Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A 16-Week, Randomized, Placebo-Controlled, Double Blind, and Parallel Group Trial to Assess the Anti-Inflammatory Effects of Roflumilast in Chronic Obstructive Pulmonary Disease. The ROBERT Study (Roflumilast Biopsy European Research Trial)

    Summary
    EudraCT number
    		 2011-000582-13
    Trial protocol
    		 DE   GB   SE   PL   DK  
    Global end of trial date
    11 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2017
    First version publication date
    08 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RO-2455-402-RD
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01509677
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Register Identifier: U1111-1155-8767
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    1800 Concord Pike, PO Box 15437, Wilmington, United States, DE 19850
    Public contact
    AstraZeneca Clinical Study Information Center, AstraZeneca, 001 18772409479 x, information.center@astrazeneca.com
    Scientific contact
    AstraZeneca Clinical Study Information Center, AstraZeneca, 001 18772409479 x, information.center@astrazeneca.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
    24 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of roflumilast 500 μg tablets once daily versus placebo on inflammation parameters in bronchial biopsy tissue specimen.
    Protection of trial subjects
    SABA or SAMA could be used as rescue medication according to the individual needs of a patient.
    Background therapy
    		 Therapy consisting of any bronchodilator such as SABA, SAMA, LABA, or LAMA starting at least 6 weeks prior to V0 was allowed. The treatment had to remain stable in the course of the whole study, that is, 6 weeks of single-blind placebo administration (run-in) and 16 weeks of double-blind treatment period.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jan 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Germany: 42
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United Kingdom: 61
    Worldwide total number of subjects
    158
    EEA total number of subjects
    158
    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)
    83
    From 65 to 84 years
    75
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 N=281

    Pre-assignment period milestones
    Number of subjects started
    		 281 [1]
    Number of subjects completed
    		 158

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 123
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: According to the CSR, 296 subject where screened, of these 15 subjects were re-enrolled in the study. This gives us 281 unique patients.
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R500
    Arm description
    		 Roflumilast 500 µg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 µg tablet once daily, oral administration

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    tablet, once daily, oral administration

    Number of subjects in period 1
    		R500 Placebo
    Started
    79
    79
    Completed
    76
    73
    Not completed
    3
    6
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    3
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    R500
    Reporting group description
    		 Roflumilast 500 µg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 R500 Placebo Total
    Number of subjects
    		 79 79 158
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 37 46 83
        65 years and over
    		 42 33 75
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 64 ± 8.23 62.5 ± 8.43 -
    Gender, Male/Female
    Units: Participants
        Female
    		 19 18 37
        Male
    		 60 61 121
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 1 1
        Black or African American
    		 1 0 1
        White
    		 77 77 154
        Other
    		 1 1 2
    Age, Customized
    Units: Subjects
        Between 18 and 65 years
    		 37 46 83
        >=65 years
    		 42 33 75
    Region of Enrollment
    Units: Subjects
        Europe
    		 79 79 158

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    R500
    Reporting group description
    		 Roflumilast 500 µg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Number of CD8+ inflammatory cells in bronchial biopsy tissue.

    		 Close Top of page
    End point title
    		 Number of CD8+ inflammatory cells in bronchial biopsy tissue. [1]
    End point description
    End point type
    Primary
    End point timeframe
    16 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses colected.
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        arithmetic mean (standard deviation)
    442.4 ± 312.74
    427.1 ± 261.42
    No statistical analyses for this end point

    Primary: Number of CD8+ inflammatory cells in bronchial biopsy tissue

    		 Close Top of page
    End point title
    		 Number of CD8+ inflammatory cells in bronchial biopsy tissue
    End point description
    End point type
    Primary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        arithmetic mean (standard deviation)
    13.4 ± 302.69
    29.4 ± 298.88
    Statistical analysis title
    		 Number of CD8+ inflammatory cells
    Statistical analysis description
    2-sided test at 5% significant level
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7922
    Method
    		 Poisson regression model
    Confidence interval

    Secondary: CD68+ Count in Biopsied Material (submucosa)

    		 Close Top of page
    End point title
    		 CD68+ Count in Biopsied Material (submucosa)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        arithmetic mean (standard deviation)
    149.1 ± 113.91
    124.4 ± 93.15
    Statistical analysis title
    		 CD68+ Cell count
    Statistical analysis description
    2-sided, 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7145
    Method
    		 Poisson regression model
    Confidence interval

    Secondary: CD68+ Cell Count in Biopsied Material (submucosa): Poisson regression (ratio)

    		 Close Top of page
    End point title
    		 CD68+ Cell Count in Biopsied Material (submucosa): Poisson regression (ratio)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    126.8
    121.6
    Statistical analysis title
    		 CD68+ Cell count (ratio)
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 7136
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.119

    Secondary: Change from V2 to V6 in CD68+ Cell Count in Biopsied Material (submucosa) (ITT)

    		 Close Top of page
    End point title
    		 Change from V2 to V6 in CD68+ Cell Count in Biopsied Material (submucosa) (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    49
    46
    Units: Cells/mm^2
        least squares mean (standard error)
    6.1 ± 10.99
    -5.3 ± 11.05
    Statistical analysis title
    		 Change from V2 to V6 in CD68+ Cell count
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4606
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.2
         upper limit
    		 42.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.45

    Secondary: CD4+ Cell Counts in biopsied Material (submucosa)

    		 Close Top of page
    End point title
    		 CD4+ Cell Counts in biopsied Material (submucosa)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    304.6
    255
    Statistical analysis title
    		 CD4+ Cell Counts in biopsied Material
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2744
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.194

    Secondary: CD45+ Cell Counts in biopsied Material (submucosa)

    		 Close Top of page
    End point title
    		 CD45+ Cell Counts in biopsied Material (submucosa)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    818.4
    960.3
    Statistical analysis title
    		 CD45+ Cell counts in biopsied Material
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1128
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.086

    Secondary: Neutrophils Cell Counts in biopsied Material (submucosa)

    		 Close Top of page
    End point title
    		 Neutrophils Cell Counts in biopsied Material (submucosa)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    118.6
    127.7
    Statistical analysis title
    		 Nuetrophils cell count in biopsied material
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.674
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.164

    Secondary: CD8+ Cell Count in biopsied material (Bronchial Epithelium)

    		 Close Top of page
    End point title
    		 CD8+ Cell Count in biopsied material (Bronchial Epithelium)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    422.1
    505.3
    Statistical analysis title
    		 CD8+ cell count (bronchial epithelium)
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0677
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.082

    Secondary: CD68+ Cell Count in biopsied material (Bronchial Epithelium)

    		 Close Top of page
    End point title
    		 CD68+ Cell Count in biopsied material (Bronchial Epithelium)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    79
    79
    Units: Cells/mm^2
        number (not applicable)
    76.3
    93.1
    Statistical analysis title
    		 CD68+ cell count (bronchial epithelium)
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3566
    Method
    		 Poisson regression model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.177

    Secondary: Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Neutrophils)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Neutrophils)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    43
    44
    Units: 10^6/mL
        least squares mean (standard error)
    1.7181 ± 1.64471
    0.0827 ± 1.6122
    Statistical analysis title
    		 V1 to V5 in Absolute cell count (Neutrophils)
    Statistical analysis description
    2 sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4794
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6354
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9429
         upper limit
    		 6.2137
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.30185

    Secondary: Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Macrophages)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Macrophages)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    43
    44
    Units: 10^6/mL
        least squares mean (standard error)
    0.1017 ± 0.23396
    -0.371 ± 0.2297
    Statistical analysis title
    		 V1 to V5 in Absolute Cell count (Macrophages)
    Statistical analysis description
    2 sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1541
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4727
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.181
         upper limit
    		 1.1264
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32866

    Secondary: Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Eosinophils)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Eosinophils)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    43
    44
    Units: 10^6/mL
        least squares mean (standard error)
    -0.0986 ± 0.02639
    -0.036 ± 0.02585
    Statistical analysis title
    		 V1 to V5 in Absolute Cell count (Eosinophils)
    Statistical analysis description
    2 sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0927
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.0626
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1358
         upper limit
    		 0.0106
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03681

    Secondary: Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Lymphocytes)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Absolute Cell Count inInduced Sputum (10^6/mL): Between-Treatment Difference (Lymphocytes)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    43
    44
    Units: 10^6/mL
        least squares mean (standard error)
    -0.0167 ± 0.01167
    0.006 ± 0.01141
    Statistical analysis title
    		 V1 to V5 in Absolute Cell count (Lymphocetes)
    Statistical analysis description
    2 sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5175
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.0107
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0435
         upper limit
    		 0.022
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01647

    Secondary: Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Neutrophils)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Neutrophils)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    45
    44
    Units: 10^6/mL
        least squares mean (standard error)
    2.527 ± 2.3571
    0.382 ± 2.3535
    Statistical analysis title
    		 V1 to V5 in Differential Cell count (Neutrophils)
    Statistical analysis description
    2-sided 5 % test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5205
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.146
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.466
         upper limit
    		 8.757
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.3253

    Secondary: Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Macrophages)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Macrophages)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    45
    44
    Units: 10^6/mL
        least squares mean (standard error)
    0.315 ± 2.1328
    -0.826 ± 2.1316
    Statistical analysis title
    		 V1 to V5 in Differential Cell count (Macrophages)
    Statistical analysis description
    2-sided 5 % test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7052
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.141
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.835
         upper limit
    		 7.117
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.0057

    Secondary: Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Eosinophils)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Eosinophils)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    45
    44
    Units: 10^6/mL
        least squares mean (standard error)
    -1.826 ± 0.5214
    0.041 ± 0.52
    Statistical analysis title
    		 V1 to V5 in Differential Cell count (Eosinophils)
    Statistical analysis description
    2-sided 5 % test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0127
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.867
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.324
         upper limit
    		 -0.409
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7331

    Secondary: Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Lymphocytes)

    		 Close Top of page
    End point title
    		 Change from V1 to V5 in Differential Cell Count in Induced Sputum(10^6/mL) (Lymphocytes)
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    45
    44
    Units: 10^6/mL
        least squares mean (standard error)
    -0.137 ± 0.1332
    -0.086 ± 1.329
    Statistical analysis title
    		 V1 to V5 in Differential Cell count (Lymphocytes)
    Statistical analysis description
    2-sided 5 % test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7862
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.423
         upper limit
    		 0.321
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1871

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (alfa- 2-Macroglobulin (µg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (alfa- 2-Macroglobulin (µg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    54
    57
    Units: µg/mL
        least squares mean (standard error)
    -0.32 ± 0.73
    -0.48 ± 0.7
    Statistical analysis title
    		 Change from Base of conc. of alfa-2-Macroglobulin
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8769
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.84
         upper limit
    		 2.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.005

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (IL-8 (pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (IL-8 (pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    54
    56
    Units: pg/mL
        least squares mean (standard error)
    -827.3 ± 1995.79
    -1538.4 ± 1941.08
    Statistical analysis title
    		 Change from Base of conc. of IL-8
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7978
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    711.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4778.3
         upper limit
    		 6200.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2768.79

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (MMP type 9 (ng/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (MMP type 9 (ng/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    55
    57
    Units: ng/mL
        least squares mean (standard error)
    80.1 ± 57.07
    -8.4 ± 55.44
    Statistical analysis title
    		 Change from Base of conc of MMP type 9
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2669
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    88.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -68.6
         upper limit
    		 245.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    79.26

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (MCP-1 (pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (MCP-1 (pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    53
    57
    Units: pg/mL
        least squares mean (standard error)
    -95.2 ± 49.23
    -69.3 ± 46.93
    Statistical analysis title
    		 Change from Base of conc MCP-1
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7033
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -25.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -160.3
         upper limit
    		 108.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    67.78

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (TIMP-1 (ng/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (TIMP-1 (ng/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    54
    57
    Units: ng/mL
        least squares mean (standard error)
    25.87 ± 13.085
    -1.92 ± 12.551
    Statistical analysis title
    		 Change from Base of conc of TIMP-1
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1264
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    27.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.97
         upper limit
    		 63.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.039

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (VEGF (pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Induced Sputum: Primary Parameters of interest (FAS) (VEGF (pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    55
    57
    Units: pg/mL
        least squares mean (standard error)
    253.1 ± 89.46
    -43.7 ± 86.84
    Statistical analysis title
    		 Change from Base of conc. VEGF
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0185
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    296.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.9
         upper limit
    		 542.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    124.07

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (alfa-2-Macroglobulin (µg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (alfa-2-Macroglobulin (µg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: µg/mL
        least squares mean (standard error)
    -0.05 ± 0.061
    -0.05 ± 0.062
    Statistical analysis title
    		 Change from Base of conc of alfa-2-Macroglobulin
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9989
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.086

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (IL-8 (pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (IL-8 (pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: pg/mL
        least squares mean (standard error)
    -4.48 ± 0.929
    -3.92 ± 0.945
    Statistical analysis title
    		 Change from Base of conc IL-8
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6701
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.15
         upper limit
    		 2.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.309

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (MMP type 9 (ng/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (MMP type 9 (ng/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: ng/mL
        least squares mean (standard error)
    0.8 ± 0.78
    -1 ± 0.79
    Statistical analysis title
    		 Change from Base of conc. of MMP type 9
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1105
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.1

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (MCP-1(pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (MCP-1(pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: pg/mL
        least squares mean (standard error)
    -24.8 ± 11
    -23.4 ± 11.21
    Statistical analysis title
    		 Change from Base of conc. of MCP-1
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9261
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.4
         upper limit
    		 29.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.62

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (TIMP-1(ng/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (TIMP-1(ng/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: ng/mL
        least squares mean (standard error)
    2.7 ± 3.19
    -7.5 ± 3.25
    Statistical analysis title
    		 Change from Base of conc. of TIMP-1
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0257
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 19
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.49

    Secondary: Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (VEGF(pg/mL))

    		 Close Top of page
    End point title
    		 Change from baseline of Concentration of Inflammatory Biomarkers in Blood Serum: Primary Parameters of interest (FAS) (VEGF(pg/mL))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    68
    66
    Units: pg/mL
        least squares mean (standard error)
    11.3 ± 12.8
    -21.5 ± 13.08
    Statistical analysis title
    		 Change from Base of conc. of VEGF
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0728
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    32.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 168.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.11

    Secondary: Change from baseline in lung function variables: Between-Treatment Differences (FAS) (FEV1 (L))

    		 Close Top of page
    End point title
    		 Change from baseline in lung function variables: Between-Treatment Differences (FAS) (FEV1 (L))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    77
    77
    Units: Litres
        least squares mean (standard error)
    0.028 ± 0.0212
    -0.035 ± 0.0212
    Statistical analysis title
    		 Change from base in lung function var (FEV1)
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.063
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.122
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03

    Secondary: Change from baseline in lung function variables: Between-Treatment Differences (FAS) (FVC (L))

    		 Close Top of page
    End point title
    		 Change from baseline in lung function variables: Between-Treatment Differences (FAS) (FVC (L))
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    77
    77
    Units: Litres
        least squares mean (standard error)
    0.031 ± 0.0391
    -0.033 ± 0.391
    Statistical analysis title
    		 Change from base in lung function var: (FVC)
    Statistical analysis description
    2-sided 5% test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2482
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.045
         upper limit
    		 0.173
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0552

    Secondary: Wicoxon Signed-rank test for Change from V2 to V6 in FEV1/FVC: Within Treatment Difference

    		 Close Top of page
    End point title
    		 Wicoxon Signed-rank test for Change from V2 to V6 in FEV1/FVC: Within Treatment Difference
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 R500 Placebo
    Number of subjects analysed
    77
    77
    Units: percentage
        number (confidence interval 95%)
    0.5 (0 to 1)
    -0.5 (-1 to 0.5)
    Statistical analysis title
    		 Mann-Whitney U-test V2 to V6 in FEV1/FVC
    Statistical analysis description
    2 sided 5 % test
    Comparison groups
    R500 v Placebo
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2629
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann point estimate
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    R500
    Reporting group description
    		 Roflumilast 500 µg

    Serious adverse events
    		 Placebo R500
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 79 (6.33%)
    8 / 79 (10.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Influenza A virus test positive
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Incarcerated hernia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Spermatocele
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    COPD
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Synovial cyst
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo R500
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 79 (72.15%)
    66 / 79 (83.54%)
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    Weight decreased
         subjects affected / exposed
    2 / 79 (2.53%)
    6 / 79 (7.59%)
         occurrences all number
    2
    6
    White blood cell count increased
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Procedural pain
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    Haedache
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 79 (5.06%)
         occurrences all number
    3
    4
    Lethargy
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    4
    Tremor
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 79 (3.80%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 79 (5.06%)
    11 / 79 (13.92%)
         occurrences all number
    4
    11
    Dry mouth
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    1 / 79 (1.27%)
    6 / 79 (7.59%)
         occurrences all number
    1
    6
    Vomiting
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 79 (6.33%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Bronchial polyp
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 79 (1.27%)
         occurrences all number
    2
    1
    COPD
         subjects affected / exposed
    12 / 79 (15.19%)
    9 / 79 (11.39%)
         occurrences all number
    13
    10
    Cough
         subjects affected / exposed
    12 / 79 (15.19%)
    10 / 79 (12.66%)
         occurrences all number
    12
    11
    Dyspnoea
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 79 (3.80%)
         occurrences all number
    1
    3
    Haemoptysis
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    4
    Productive cough
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences all number
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 79 (2.53%)
    7 / 79 (8.86%)
         occurrences all number
    2
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 79 (6.33%)
         occurrences all number
    2
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Muscle spasms
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 79 (2.53%)
         occurrences all number
    2
    2
    Myalgia
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 79 (3.80%)
         occurrences all number
    0
    5
    Pain in extremity
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Synovial cyst
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Infections and infestations
    Eye infection
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Herpes zoster
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    12 / 79 (15.19%)
    13 / 79 (16.46%)
         occurrences all number
    15
    14
    Rhinitis
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 79 (3.80%)
         occurrences all number
    3
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    0
    2
    Viral infection
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 79 (2.53%)
         occurrences all number
    1
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2012
    Incl AM 5
    06 Nov 2012
    9
    30 Nov 2012
    Incl Am 5, 9
    23 May 2013
    Incl Am 5, 9, 10
    06 Oct 2014
    Incl all amendments
    21 May 2015
    Incl. all amendments AM 12

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu Apr 25 01:42:28 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA