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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group, Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety and Tolerability of SAR440340/REGN3500, in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2017-003290-34
    Trial protocol
    		 DE   PL  
    Global end of trial date
    21 Feb 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Dec 2022
    First version publication date
    07 Mar 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor update to current information

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT15104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03546907
    WHO universal trial number (UTN)
    		 U1111-1194-2134
    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
    20 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate effects of SAR440340 (anti-interleukin-33 [IL33] monoclonal antibody [mAb]) compared with placebo, on the annualised rate of moderate-to-severe acute exacerbations of COPD (AECOPD) over up to 52 weeks of treatment.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 At screening, subjects were on standard of care background therapy, for 3 months prior to Visit 2/Randomisation and at a stable dose for at least 1 month prior to the Screening Visit 1, including either: Double therapy: long-acting beta2 [β2] adrenergic agonist (LABA) + Long-acting muscarinic antagonist (LAMA) or inhaled corticosteroid (ICS) + LABA or ICS + LAMA; or Triple therapy: ICS + LABA + LAMA.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 41
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Chile: 38
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    Ukraine: 40
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    343
    EEA total number of subjects
    67
    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)
    176
    From 65 to 84 years
    167
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 83 centers in 10 countries, out of which 78 centers randomised at least 1 subject. A total of 653 subjects were screened from 16-July-2018 to 01-April-2019, of which 310 subjects were screen failures mainly due to selection criteria not met.

    Pre-assignment
    Screening details
    		 A total of 343 subjects were randomised and treated in this study. Subjects were randomised in 1:1 ratio to receive treatment SAR440340 and matching placebo for SAR440340.

    Period 1
    Period 1 title
    Overall (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
    		 Subjects received placebo matched to SAR440340 administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W). Subjects were treated for a minimum of 24 weeks and 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 investigational medical product [IMP] i.e., at Week 52)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to SAR440340 Q2W was administered as 2 SC injection (1.5 millilitres [mL]).

    Arm title
    		 SAR440340
    Arm description
    		 Subjects received SAR440340 300 milligrams (mg) administered as 2 SC injections Q2W. Subjects were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Itepekimab
    Investigational medicinal product code
    SAR440340/REGN3500
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR440340 300 mg Q2W was administered as 2 SC injections (1.5 mL).

    Number of subjects in period 1
    		Placebo SAR440340
    Started
    171
    172
    Completed
    154
    151
    Not completed
    17
    21
         Adverse events (AEs)
    7
    10
         Other-unspecified
    1
    1
         Lack of efficacy
    1
    1
         Withdrawal by subject
    8
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to SAR440340 administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W). Subjects were treated for a minimum of 24 weeks and 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 investigational medical product [IMP] i.e., at Week 52)

    Reporting group title
    SAR440340
    Reporting group description
    		 Subjects received SAR440340 300 milligrams (mg) administered as 2 SC injections Q2W. Subjects were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52).

    Reporting group values
    		 Placebo SAR440340 Total
    Number of subjects
    		 171 172 343
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.0 ( 6.5 ) 63.7 ( 6.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 76 73 149
        Male
    		 95 99 194
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 169 170 339
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Number of subjects with smoking history
    Subjects with current and former smoking history status were reported in this baseline measure.
    Units: Subjects
        Current
    		 82 74 156
        Former
    		 89 98 187
    Standard of care background therapy
    At screening, subjects were on standard of care background therapy, for 3 months prior to Visit 2/Randomisation and at a stable dose for at least 1 month prior to the Screening Visit 1, including either: Double therapy: LABA + LAMA or ICS + LABA or ICS + LAMA; or Triple therapy: ICS + LABA + LAMA.
    Units: Subjects
        LABA+LAMA
    		 24 23 47
        ICS+LABA
    		 36 33 69
        ICS+LAMA
    		 0 1 1
        ICS+LABA+LAMA
    		 111 115 226
    Age at diagnosis of chronic obstructive pulmonary disease (COPD)
    Units: years
        arithmetic mean (standard deviation)
    		 55.5 ( 8.0 ) 55.4 ( 7.8 ) -
    Mean number of moderate COPD exacerbations experienced within 1 year before screening visit
    Moderate exacerbations events were defined as acute exacerbation of chronic obstructive pulmonary disease (AECOPD) that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics.
    Units: exacerbations
        arithmetic mean (standard deviation)
    		 1.8 ( 1.2 ) 1.8 ( 1.1 ) -
    Mean number of severe COPD exacerbations experienced within 1 year before screening visit
    Severe exacerbations events were defined as AECOPD requiring hospitalisation, emergency medical care visit or resulting in death.
    Units: exacerbations
        arithmetic mean (standard deviation)
    		 0.4 ( 0.6 ) 0.3 ( 0.6 ) -
    Predicted baseline post-bronchodilator forced expiratory volume in 1 second (FEV1)
    FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer.
    Units: percent predicted FEVI
        arithmetic mean (standard deviation)
    		 49.02 ( 12.18 ) 49.62 ( 12.34 ) -
    Baseline COPD assessment test (CAT) score
    The CAT is a 8-item self-administered questionnaire that is designed for participants with COPD to measure the effects of the disease on their quality of lives. Each question is scored in a range between 0 to 5 according to subjects feelings about the disease, where 0 = "I am very happy" to 5 = "I am very sad". Total CAT score (sum of the 8 individual question scores) ranged from 0 to 40, where 0 to 10= mild, 11 to 20= moderate, 21 to 30= severe, 31 to 40= very severe; higher score indicated worse symptoms.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 21.66 ( 5.23 ) 21.89 ( 5.84 ) -
    Baseline blood eosinophil count
    Units: Giga cells per litre
        arithmetic mean (standard deviation)
    		 0.25 ( 0.19 ) 0.27 ( 0.24 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to SAR440340 administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W). Subjects were treated for a minimum of 24 weeks and 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 investigational medical product [IMP] i.e., at Week 52)

    Reporting group title
    SAR440340
    Reporting group description
    		 Subjects received SAR440340 300 milligrams (mg) administered as 2 SC injections Q2W. Subjects were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52).

    Primary: Annualised Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Subjects

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    End point title
    		 Annualised Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Subjects
    End point description
    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 events were defined as AECOPD requiring hospitalisation, emergency medical care visit or resulting in death. Annualised event rate was calculated as the total number of exacerbations that occurred during the treatment period divided by the total number of subject-years treated. Analysis was performed on modified intent-to-treat (mITT) population that included all randomised subjects who had received at least 1 dose of IMP, analysed according to the treatment group allocated by randomisation.
    End point type
    Primary
    End point timeframe
    From Baseline up to Week 52
    End point values
    		 Placebo SAR440340
    Number of subjects analysed
    171
    172
    Units: exacerbation per subject-years
        number (confidence interval 95%)
    1.610 (1.318 to 1.968)
    1.301 (1.052 to 1.61)
    Statistical analysis title
    		 SAR440340 versus (vs.) Placebo
    Statistical analysis description
    Analysis was performed using negative binomial regression model with total number of events occurring during observation duration as response variable, treatment, baseline eosinophil strata, region, number of severe COPD exacerbations experienced in previous year(0 vs. 1+) at baseline, smoking history (current vs. former smoker), post-BD FEV1 percent(%) predicted (less than[<]50% vs greater than equal[>=]50%) at baseline as covariates, and log-transformed observation duration as offset variable.
    Comparison groups
    SAR440340 v Placebo
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1296 [1]
    Method
    		 Negative binomial regression model
    Parameter type
    		 Rate ratio
    Point estimate
    0.808
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.613
         upper limit
    		 1.065
    Notes
    [1] - Threshold for significance for p-value was 0.05.

    Secondary: Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24

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    End point title
    		 Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24
    End point description
    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. A mixed-effect model with repeated measures (MMRM) was first used to model the change from baseline at each post randomisation timepoint up to Week 24, then the predicted values of Week 16 to Week 24 were averaged to provide an overall assessment of change from baseline in FEV1. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 16 through Week 24
    End point values
    		 Placebo SAR440340
    Number of subjects analysed
    171
    172
    Units: litres
        least squares mean (standard error)
    0.0 ( 0.02 )
    0.06 ( 0.02 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 24

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    End point title
    		 Change From Baseline in Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 24
    End point description
    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 within 30 minutes after administration of bronchodilator (4 puffs of albutamol/albuterol [100 micrograms {mcg}] or ipratropium bromide [20 mcg]). Analysis was performed on mITT population. Here, ‘Number of subjects analysed’ signifies number of subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo SAR440340
    Number of subjects analysed
    163
    165
    Units: litres
        arithmetic mean (standard deviation)
    0.01 ( 0.22 )
    0.04 ( 0.24 )
    No statistical analyses for this end point

    Secondary: Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)

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    End point title
    		 Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
    End point description
    Time to first moderate or severe exacerbation was calculated as onset date of first moderate or severe AECOPD minus randomisation date + 1. Median time to first severe exacerbation was derived from Kaplan-Meier estimates. Moderate exacerbations events were recorded by investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events: defined as AECOPD requiring hospitalisation, emergency medical care visit or resulting in death. Analysis was performed on mITT population. Here, '99999' signifies that upper limit of 95% confidence interval was not computable because the curve that represents upper confidence limits for survivor function lies above 0.5.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 52 weeks
    End point values
    		 Placebo SAR440340
    Number of subjects analysed
    171
    172
    Units: days
        median (confidence interval 95%)
    199.0 (139.00 to 266.00)
    277.0 (204.00 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of IMP up to 22 weeks after last dose of IMP (i.e., minimum up to 46 weeks and a maximum of up to 72 weeks) regardless of seriousness or relationship to IMP
    Adverse event reporting additional description
    Analysis was performed on safety population that included all randomised subjects who received at least 1 injection of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to SAR440340 administered as 2 SC injections Q2W. Subjects were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52).

    Reporting group title
    SAR440340
    Reporting group description
    		 Subjects received SAR440340 300 mg administered as 2 SC injections Q2W. Subjects were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52).

    Serious adverse events
    		 Placebo SAR440340
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 171 (21.05%)
    29 / 172 (16.86%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial Adenocarcinoma
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Lobular Breast Carcinoma
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Adenocarcinoma Stage Iii
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Cell Lung Cancer
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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
    14 / 171 (8.19%)
    11 / 172 (6.40%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pickwickian Syndrome
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 171 (1.17%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    4 / 171 (2.34%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol Abuse
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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
    Burns Second Degree
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 171 (0.58%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary Artery Stenosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress Cardiomyopathy
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial Paresis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic Cerebral Infarction
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    2 / 171 (1.17%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic Gastritis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive Pancreatitis
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Chronic
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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
    Renal Colic
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         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
    Back Pain
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Babesiosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis Of Male External Genital Organ
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Infective
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective Exacerbation Of Chronic Obstructive Airways Disease
         subjects affected / exposed
    5 / 171 (2.92%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 171 (1.75%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subperiosteal Abscess
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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 Bacterial
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo SAR440340
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 171 (45.61%)
    60 / 172 (34.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 171 (6.43%)
    3 / 172 (1.74%)
         occurrences all number
    12
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 171 (13.45%)
    14 / 172 (8.14%)
         occurrences all number
    35
    24
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 171 (8.19%)
    16 / 172 (9.30%)
         occurrences all number
    17
    20
    Nasopharyngitis
         subjects affected / exposed
    29 / 171 (16.96%)
    28 / 172 (16.28%)
         occurrences all number
    43
    40
    Upper Respiratory Tract Infection
         subjects affected / exposed
    14 / 171 (8.19%)
    13 / 172 (7.56%)
         occurrences all number
    17
    17

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2018
    Following amendments were made: 1) Clarification for the biomarker blood eosinophils and neutrophils collection visits per Health Authorities’ request. 2) Details added to the justification for dose. 3) Exclusion criteria was modified: -subjects with COPD diagnosed within the 6 months prior to randomisation was deleted. -Known allergy to doxycycline or related compounds was modified per the Healthy Authorities' request, to also exclude subjects with a history of systemic hypersensitivity to any excipients of the IMP. -Subjects with cardiovascular diseases/conditions was modified per the Health Authorities' request, to exclude subjects with grade 3 hypertension (high cardiovascular risk). 4) Removed intra-articular steroids from permitted concomitant therapy. 5) COPD exacerbation: “Any course of systemic steroids/antibiotics started <7 days of finishing a previous course should be considered as treatment for a single exacerbation” was added, to provide clarification with regard to reporting of COPD exacerbations. 6) Subject reported outcomes questionnaires: inconsistency between set-up of e-diary and the protocol e-diary language was corrected.

    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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