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    Clinical Trial Results:
    A Phase IIa, two-part, randomised, multi-centre, multinational, double-blind, placebo-controlled, parallel group study to compare the efficacy and safety of BCT197 when added on to standard of care for the treatment of acute respiratory exacerbations of chronic obstructive pulmonary disease (COPD) requiring hospitalisation in adults.

    Summary
    EudraCT number
    		 2015-004631-13
    Trial protocol
    		 LV   HU   GB   RO   CZ   DE   BG   IT  
    Global end of trial date
    07 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MBCT206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02700919
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mereo BioPharma 1 Ltd
    Sponsor organisation address
    4th Floor, 1 Cavendish Place, London, United Kingdom, W1G 0QF
    Public contact
    William Moore, Mereo BioPharma Group, +44 (0) 333 023 7300, enquiries@mereobiopharma.com
    Scientific contact
    Jackie Parkin, Mereo BioPharma Group, +44 (0) 333 023 7300, enquiries@mereobiopharma.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
    07 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of two different dosing regimens of BCT197 added to standard of care (SoC) versus placebo added to SoC in the treatment of acute respiratory exacerbations of COPD that required hospitalisation by comparison of change in forced expiratory volume in 1 second (FEV1) from Baseline (pre-dose) to Day 7.
    Protection of trial subjects
    This study was conducted in accordance with current applicable regulations, International Council for Harmonisation (ICH) guidelines, and local legal requirements. It complies with the ethical principles described in the 18th World Medical Assembly (Helsinki 1964) and amendments of the 29th (Tokyo 1975), 35th (Venice 1983), 41st (Hong Kong 1989), and 48th (South Africa 1996) World Medical Assemblies, Declaration of Helsinki. The risk to subjects in this study were minimised by compliance with the inclusion/exclusion criteria, close clinical monitoring, including signs and symptoms related to the potential risks of p38 mitogen-activated protein kinase inhibitors for at least 25 weeks following the last dose of study medication. Additional stringent monitoring for inclusion in the study with specific observation for any class effects was performed throughout the study.
    Background therapy
    		 This study did not restrict the appropriate care of the subject and allowed the use of the current institution SoC with respect to dose, regimens, duration of treatment for medical treatment of the subject. In agreement with the updated version of global initiative for chronic obstructive lung disease (2015) for the treatment of acute exacerbations of COPD, subjects must have been receiving at least steroids and/or antibiotics. However medications that may have interfered with metabolism of the study drug or that may have brought additional risk to the subject were to be avoided. Subjects were eligible only if their SoC treatment had been initiated less than 24 hours before randomisation and dosing.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Romania: 30
    Country: Number of subjects enrolled
    Bulgaria: 94
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 64
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    279
    EEA total number of subjects
    241
    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)
    137
    From 65 to 84 years
    140
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 52 investigator centres in 10 countries worldwide. The target population was subjects with acute severe exacerbations requiring hospitalisation; patients with this condition are usually expected to be treated in the emergency room (ER). Multiple inclusion criteria were used to enrich for the diagnosis of COPD.

    Pre-assignment
    Screening details
    		 Subjects were screened on the day they presented with an acute exacerbation (Day 1); there was no separate Screening Visit as subjects received their first dose of study treatment within 24 hours of presenting with an acute exacerbation. Of the 335 subjects screened for entry into the study, 282 were randomized and 279 received study treatment.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BCT197 High Dose Regimen
    Arm description
    		 Participants received 75 mg BCT197 orally on Day 1. Subsequent doses with 40 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BCT197
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BCT197 hard gelatine capsules were administered orally with fluids at the same time of day at a dose of 75 mg (1 capsule of 50 mg and 1 capsule of 25 mg) on Day 1 and at a dose of 40 mg (2 capsules of 20 mg) on Day 3 and Day 5.

    Arm title
    		 BCT197 Low Dose Regimen
    Arm description
    		 Participants received 40 mg BCT197 orally on Day 1. Subsequent doses with 20 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BCT197
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    BCT197 hard gelatine capsules were administered orally with fluids at the same time of day at a dose of 40 mg (2 capsules of 20 mg) on Day 1 and at a dose of 20 mg (1 capsule of 20 mg) on Day 3 and Day 5.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo orally on Day 1. Subsequent doses with placebo were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two matching placebo capsules were administered orally with fluids at the same time of day on Day 1, Day 3, and Day 5.

    Number of subjects in period 1
    		BCT197 High Dose Regimen BCT197 Low Dose Regimen Placebo
    Started
    92
    96
    91
    Completed
    82
    85
    87
    Not completed
    10
    11
    4
         Adverse event, serious fatal
    1
    -
    -
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    5
    8
    2
         Adverse event, non-fatal
    -
    3
    1
         Not specified
    1
    -
    1
         Lost to follow-up
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BCT197 High Dose Regimen
    Reporting group description
    		 Participants received 75 mg BCT197 orally on Day 1. Subsequent doses with 40 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    BCT197 Low Dose Regimen
    Reporting group description
    		 Participants received 40 mg BCT197 orally on Day 1. Subsequent doses with 20 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo orally on Day 1. Subsequent doses with placebo were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group values
    		 BCT197 High Dose Regimen BCT197 Low Dose Regimen Placebo Total
    Number of subjects
    		 92 96 91 279
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ± 8.21 63.3 ± 8.68 64.9 ± 7.34 -
    Gender categorical
    Units: Subjects
        Female
    		 24 28 30 82
        Male
    		 68 68 61 197
    Race/Ethnicity
    Units: Subjects
        Asian
    		 0 1 0 1
        White
    		 92 95 90 277
        Other
    		 0 0 1 1
    FEV1 at Screening: Pre-bronchodilator
    Until Protocol V3.0 (Amendment 2), all spirometry measurements at Screening were conducted pre- and post-bronchodilator. From Protocol V4.0 (Amendment 3), spirometry at Screening was performed on-bronchodilator in the acute exacerbation setting. This was taken after any regular long acting bronchodilator administration and 30 minutes after short acting bronchodilator medication.
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 0.875 ± 0.3649 0.871 ± 0.3091 0.921 ± 0.2775 -
    FEV1 at Screening: Post-bronchodilator
    Until Protocol V3.0 (Amendment 2), all spirometry measurements at Screening were conducted pre- and post-bronchodilator. From Protocol V4.0 (Amendment 3), spirometry at Screening was performed on-bronchodilator in the acute exacerbation setting. This was taken after any regular long acting bronchodilator administration and 30 minutes after short acting bronchodilator medication.
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 1.149 ± 0.4051 1.040 ± 0.4030 1.029 ± 0.3551 -
    Forced Vital Capacity (FVC) at Screening: Pre-bronchodilator
    Until Protocol V3.0 (Amendment 2), all spirometry measurements at Screening were conducted pre- and post-bronchodilator. From Protocol V4.0 (Amendment 3), spirometry at Screening was performed on-bronchodilator in the acute exacerbation setting. This was taken after any regular long acting bronchodilator administration and 30 minutes after short acting bronchodilator medication.
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.410 ± 0.8883 2.137 ± 0.8675 2.352 ± 0.7623 -
    FVC at Screening – Post-bronchodilator
    Until Protocol V3.0 (Amendment 2), all spirometry measurements at Screening were conducted pre- and post-bronchodilator. From Protocol V4.0 (Amendment 3), spirometry at Screening was performed on-bronchodilator in the acute exacerbation setting. This was taken after any regular long acting bronchodilator administration and 30 minutes after short acting bronchodilator medication.
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.644 ± 0.8443 2.503 ± 0.8507 2.424 ± 0.7262 -

    End points

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    End points reporting groups
    Reporting group title
    BCT197 High Dose Regimen
    Reporting group description
    		 Participants received 75 mg BCT197 orally on Day 1. Subsequent doses with 40 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    BCT197 Low Dose Regimen
    Reporting group description
    		 Participants received 40 mg BCT197 orally on Day 1. Subsequent doses with 20 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo orally on Day 1. Subsequent doses with placebo were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Subject analysis set title
    BCT197 High Dose Regimen - ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included all randomized subjects who received at least one high dose of BCT197 and who provided a Baseline and at least one post-Baseline FEV1 value.

    Subject analysis set title
    BCT197 Low Dose Regimen - ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included all randomized subjects who received at least one low dose of BCT197 and who provided a Baseline and at least one post-Baseline FEV1 value.

    Subject analysis set title
    Placebo - ITT Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Included all randomized subjects who received at least one dose of placebo study medication and who provided a Baseline and at least one post-Baseline FEV1 value.

    Subject analysis set title
    BCT197 High Dose Regimen - PK Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic (PK) Population - All participants who received at least one high dose BCT197 administration and had at least one quantifiable plasma concentration.

    Subject analysis set title
    BCT197 Low Dose Regimen - PK Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who received at least one low dose BCT197 administration and had at least one quantifiable plasma concentration.

    Primary: Change From Baseline in FEV1 to Day 7 - ITT Population

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    End point title
    		 Change From Baseline in FEV1 to Day 7 - ITT Population
    End point description
    FEV1 data were recorded daily from Days 1 to 7 of the study using a computer-operated spirometer. Analysis was based on a linear Mixed Model for Repeated Measures (MMRM) with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first study treatment dosing, presence of cardiovascular comorbidities at Screening and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates. Baseline was defined as the last non-missing value collected before the first study treatment administration, including unscheduled assessments. Results were presented with adjusted mean difference (95% confidence interval [CI]).
    End point type
    Primary
    End point timeframe
    Days 1 to 7
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: litre(s)
        arithmetic mean (confidence interval 95%)
    0.084 (0.019 to 0.149)
    0.115 (0.049 to 0.180)
    0.057 (-0.011 to 0.125)
    Statistical analysis title
    		 Analysis of High Dose regimen
    Statistical analysis description
    Linear mixed model for repeated measures (MMRMs) with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v BCT197 Low Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Analysis of Low Dose regimen
    Statistical analysis description
    Linear MMRMs with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    BCT197 Low Dose Regimen - ITT Population v BCT197 High Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Analysis of Placebo
    Statistical analysis description
    Linear MMRMs with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first IMP dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    Placebo - ITT Population v BCT197 High Dose Regimen - ITT Population v BCT197 Low Dose Regimen - ITT Population
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.102
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Analysis of High Dose regimen vs Placebo
    Statistical analysis description
    Linear MMRMs with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.507
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.053
         upper limit
    		 0.107
    Statistical analysis title
    		 Analysis of Low Dose Regimen vs Placebo
    Statistical analysis description
    Linear MMRMs with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    BCT197 Low Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.148
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.136
    Statistical analysis title
    		 Analysis of High vs Low Dose Regimen
    Statistical analysis description
    Linear MMRMs with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v BCT197 Low Dose Regimen - ITT Population
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.443
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.031
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.109
         upper limit
    		 0.048

    Secondary: Change From Baseline in FEV1 on Days 3, 10, and 14 - ITT Population

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    End point title
    		 Change From Baseline in FEV1 on Days 3, 10, and 14 - ITT Population
    End point description
    FEV1 data were recorded daily from Days 1 to 7, and Days 10 and 14 of the study using a computer-operated spirometer. Analysis was based on a linear MMRM with change from Baseline in parameter as outcome; including treatment, visit, treatment by visit interaction, severity of airflow limitation at Baseline, blood eosinophils (%) at Baseline, time from start of current COPD exacerbation to first study treatment dosing, presence of cardiovascular comorbidities at Screening, and COPD exacerbation treatment at Screening as fixed effects, and Baseline value and Baseline by visit interaction as covariates. Baseline was defined as the last non-missing value collected before the first study treatment administration, including unscheduled assessments.
    End point type
    Secondary
    End point timeframe
    Days 3, 10, and 14
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: litre(s)
    arithmetic mean (standard deviation)
        Day 3
    0.026 ± 0.2118
    0.059 ± 0.2101
    0.063 ± 0.2392
        Day 10
    0.095 ± 0.2900
    0.071 ± 0.1995
    0.063 ± 0.2879
        Day 14
    0.047 ± 0.2627
    0.056 ± 0.2782
    0.056 ± 0.2670
    No statistical analyses for this end point

    Secondary: Normalisation Evaluation of FEV1 Over Time (Days 1 to 7, Days 10 and 14, and Weeks 8, 12 and 26) Compared With the Most Recent Test Performed Within the Last 12 Months Outside an Exacerbation - ITT Population

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    End point title
    		 Normalisation Evaluation of FEV1 Over Time (Days 1 to 7, Days 10 and 14, and Weeks 8, 12 and 26) Compared With the Most Recent Test Performed Within the Last 12 Months Outside an Exacerbation - ITT Population
    End point description
    FEV1 data were recorded daily from Days 1 to 7 and on Days 10 and 14 and Weeks 8, 12, and 26 of the study using a computer-operated spirometer. FEV1 normalisation was achieved if FEV1 returned to a value ≥ 89% of the most recent FEV1 value measured within the last 12 months outside an exacerbation (pre-study FEV1 value). Baseline was defined as the last non-missing value collected before the first study treatment administration, including unscheduled assessments. Percentages (%) were based on number of non-missing values as denominator.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1 to 7, Days 10 and 14, Week 8, Week 12, and Week 26.
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: percentage of participants
    number (not applicable)
        Baseline
    67.9
    59.3
    64.6
        Day 2
    61.9
    65.2
    73.2
        Day 3
    67.5
    62.6
    75.0
        Day 4
    62.7
    65.9
    75.0
        Day 5
    71.1
    70.2
    74.7
        Day 6
    76.8
    70.5
    75.0
        Day 7
    71.6
    71.6
    70.4
        Day 10
    77.2
    65.9
    66.7
        Day 14
    69.1
    61.6
    75.3
        Week 8
    74.0
    65.4
    71.4
        Week 12
    70.5
    63.0
    68.8
        Week 26
    75.7
    67.1
    69.3
    No statistical analyses for this end point

    Secondary: Normalisation Evaluation of FEV1/FVC Over Time (Days 1 to 7, Days 10 and 14, and Weeks 8, 12 and 26) Compared With the Most Recent Test Performed Within the Last 12 Months Outside an Exacerbation - ITT Population

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    End point title
    		 Normalisation Evaluation of FEV1/FVC Over Time (Days 1 to 7, Days 10 and 14, and Weeks 8, 12 and 26) Compared With the Most Recent Test Performed Within the Last 12 Months Outside an Exacerbation - ITT Population
    End point description
    FEV1 and FVC were recorded daily from Days 1 to 7 and on Days 10 and 14 and Weeks 8, 12, and 26 of the study using a computer-operated spirometer. FEV1/FVC normalisation was achieved if FEV1/FVC returned to a value ≥ 89% of the most recent FEV1/FVC value measured within the last 12 months outside an exacerbation (pre-study FEV1/FVC value). Baseline was defined as the last non-missing value collected before the first study treatment administration, including unscheduled assessments.
    End point type
    Secondary
    End point timeframe
    Days 1 to 7, Days 10 and 14, Week 8, Week 12, and Week 26.
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: percentage of participants
    number (not applicable)
        Baseline
    49.4
    47.8
    45.8
        Day 2
    51.8
    50.0
    55.4
        Day 3
    54.9
    53.3
    50.6
        Day 4
    53.7
    48.8
    51.9
        Day 5
    57.3
    47.0
    48.8
        Day 6
    51.9
    50.6
    51.9
        Day 7
    53.8
    51.7
    51.2
        Day 10
    52.6
    47.1
    46.3
        Day 14
    50.0
    48.2
    47.6
        Week 8
    53.9
    46.3
    51.3
        Week 12
    51.9
    43.8
    51.3
        Week 26
    54.8
    47.4
    51.3
    No statistical analyses for this end point

    Secondary: Time to Improvement of 100 mL in FEV1 Over Time - ITT Population

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    End point title
    		 Time to Improvement of 100 mL in FEV1 Over Time - ITT Population
    End point description
    Time to improvement of 100 mL in FEV1 was defined as time (in days) from initiation of study treatment until the change in FEV1 was ≥ +100 mL.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: day
        median (confidence interval 95%)
    3.0 (2.0 to 5.0)
    2.0 (2.0 to 4.0)
    4.0 (2.0 to 9.0)
    Statistical analysis title
    		 Analysis of High Dose regimen vs Placebo
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.399
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Analysis of Low Dose regimen vs Placebo
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 Low Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.091
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Analysis of High vs Low Dose regimen
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v BCT197 Low Dose Regimen - ITT Population
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.437
    Method
    		 Logrank
    Confidence interval

    Secondary: AUC of FEV1 Over Time - ITT Population

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    End point title
    		 AUC of FEV1 Over Time - ITT Population
    End point description
    AUC was calculated according to the trapezoidal rule. The trapezoidal rule is a numerical method to be used to approximate the integral or the area under a curve. Using trapezoidal rule to approximate the area under a curve first involves dividing the area into a number of strips of equal width. Then, approximating the area of each strip by the area of the trapezium formed when the upper end is replaced by a chord. The sum of these approximations gives the final numerical result of the AUC.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: mg/(mL*min)
    arithmetic mean (standard deviation)
        Day 1-3
    1.207 ± 0.4090
    1.111 ± 0.4245
    1.097 ± 0.3876
        Day 1-7
    1.232 ± 0.4296
    1.143 ± 0.4433
    1.108 ± 0.3980
        Day 1-10
    1.263 ± 0.4934
    1.174 ± 0.4380
    1.155 ± 0.4061
        Day 1-14
    1.293 ± 0.4743
    1.192 ± 0.4007
    1.125 ± 0.4293
    No statistical analyses for this end point

    Secondary: Normalisation of Respiratory Rate (RR) Over Time During Acute Exacerbation Phase - ITT Population

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    End point title
    		 Normalisation of Respiratory Rate (RR) Over Time During Acute Exacerbation Phase - ITT Population
    End point description
    RR was normalised when it returned to a baseline plateau level achieved after the acute COPD exacerbation during the Stabilization Phase. Baseline was defined as the last non-missing value collected before the first study treatment administration, including unscheduled assessments.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: percentage of participants
    number (not applicable)
        Baseline
    14.9
    20.4
    17.4
        Day 2
    28.7
    26.9
    26.7
        Day 3
    28.7
    39.8
    29.4
        Day 4
    37.9
    45.1
    37.6
        Day 5
    41.4
    52.7
    39.3
        Day 6
    44.8
    48.4
    48.2
        Day 7
    51.2
    51.6
    47.1
        Day 10
    47.6
    60.4
    48.2
        Day 14
    57.8
    52.3
    56.5
    No statistical analyses for this end point

    Secondary: Change From Baseline in RR on Days 3, 7, 10 and 14 - ITT Population

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    End point title
    		 Change From Baseline in RR on Days 3, 7, 10 and 14 - ITT Population
    End point description
    RR (breaths/min) was recorded over time during the acute exacerbation phase.
    End point type
    Secondary
    End point timeframe
    Days 1 to 14
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: breaths/min
    median (full range (min-max))
        Day 3
    -2.0 (-8.0 to 3.0)
    -1.0 (-8.0 to 5.0)
    -2.0 (-8.0 to 2.0)
        Day 7
    -3.0 (-13.0 to 8.0)
    -2.0 (-13.0 to 4.0)
    -2.0 (-12.0 to 1.0)
        Day 10
    -3.0 (-13.0 to 4.0)
    -2.0 (-14.0 to 4.0)
    -2.0 (-12.0 to 2.0)
        Day 14
    -3.0 (-13.0 to 4.0)
    -2.0 (-16.0 to 6.0)
    -3.0 (-12.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Time to Improvement Based on the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) - Patient Reported Outcome (PRO) Total Score During the Acute Exacerbation Phase - ITT Population

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    End point title
    		 Time to Improvement Based on the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) - Patient Reported Outcome (PRO) Total Score During the Acute Exacerbation Phase - ITT Population
    End point description
    Improvement based on EXACT-PRO total score is defined as a decrease in the Rolling Average EXACT score ≥ 9 points from the previous day's maximum observed value during an event. The EXACT is a 14-item PRO daily diary used to quantify and measure exacerbations of COPD. The health status of the participant is correlated to the global score, meaning a higher score corresponds to a more severe health status of the participant. An EXACT total score is computed for each day of diary collection. The EXACT total score is based on a logit scoring system with conversion to a 0 to 100 scale for ease of interpretation and use. The total score was used in the determination of exacerbation frequency, severity, and duration of exacerbation. Specifically, changes in the total score were used to define onset and recovery from an exacerbation event and the magnitude of that event. 999 = Insufficient data to evaluate the upper or lower limit.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: day
        median (confidence interval 95%)
    5.0 (3.0 to 16.0)
    6.0 (3.0 to 999)
    5.0 (3.0 to 7.0)
    Statistical analysis title
    		 Analysis of High Dose Regimen vs Placebo
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Analysis of Low Dose Regimen vs Placebo
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 Low Dose Regimen - ITT Population v Placebo - ITT Population
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.298
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Analysis of High vs Low Dose Regimen
    Statistical analysis description
    Log-rank comparison between treatment regimens.
    Comparison groups
    BCT197 High Dose Regimen - ITT Population v BCT197 Low Dose Regimen - ITT Population
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Recovery Based on EXACT-PRO Total Score During the Acute Exacerbation Phase - ITT Population

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    End point title
    		 Time to Recovery Based on EXACT-PRO Total Score During the Acute Exacerbation Phase - ITT Population
    End point description
    Recovery based on EXACT-PRO total score was defined as the first day in which a participant experiences a persistent, sustained improvement in their condition over the observed period (Day 1 to Day 29). Improvement had to be present for 7 consecutive days. The first day of the 7-day period was designated as the first day of Recovery. An EXACT total score was computed for each day of diary collection. CI: 0 to 999 = Insufficient data to evaluate the upper or lower limit.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: days
        median (confidence interval 95%)
    6.0 (0 to 999)
    6.0 (0 to 999)
    6.0 (6.0 to 7.0)
    No statistical analyses for this end point

    Secondary: Standardised AUC of EXACT-PRO Rolling Average Over Time During Acute Exacerbation Phase - ITT Population

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    End point title
    		 Standardised AUC of EXACT-PRO Rolling Average Over Time During Acute Exacerbation Phase - ITT Population
    End point description
    The standardised AUC of the EXACT-PRO were calculated from Day (a) to Day (b) using the trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: mg/(mL*min)
    median (full range (min-max))
        Day 1-7
    45.389 (20.58 to 64.94)
    44.736 (19.61 to 63.19)
    43.938 (19.00 to 67.75)
        Day 1-14
    42.641 (21.81 to 63.38)
    42.250 (22.80 to 64.87)
    42.590 (17.74 to 65.42)
        Day 1-29
    41.470 (19.43 to 62.92)
    40.932 (19.81 to 65.25)
    41.652 (20.35 to 61.27)
    No statistical analyses for this end point

    Secondary: Standardised AUC of EXACT-PRO (Breathlessness) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population

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    End point title
    		 Standardised AUC of EXACT-PRO (Breathlessness) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population
    End point description
    Information regarding the participant's condition can be obtained through 3 domain scores embedded within the EXACT measure: Breathlessness, Cough and Sputum, and Chest Symptoms. These scores also range from 0 to 100 with higher scores indicating more severe symptoms. The standardised AUC of the EXACT-PRO were calculated from Day (a) to Day (b) using the trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: mg/(mL*min)
    median (full range (min-max))
        Day 1-7
    50.083 (21.58 to 80.00)
    47.861 (15.58 to 78.00)
    47.556 (13.13 to 85.50)
        Day 1-14
    45.417 (21.27 to 79.65)
    45.577 (20.60 to 77.73)
    44.436 (17.41 to 80.69)
        Day 1-29
    44.911 (23.27 to 79.41)
    45.315 (17.84 to 77.63)
    43.387 (18.65 to 74.91)
    No statistical analyses for this end point

    Secondary: Rate of Positively Adjudicated Moderate/Severe COPD Exacerbations - ITT Population

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    End point title
    		 Rate of Positively Adjudicated Moderate/Severe COPD Exacerbations - ITT Population
    End point description
    Follow-up time per participant (years) was defined as (date of last contact - date of first study drug administration + 1)/ 365.25. Total follow-up time (years) = sum of individual participant follow-up times. Rate was calculated as total number of positively adjudicated exacerbations divided by the total follow-up time in years of the treatment group.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of study
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: per patient per year
        number (not applicable)
    0.744
    0.921
    0.904
    No statistical analyses for this end point

    Secondary: Number of COPD-Related Deaths During the Study - ITT Population

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    End point title
    		 Number of COPD-Related Deaths During the Study - ITT Population
    End point description
    Cumulative incidences of COPD-related deaths until Day 30/60/90/120/150/180 were obtained.
    End point type
    Secondary
    End point timeframe
    Days 1 to 180
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: participants
        Until Day 30
    0
    0
    1
        Until Day 60
    0
    0
    1
        Until Day 90
    0
    0
    1
        Until Day 120
    0
    0
    1
        Until Day 150
    1
    0
    1
        Until Day 180
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Time to Next Positively Adjudicated Moderate/Severe COPD Exacerbation- ITT Population

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    End point title
    		 Time to Next Positively Adjudicated Moderate/Severe COPD Exacerbation- ITT Population
    End point description
    Time to next positively adjudicated moderate/severe COPD exacerbation (in days) was defined as date when first moderate/severe COPD exacerbation symptoms started - date when current COPD exacerbation symptoms stopped, where COPD exacerbations experienced during the study were positively adjudicated by the Independent Adjudication Committee. Time to next positively adjudicated COPD exacerbation was presented in 25th percentile (95% CI) as medians were not evaluable. 999 = Insufficient data to evaluate the upper or lower limit.
    End point type
    Secondary
    End point timeframe
    Day 1 to date of next COPD exacerbation after entering the study, withdrawal or last contact date, or death date
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: days
        median (confidence interval 95%)
    168.0 (70.0 to 999)
    75.0 (45.0 to 136.0)
    143.0 (48.0 to 999)
    No statistical analyses for this end point

    Secondary: Time From Hospitalisation Admission Until the Participant Is Medically Ready for Discharge (Current COPD) - ITT Population

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    End point title
    		 Time From Hospitalisation Admission Until the Participant Is Medically Ready for Discharge (Current COPD) - ITT Population
    End point description
    Time from hospitalisation admission until the participant is medically ready for discharge (in days) = Date participant was medically ready for discharge from hospital - Date of hospitalisation admission. 'Date of hospitalisation admission' and 'Date participant was medically ready for discharge from hospital' were recorded on the 'Current COPD Exacerbation' form of the electronic case report form. Results were presented with 75th percentile (95% CI) due to the fact that 95% CI for the median was not evaluable.
    End point type
    Secondary
    End point timeframe
    Date of hospital admission to date medically ready for discharge by investigator judgement
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: days
        median (confidence interval 95%)
    9.0 (8.0 to 12.0)
    9.0 (8.0 to 13.0)
    9.0 (8.0 to 10.0)
    No statistical analyses for this end point

    Secondary: Percentage of Days With Intake of COPD Rescue Therapy - ITT Population

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    End point title
    		 Percentage of Days With Intake of COPD Rescue Therapy - ITT Population
    End point description
    Participants completed the EXACT-PRO starting from Day 1 and recorded rescue medication use and any occurrences of COPD once a day (evening) in the diary. The percentage of days with intake of rescue medications was evaluated on the basis of the information recorded daily by the participant on the diaries. A day was considered with intake of rescue medications if the answer to the question "How many puffs of rescue medication did you take since last evening?" was> 0.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: days
    arithmetic mean (standard deviation)
        Acute Exacerbation Phase (Overall)
    73.28 ± 32.721
    71.90 ± 33.565
    69.65 ± 35.674
        Stabilization Phase (Overall)
    70.78 ± 37.122
    71.08 ± 40.299
    67.35 ± 38.953
    No statistical analyses for this end point

    Secondary: Standardised AUC of EXACT-PRO (Cough and Sputum) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population

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    End point title
    		 Standardised AUC of EXACT-PRO (Cough and Sputum) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population
    End point description
    Information regarding the participant's condition can be obtained through 3 domain scores embedded within the EXACT measure: Breathlessness, Cough and Sputum, and Chest Symptoms. These scores also range from 0 to 100 with higher scores indicating more severe symptoms. The standardised AUC of the EXACT-PRO were calculated from Day (a) to Day (b) using the trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: mg/(mL*min)
    median (full range (min-max))
        Day 1-7
    36.792 (14.00 to 61.81)
    39.000 (13.00 to 71.97)
    39.035 (20.58 to 65.17)
        Day 1-14
    33.077 (16.31 to 55.35)
    36.006 (17.46 to 77.91)
    34.397 (16.50 to 66.59)
        Day 1-29
    33.467 (18.46 to 59.23)
    35.155 (16.36 to 70.85)
    32.086 (17.63 to 61.58)
    No statistical analyses for this end point

    Secondary: Standardised AUC of EXACT-PRO (Chest Symptoms) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population

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    End point title
    		 Standardised AUC of EXACT-PRO (Chest Symptoms) Rolling Average Over Time During Acute Exacerbation Phase - ITT Population
    End point description
    Information regarding the participant's condition can be obtained through 3 domain scores embedded within the EXACT measure: Breathlessness, Cough and Sputum, and Chest Symptoms. These scores also range from 0 to 100 with higher scores indicating more severe symptoms. The standardised AUC of the EXACT-PRO were calculated from Day (a) to Day (b) using the trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Days 1 to 29
    End point values
    		 BCT197 High Dose Regimen - ITT Population BCT197 Low Dose Regimen - ITT Population Placebo - ITT Population
    Number of subjects analysed
    87
    93
    86
    Units: mg/(mL*min)
    median (full range (min-max))
        Day 1-7
    41.069 (17.25 to 66.75)
    38.583 (12.00 to 65.38)
    40.722 (12.00 to 69.08)
        Day 1-14
    37.446 (14.42 to 64.54)
    36.330 (12.14 to 66.52)
    38.301 (12.00 to 67.46)
        Day 1-29
    37.717 (13.13 to 65.65)
    36.012 (13.62 to 68.75)
    37.750 (15.06 to 61.17)
    No statistical analyses for this end point

    Other pre-specified: PK of BCT197 in Adults With COPD – PK Population

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    End point title
    		 PK of BCT197 in Adults With COPD – PK Population
    End point description
    Descriptive summary of PK plasma concentration is presented as no-specific PK report is available.
    End point type
    Other pre-specified
    End point timeframe
    Days 1 to 5
    End point values
    		 BCT197 High Dose Regimen - PK Population BCT197 Low Dose Regimen - PK Population
    Number of subjects analysed
    92
    92
    Units: ng/mL
    geometric mean (confidence interval 95%)
        Day 1 (0-2 h post-dose)
    97.40 (65.13 to 145.66)
    75.98 (47.81 to 120.73)
        Day 1 (4-8h post dose)
    387.65 (343.22 to 437.83)
    283.79 (261.28 to 308.25)
        Day 1 (>12h post-dose)
    413.85 (376.28 to 455.17)
    286.40 (267.20 to 306.97)
        Day 3 (predose)
    271.10 (251.34 to 292.41)
    161.13 (147.69 to 175.80)
        Day 3 (0-2h post-dose)
    318.88 (290.57 to 349.95)
    184.46 (165.72 to 205.31)
        Day 3 (4-8h post-dose)
    496.31 (457.30 to 538.64)
    299.79 (281.99 to 318.71)
        Day 3 (>12h post-dose)
    466.86 (434.70 to 501.40)
    249.60 (231.21 to 269.46)
        Day 5 (predose)
    272.43 (246.62 to 300.95)
    128.38 (111.99 to 147.17)
        Day 5 (0-2h post-dose)
    310.20 (277.37 to 346.91)
    155.10 (130.77 to 183.94)
        Day 5 (4-8h post-dose)
    504.53 (453.33 to 561.52)
    278.73 (246.56 to 315.10)
        Day 5 (>12h post-dose)
    465.28 (423.05 to 511.72)
    240.31 (215.77 to 267.63)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from signing the informed consent form to completion of the 26 week follow-up period after the last administration of study drug.
    Adverse event reporting additional description
    Serious AEs are also included in the non-serious AE section as a non-serious AE table was not available.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    BCT197 High Dose Regimen
    Reporting group description
    		 Participants received 75 mg BCT197 orally on Day 1. Subsequent doses with 40 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    BCT197 Low Dose Regimen
    Reporting group description
    		 Participants received 40 mg BCT197 orally on Day 1. Subsequent doses with 20 mg BCT197 were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo orally on Day 1. Subsequent doses with placebo were administered orally on Day 3 and Day 5. All participants also received SoC treatment for the acute exacerbation of COPD.

    Serious adverse events
    		 BCT197 High Dose Regimen BCT197 Low Dose Regimen Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 92 (18.48%)
    27 / 96 (28.13%)
    29 / 91 (31.87%)
         number of deaths (all causes)
    2
    3
    2
         number of deaths resulting from adverse events
    2
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Laryngeal cancer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Apallic syndrome
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    13 / 92 (14.13%)
    21 / 96 (21.88%)
    22 / 91 (24.18%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 28
    0 / 25
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 92 (1.09%)
    3 / 96 (3.13%)
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 BCT197 High Dose Regimen BCT197 Low Dose Regimen Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 92 (60.87%)
    63 / 96 (65.63%)
    62 / 91 (68.13%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Laryngeal cancer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Phaeochromocytoma
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Prostate cancer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Circulatory collapse
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 92 (4.35%)
    2 / 96 (2.08%)
    4 / 91 (4.40%)
         occurrences all number
    5
    2
    4
    Hypertensive crisis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    2
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    3 / 91 (3.30%)
         occurrences all number
    2
    0
    3
    Chest discomfort
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    2 / 92 (2.17%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    2
    1
    1
    Chills
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Death
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Extravasation
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Generalised oedema
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    0
    1
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 92 (0.00%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Reproductive system and breast disorders
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Bronchospasm
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    24 / 92 (26.09%)
    32 / 96 (33.33%)
    28 / 91 (30.77%)
         occurrences all number
    33
    42
    41
    Chronic respiratory failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    3 / 92 (3.26%)
    2 / 96 (2.08%)
    4 / 91 (4.40%)
         occurrences all number
    3
    2
    5
    Emphysema
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    2
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Hypoxia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    0
    1
    1
    Paranasal cyst
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Pleural thickening
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Rales
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Respiratory failure
         subjects affected / exposed
    1 / 92 (1.09%)
    2 / 96 (2.08%)
    3 / 91 (3.30%)
         occurrences all number
    1
    2
    3
    Rhinorrhoea
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    2
    0
    0
    Tonsillar erythema
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Wheezing
         subjects affected / exposed
    2 / 92 (2.17%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    2
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 92 (0.00%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Depression
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Dysphoria
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 92 (3.26%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    3
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 92 (3.26%)
    3 / 96 (3.13%)
    2 / 91 (2.20%)
         occurrences all number
    3
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 92 (1.09%)
    4 / 96 (4.17%)
    1 / 91 (1.10%)
         occurrences all number
    1
    5
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 92 (0.00%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    0
    4
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    1
    0
    2
    Blood potassium increased
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    1
    1
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    2
    0
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 92 (0.00%)
    3 / 96 (3.13%)
    0 / 91 (0.00%)
         occurrences all number
    0
    3
    0
    Gamma-glutamyltransferase abnormal
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 92 (2.17%)
    2 / 96 (2.08%)
    1 / 91 (1.10%)
         occurrences all number
    2
    2
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    2
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Monocyte count increased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Platelet count increased
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Protein total decreased
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Fall
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Tendon injury
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Angina unstable
         subjects affected / exposed
    0 / 92 (0.00%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Atrial fibrillation
         subjects affected / exposed
    3 / 92 (3.26%)
    2 / 96 (2.08%)
    1 / 91 (1.10%)
         occurrences all number
    3
    2
    1
    Atrial tachycardia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Bundle branch block left
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac aneurysm
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac failure
         subjects affected / exposed
    1 / 92 (1.09%)
    2 / 96 (2.08%)
    2 / 91 (2.20%)
         occurrences all number
    1
    2
    2
    Cardiac failure acute
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Cor pulmonale
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Right ventricular failure
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 92 (0.00%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    2
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    2 / 91 (2.20%)
         occurrences all number
    0
    1
    2
    Ventricular tachycardia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Apallic syndrome
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Arachnoid cyst
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Brain oedema
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Coma
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    2
    0
    0
    Epilepsy
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    3 / 92 (3.26%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    3
    1
    1
    Hypotonia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    3 / 92 (3.26%)
    2 / 96 (2.08%)
    0 / 91 (0.00%)
         occurrences all number
    4
    2
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Lymphadenopathy mediastinal
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocytosis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    1
    1
    1
    Neutropenia
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Thrombocytosis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    2
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Retinal vein occlusion
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Scleral hyperaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    4 / 91 (4.40%)
         occurrences all number
    1
    0
    4
    Dyspepsia
         subjects affected / exposed
    0 / 92 (0.00%)
    4 / 96 (4.17%)
    0 / 91 (0.00%)
         occurrences all number
    0
    6
    0
    Gastric polyps
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Cholecystitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Cholelithiasis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    1
    1
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Liver injury
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Non-alcoholic fatty liver
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    1
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Pemphigoid
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    0
    1
    1
    Diabetic nephropathy
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    2
    0
    Haematuria
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Renal artery stenosis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Renal colic
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Renal cyst
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 92 (2.17%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    2
    1
    0
    Bone swelling
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    2
    0
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Infection
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    1
    1
    1
    Mastoiditis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 92 (4.35%)
    4 / 96 (4.17%)
    2 / 91 (2.20%)
         occurrences all number
    4
    4
    2
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    1
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 92 (3.26%)
    3 / 96 (3.13%)
    2 / 91 (2.20%)
         occurrences all number
    3
    3
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    3 / 92 (3.26%)
    3 / 96 (3.13%)
    0 / 91 (0.00%)
         occurrences all number
    3
    3
    0
    Sepsis
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 92 (1.09%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    1
    1
    1
    Viral infection
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 92 (1.09%)
    0 / 96 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    2
    Diabetes mellitus
         subjects affected / exposed
    2 / 92 (2.17%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    2
    0
    1
    Dyslipidaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 92 (2.17%)
    4 / 96 (4.17%)
    2 / 91 (2.20%)
         occurrences all number
    2
    4
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 92 (1.09%)
    2 / 96 (2.08%)
    1 / 91 (1.10%)
         occurrences all number
    2
    3
    1
    Hypochloraemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 92 (2.17%)
    1 / 96 (1.04%)
    1 / 91 (1.10%)
         occurrences all number
    2
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    2
    Hypoproteinaemia
         subjects affected / exposed
    0 / 92 (0.00%)
    1 / 96 (1.04%)
    0 / 91 (0.00%)
         occurrences all number
    0
    1
    0
    Obesity
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    1 / 91 (1.10%)
         occurrences all number
    0
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 92 (0.00%)
    0 / 96 (0.00%)
    2 / 91 (2.20%)
         occurrences all number
    0
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2015
    Changes were made to the original protocol at the request of the Food and Drug Administration (FDA). These included the removal of the caveat that increased creatinine or proteinuria was a discontinuation criterion unless it was due to disease progression, amendment of liver laboratory values requiring study drug discontinuation to be consistent with the FDA Drug-induced Liver Injury Premarketing Clinical Evaluation, the addition of pulse oximeter measurements was to be carried out as part of vital sign measurements. Administrative changes were also included.
    10 Mar 2016
    Amendments as required by the United Kingdom Regulatory Agency included the removal of the method of contraception under the heading “highly effective” that was not so defined in the Clinical Trials Facilitation Group guidance document, introduction of a discontinuation criterion of change in Baseline corrected QT interval by Fredericia (QTcF) ≥ 60 msec, clarification of study stopping criteria to include stopping the study at the request of the Data Monitoring Committee, definition of End of Study was added, and addition of inflammation of cervix and vagina as an adverse event of special interest to be in line with the Investigator’s Brochure. Other changes included the requirement for the initial blood sample to be collected when the subject was in a fasting state being waived due to the nature of the disease and the need to begin treatment as soon as possible, clarification provided that spirometry testing carried out at Visit 2 were used for the body mass index, airflow obstruction, dyspnoea and exercise index at Day 1 if the subject was randomised based on previous spirometry, the requirement for international normalised ratio and prothrombin time sampling and testing after Day 14 was removed as there was no systemic study drug exposure beyond that time, and reduction of electrocardiogram testing from triplicate to a single test. Clarification provided that barrier contraception was only required during the dosing period and for 5 half-lives (8 days) afterwards and that azithromycin was a prohibited medication. Other clarifications, administrative changes, and corrections of typographical errors were made.
    26 May 2016
    Changes included modification of inclusion/exclusion criteria, modifications of clinical and laboratory assessments, revision of the time frame for permitted concomitant medications, addition of theophylline to permitted concomitant medications, modification of rescue medication use, the medically fit for discharge endpoint was further clarified from a COPD perspective, suspected unexpected serious adverse reaction reporting to regulatory and ethics committees was added, the number of countries was updated from ‘approximately 8’ to ‘approximately 12’ and correction of previous clinical dosing from 14 weeks to 14 days. Administrative changes were also included.
    08 Nov 2016
    The following updates were made: clarification that the P-gp inhibitor azithromycin was not prohibited following results from a drug interaction study (Study MBCT102), removal of the use of killed vaccine within the last 14 days from exclusion criterion 10 as not considered a safety risk (exclusion limited to live vaccines), removal of killed vaccine from the list of prohibited medications as not considered a safety risk (exclusion limited to live vaccines), protocol guidance that if vaccine was given 14 days prior to, or concomitant with study drug, consideration should have been given to checking vaccine responses and/or revaccinating, visit descriptions were updated to be consistent with the schedule of assessments, removal of oral requirement for body temperature, removal of exclusion criterion 7 because long-term oxygen therapy was not prohibited since protocol amendment 3.

    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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