recorded by the Investigator and defined as AECOPD 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 among participants with baseline FeNO >=20 ppb was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party. The subgroup of participants with baseline FeNO >=20 ppb within the ITT population were included.
    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
    188
    195
    Units: exacerbation per participant-year
        number (confidence interval 95%)
    1.117 (0.831 to 1.502)
    0.699 (0.510 to 0.958)
    Statistical analysis title
    		 Annualized rate-subgroup FeNO>=20 ppb: 52 weeks
    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
    Placebo v Dupilumab 300 mg q2w
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0052
    Method
    		 Negative binomial model
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.418
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.728
         upper limit
    		 -0.109
    Notes
    [9] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Threshold for significance at 0.049 level. Parameter estimate was derived using delta method.

    Secondary: Change From Baseline in Pre-BD FEV1 to Weeks 2, 4, 8, 24, 36 and 44

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    End point title
    		 Change From Baseline in Pre-BD FEV1 to Weeks 2, 4, 8, 24, 36 and 44
    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. Spirometry was performed after a wash out period of bronchodilators according to their action duration. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 2, 4, 8, 24, 36 and 44
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    469
    466
    Units: liters
    least squares mean (standard error)
        Week 2
    0.075 ± 0.017
    0.159 ± 0.017
        Week 4
    0.069 ± 0.017
    0.163 ± 0.017
        Week 8
    0.069 ± 0.017
    0.149 ± 0.017
        Week 24
    0.068 ± 0.018
    0.170 ± 0.018
        Week 36
    0.072 ± 0.018
    0.155 ± 0.018
        Week 44
    0.089 ± 0.019
    0.176 ± 0.019
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-BD FEV1 to Weeks 2, 4, 8, 12, 24, 36 and 52

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    End point title
    		 Change From Baseline in Post-BD FEV1 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-BD FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    469
    467
    Units: liters
    least squares mean (standard error)
        Week 2
    0.071 ± 0.017
    0.158 ± 0.017
        Week 4
    0.080 ± 0.017
    0.158 ± 0.017
        Week 8
    0.077 ± 0.018
    0.153 ± 0.018
        Week 12
    0.084 ± 0.018
    0.156 ± 0.018
        Week 24
    0.072 ± 0.019
    0.169 ± 0.019
        Week 36
    0.072 ± 0.019
    0.155 ± 0.019
        Week 52
    0.058 ± 0.019
    0.138 ± 0.019
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pre-BD Forced Expiratory Flow at 25 Percent (%) to 75% (FEF 25-75%) of Forced Vital Capacity (FVC) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52

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    End point title
    		 Change From Baseline in Pre-BD Forced Expiratory Flow at 25 Percent (%) to 75% (FEF 25-75%) of Forced Vital Capacity (FVC) to Weeks 2, 4, 8, 12, 24, 36, 44, and 52
    End point description
    FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) 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. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36, 44 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    469
    466
    Units: liters/second
    least squares mean (standard error)
        Week 2
    0.065 ± 0.016
    0.110 ± 0.016
        Week 4
    0.066 ± 0.015
    0.115 ± 0.015
        Week 8
    0.069 ± 0.016
    0.114 ± 0.016
        Week 12
    0.076 ± 0.016
    0.137 ± 0.016
        Week 24
    0.080 ± 0.017
    0.142 ± 0.017
        Week 36
    0.087 ± 0.017
    0.132 ± 0.017
        Week 44
    0.091 ± 0.017
    0.162 ± 0.017
        Week 52
    0.088 ± 0.017
    0.135 ± 0.017
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-BD FEF 25-75% to Weeks 2, 4, 8, 12, 24, 36 and 52

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    End point title
    		 Change From Baseline in Post-BD FEF 25-75% to Weeks 2, 4, 8, 12, 24, 36 and 52
    End point description
    FEF is the amount of air (in liters) which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air (in liters) 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. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Weeks 2, 4, 8, 12, 24, 36 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    469
    467
    Units: liters/second
    least squares mean (standard error)
        Week 2
    0.074 ± 0.017
    0.135 ± 0.017
        Week 4
    0.087 ± 0.017
    0.144 ± 0.017
        Week 8
    0.083 ± 0.017
    0.144 ± 0.017
        Week 12
    0.089 ± 0.018
    0.161 ± 0.018
        Week 24
    0.093 ± 0.019
    0.169 ± 0.019
        Week 36
    0.093 ± 0.019
    0.161 ± 0.018
        Week 52
    0.093 ± 0.019
    0.153 ± 0.019
    No statistical analyses for this end point

    Secondary: Annualized Rate of Severe COPD Exacerbations Over the 52-Week Treatment Period

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    End point title
    		 Annualized Rate of Severe COPD Exacerbations Over the 52-Week Treatment Period
    End point description
    Moderate exacerbations were recorded by the Investigator and defined as AECOPD 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 requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting 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 exacerbations that occurred during the treatment period divided by the total number of participant-years treated. Events were adjudicated by independent third party. The ITT population consisted of the randomized population 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
    471
    468
    Units: exacerbation per participant-years
        number (confidence interval 95%)
    0.086 (0.050 to 0.147)
    0.072 (0.040 to 0.132)
    No statistical analyses for this end point

    Secondary: Time to First Moderate or Severe COPD Exacerbation During the 52-Week Treatment Period

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    End point title
    		 Time to First Moderate or Severe COPD Exacerbation 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. The median time to first severe exacerbation was derived from Cox regression model. Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations were recorded by the Investigator and defined as AECOPD requiring hospitalization, or observation for >24 hours in an emergency department/urgent care facility or resulting in death. For both moderate and severe events to be counted as separate events, they were separated by at least 14 days. The ITT population consisted of the randomized population analyzed according to the treatment group allocated by randomization.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Weeks 12, 24, 36 and 52
    End point values
    		 Placebo Dupilumab 300 mg q2w
    Number of subjects analysed
    471
    468
    Units: weeks
    median (confidence interval 95%)
        Up to Week 12
    0.019 (0.009 to 0.035)
    0.024 (0.013 to 0.041)
        Up to Week 24
    0.039 (0.024 to 0.059)
    0.034 (0.021 to 0.054)
        Up to Week 36
    0.045 (0.029 to 0.067)
    0.039 (0.024 to 0.059)
        Up to Week 52
    0.061 (0.042 to 0.086)
    0.043 (0.027 to 0.065)
    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) [10]
    End point description
    An Adverse Event (AE):Any untoward medical occurrence in participant temporally associated with use of study treatment, whether or not considered related to study treatment. TEAEs:AEs that developed or worsened in grade or became serious during TE period which was defined as the period from time of first dose of study treatment until last visit in study. Serious adverse events (SAE):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 or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. The Safety population consisted of 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
    TEAEs were collected from the time from the first administration of study treatment to the last administration of the study treatment + 98 days, up to 491 days
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: One participant was exposed to different treatment other than planned (was randomized to placebo arm and received dupilumab on Day 40). The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used.
    End point values
    		 Placebo Dupilumab 300 mg q2w-Safety population
    Number of subjects analysed
    470
    469 [11]
    Units: participants
    number (not applicable)
        Any TEAE
    359
    365
        Any TESAE
    74
    65
    Notes
    [11] - One participant exposed to different treatment other than planned.
    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
    Number of participants with treatment-emergent response to dupilumab with peak post-baseline titers during the on-treatment period are reported. Treatment-emergent response was defined as a positive response in the ADA assay post first dose, when baseline results were negative or missing. Categories were based on titer values and included: low (Titer <1000); moderate (1000<=Titer<=10,000); and high (Titer >10,000). On-treatment period was defined as last study treatment administration plus 14 days; that is, Week 52. The ADA population consisted of all participants in the Safety population with at least 1 reportable ADA results (either ‘ADA negative’ or ‘ADA positive’) 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
    453
    462
    Units: participants
    number (not applicable)
        Low titer
    7
    27
        Moderate titer
    0
    1
        High titer
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were collected from the time from the first administration of study treatment to the last administration of the study treatment + 98 days, up to 491 days
    Adverse event reporting additional description
    Analysis was performed on the Safety population. One participant was exposed to different treatment other than planned (was randomized to placebo arm but received dupilumab on Day 40). 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
    25.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to dupilumab 300 mg as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52).

    Reporting group title
    Dupilumab 300 mg q2w-Safety population
    Reporting group description
    		 Participants received dupilumab 300 mg administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52). One participant was exposed to different treatment other than planned (was randomized to placebo arm and received dupilumab on Day 40. The actual arm was considered as dupilumab 300 mg q2w. In safety analyses, the actual arms are used).

    Serious adverse events
    		 Placebo Dupilumab 300 mg q2w-Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 470 (15.74%)
    65 / 469 (13.86%)
         number of deaths (all causes)
    9
    8
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Glioblastoma
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ductal Adenocarcinoma Of Pancreas
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung Carcinoma Cell Type Unspecified Stage Iv
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung Adenocarcinoma
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Lung
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Emergency
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Vascular Disorder
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Artery Occlusion
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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
    Ovarian Cyst
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (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
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    2 / 470 (0.43%)
    2 / 469 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atelectasis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Respiratory Failure
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    26 / 470 (5.53%)
    28 / 469 (5.97%)
         occurrences causally related to treatment / all
    0 / 34
    0 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    3 / 470 (0.64%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic Disorder
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax Traumatic
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    2 / 470 (0.43%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Abrasion
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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
    2 / 470 (0.43%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Second Degree
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    2 / 470 (0.43%)
    2 / 469 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    2 / 470 (0.43%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cor Pulmonale Acute
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 470 (0.21%)
    2 / 469 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal Rhythm
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Basal Ganglia Haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 470 (0.00%)
    2 / 469 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    2 / 470 (0.43%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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 / 470 (0.21%)
    0 / 469 (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
    Anaemia
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Loss Anaemia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Polyp
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Ischaemia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         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
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal Syndrome
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Wall Abscess
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (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
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Bacterial
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Infective
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    5 / 470 (1.06%)
    2 / 469 (0.43%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Covid-19
         subjects affected / exposed
    4 / 470 (0.85%)
    3 / 469 (0.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 470 (0.43%)
    3 / 469 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 470 (2.55%)
    6 / 469 (1.28%)
         occurrences causally related to treatment / all
    0 / 13
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epiglottitis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    2 / 470 (0.43%)
    0 / 469 (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
    1 / 470 (0.21%)
    0 / 469 (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
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 469 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 469 (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
    		 Placebo Dupilumab 300 mg q2w-Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 470 (36.60%)
    168 / 469 (35.82%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    30 / 470 (6.38%)
    26 / 469 (5.54%)
         occurrences all number
    36
    28
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 470 (5.96%)
    17 / 469 (3.62%)
         occurrences all number
    32
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 470 (7.02%)
    38 / 469 (8.10%)
         occurrences all number
    39
    57
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 470 (3.62%)
    25 / 469 (5.33%)
         occurrences all number
    18
    34
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    16 / 470 (3.40%)
    25 / 469 (5.33%)
         occurrences all number
    17
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    45 / 470 (9.57%)
    45 / 469 (9.59%)
         occurrences all number
    60
    55
    Upper Respiratory Tract Infection
         subjects affected / exposed
    46 / 470 (9.79%)
    37 / 469 (7.89%)
         occurrences all number
    66
    49

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2019
    The overall rationale for the changes implemented in the protocol amendment was to address feedback from Health authorities.
    29 Sep 2020
    This amendment was implemented to replace some on-site study visits and assessments by telephone visits to decrease the burden on participants, to minimize Coronavirus disease-2019 pandemic-related risks in this vulnerable and elderly population of participants with COPD, as well as to update the list of adverse events of special interest with the updated Sponsor safety information related to eye disorders, that is, addition of any severe type of conjunctivitis or blepharitis, and keratitis. Specified that self-injection of dupilumab required training and documentation and it also specifies with approved label. Correction on type of COPD exacerbations assessed by the EXACT. Update based on deleted assessments for FEV1 and FEF because of replacement of on-site visits to telephone visits. Allowed more flexibility for rescreening of participants. Provided further clarity for supply and administration of study treatment. Updated contraceptive guidance and collection of pregnancy information as per sponsor standard operating procedures.

    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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