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    Clinical Trial Results:
    Effect of Roflumilast on Exacerbation Rate in Patients With COPD Treated With Fixed Combinations of LABA and ICS. A 52-week, Randomised Double-blind Trial With Roflumilast 500 µg Versus Placebo. The REACT Trial

    Summary
    EudraCT number
    2010-019685-87
    Trial protocol
    GB   BE   DE   AT   DK   GR   NL   HU   SK   IT   ES  
    Global end of trial date
    27 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RO-2455-404-RD
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01329029
    WHO universal trial number (UTN)
    U1111-1141-7422
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the REACT trial is to investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate and pulmonary function in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS). In addition, data on safety and tolerability of roflumilast will be obtained. An additional objective is to further characterize the population pharmacokinetic profile of roflumilast and roflumilast N oxide and to further characterize their pharmacokinetics/pharmacodynamics (PK/PD) relationship in terms of efficacy and relevant safety aspects. Patients to be included are required to have severe COPD associated with chronic bronchitis and a history of frequent exacerbations and must be concomitantly treated with a fixed combination of LABA and ICS. Two parallel treatment arms (roflumilast 500 μg once daily and placebo) are included.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Poland: 176
    Country: Number of subjects enrolled
    Slovakia: 58
    Country: Number of subjects enrolled
    Spain: 70
    Country: Number of subjects enrolled
    United Kingdom: 50
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 37
    Country: Number of subjects enrolled
    Denmark: 34
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 133
    Country: Number of subjects enrolled
    Greece: 68
    Country: Number of subjects enrolled
    Hungary: 236
    Country: Number of subjects enrolled
    Italy: 115
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Brazil: 80
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Israel: 240
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    Russian Federation: 358
    Country: Number of subjects enrolled
    South Africa: 53
    Country: Number of subjects enrolled
    Turkey: 96
    Worldwide total number of subjects
    1935
    EEA total number of subjects
    1039
    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)
    961
    From 65 to 84 years
    965
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 203 investigative sites in Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Korea (Republic of), Netherlands, Poland, Russia, Slovak Republic, South Africa, Spain, Turkey and United Kingdom from 28 May 2011 to 27 May 2014.

    Pre-assignment
    Screening details
    Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) entered a 4 week baseline period during which all patients received placebo then were enrolled equally in 1 of 2 treatment groups, once a day placebo or roflumilast 500 µg.

    Pre-assignment period milestones
    Number of subjects started
    1945 [1]
    Number of subjects completed
    1935

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Did not receive treatment: 10
    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: 10 participants did not receive study medication and therefore were not accounted for in the worldwide number enrolled.
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Roflumilast 500 µg
    Arm description
    Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
    Arm type
    Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast 500 µg tablet, orally, once daily for 52 weeks.

    Arm title
    Placebo
    Arm description
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks.

    Number of subjects in period 1
    Roflumilast 500 µg Placebo
    Started
    969
    966
    Full Analysis Set (FAS)
    969
    966
    Completed
    704
    780
    Not completed
    265
    186
         Death
    16
    19
         Met Pre-defined Discontinuation Criteria
    5
    1
         Physician decision
    16
    13
         Other
    10
    14
         Withdrawal by Subject
    117
    87
         COPD Exacerbation
    11
    18
         Adverse Event
    82
    29
         Lost to follow-up
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roflumilast 500 µg
    Reporting group description
    Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Reporting group title
    Placebo
    Reporting group description
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Reporting group values
    Roflumilast 500 µg Placebo Total
    Number of subjects
    969 966 1935
    Age categorical
    Units: Subjects
        ≤ 65 years
    527 542 1069
        > 65 years
    442 424 866
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.7 ± 8.38 64.7 ± 8.37 -
    Gender categorical
    Units: Subjects
        Female
    251 241 492
        Male
    718 725 1443
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    20 16 36
        Black or African American
    6 5 11
        White
    940 943 1883
        Other
    3 2 5
    Region of Enrollment
    Units: Subjects
        Australia
    9 16 25
        Austria
    11 3 14
        Belgium
    19 18 37
        Brazil
    42 38 80
        Canada
    14 12 26
        Denmark
    15 19 34
        France
    16 13 29
        Germany
    70 63 133
        Greece
    38 30 68
        Hungary
    111 125 236
        Israel
    114 126 240
        Italy
    64 51 115
        Korea, Republic of
    11 7 18
        Netherlands
    11 8 19
        Poland
    88 88 176
        Russia Federation
    177 181 358
        Slovakia
    25 33 58
        South Africa
    23 30 53
        Spain
    37 33 70
        Turkey
    52 44 96
        United Kingdom
    22 28 50
    Chronic Obstructive Pulmonary Disease (COPD) Severity
    COPD severity was classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline (2009) as: - Very severe COPD: baseline post-bronchodilator FEV1 %predicted < 30% - Severe COPD: baseline post-bronchodilator FEV1 %predicted ≥ 30% to < 50% - Moderate COPD: baseline post-bronchodilator FEV1 %predicted ≥ 50% to < 80% - Mild COPD: baseline post-bronchodilator FEV1 %predicted ≥ 80%.
    Units: Subjects
        Mild
    2 0 2
        Moderate
    18 16 34
        Severe
    658 677 1335
        Very Severe
    291 273 564
    COPD Disease Characteristics
    Units: Subjects
        Pure emphysema
    4 2 6
        Predominantly chronic bronchitis
    338 330 668
        Combined emphysema and chronic bronchitis
    626 634 1260
        Missing
    1 0 1
    Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group
    Patients were classified based on spirometry, symptoms and exacerbation risk.
    Units: Subjects
        A: low risk, less symptoms
    0 0 0
        B: low risk, more symptoms
    0 0 0
        C: high risk, less symptoms
    62 57 119
        D: high risk, more symptoms
    905 907 1812
        Missing
    2 2 4
    Smoking Status
    Units: Subjects
        Current smoker
    411 432 843
        Former smoker
    558 534 1092
        Non-smoker
    0 0 0
    Height
    Units: cm
        arithmetic mean (standard deviation)
    168.2 ± 8.652 168.33 ± 8.198 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    75.07 ± 17.275 75.6 ± 17.238 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    26.45 ± 5.474 26.58 ± 5.359 -
    Cigarette Pack Years
    Units: pack years
        arithmetic mean (standard deviation)
    47.6 ± 24.55 47.6 ± 23.56 -
    Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1)
    Number of participants for whom pre-bronchodilator FEV1 data was available was 938 and 937 in each treatment arm, respectively.
    Units: Liters
        arithmetic mean (standard deviation)
    0.999 ± 0.3149 1.016 ± 0.3209 -
    Post-bronchodilator FEV1
    Units: Liters
        arithmetic mean (standard deviation)
    1.066 ± 0.3317 1.078 ± 0.3244 -
    Pre-bronchodilator FEV1 Predicted
    Number of participants for whom pre-bronchodilator FEV1 data was available was 938 and 933 in each treatment arm, respectively.
    Units: percent predicted
        arithmetic mean (standard deviation)
    33.259 ± 9.0781 33.562 ± 9.0043 -
    Post-bronchodilator FEV1 Predicted
    Units: percent predicted
        arithmetic mean (standard deviation)
    35.392 ± 9.2484 35.532 ± 8.7573 -
    FEV1 Reversibility % Increase
    FEV reversibility (%) = (post-bronchodilator FEV minus pre-bronchodilator FEV) / pre-bronchodilator FEV * 100. Number of participants for whom FEV1 reversibility % increase data was available was 912 and 915 in each treatment arm, respectively.
    Units: percent reversibility
        arithmetic mean (standard deviation)
    7.465 ± 11.2559 7.383 ± 12.0752 -
    FEV1 Reversibility Increase
    Number of participants for whom FEV1 reversibility increase data was available was 912 and 915 in each treatment arm, respectively.
    Units: mL
        arithmetic mean (standard deviation)
    65.2 ± 108.72 65.4 ± 121.55 -
    Post-bronchodilator FEV1/Forced Vital Capacity (FVC)
    Calculated as FEV1/FVC * 100
    Units: FEV1/FVC percent
        arithmetic mean (standard deviation)
    40.2 ± 10.81 40.1 ± 10.26 -

    End points

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    End points reporting groups
    Reporting group title
    Roflumilast 500 µg
    Reporting group description
    Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Reporting group title
    Placebo
    Reporting group description
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks (following a 4 week placebo run-in period) and concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Primary: Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year

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    End point title
    Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: exacerbations per patient per year
        arithmetic mean (confidence interval 95%)
    0.805 (0.724 to 0.895)
    0.927 (0.843 to 1.02)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0529 [1]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.868
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.753
         upper limit
    1.002
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0633
    Notes
    [1] - Level of significance: 5% 2-sided Poisson regression model (estimates of exacerbation rates using time in trial as model offset).

    Secondary: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)

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    End point title
    Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)
    End point description
    Pulmonary function testing was performed using centralised spirometry. FEV1 is the maximum amount of air that can be forcefully exhaled in one second. Least-squares means is from Analysis of Covariance (ANCOVA) including treatment by time interaction. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    928
    941
    Units: liters
        least squares mean (standard error)
    0.052 ± 0.0064
    -0.004 ± 0.0062
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1869
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.073
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0089
    Notes
    [2] - Analysis of Covariance (ANCOVA) including treatment by time interaction.

    Secondary: Rate of Severe COPD Exacerbations Per Patient Per Year

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    End point title
    Rate of Severe COPD Exacerbations Per Patient Per Year
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. Severe COPD exacerbations were categorized as requiring hospitalization and/or leading to death. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: exacerbations per patient per year
        arithmetic mean (confidence interval 95%)
    0.239 (0.201 to 0.283)
    0.315 (0.27 to 0.368)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0175 [3]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.757
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.601
         upper limit
    0.952
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0889
    Notes
    [3] - Analyzed using a negative binomial regression model excluding a correction for overdispersion.

    Secondary: Rate of COPD Exacerbations Per Patient Per Year All Categories

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    End point title
    Rate of COPD Exacerbations Per Patient Per Year All Categories
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: exacerbations per patient per year
    arithmetic mean (confidence interval 95%)
        Moderate
    0.574 (0.508 to 0.648)
    0.627 (0.561 to 0.702)
        Mild, Moderate or Severe
    3.078 (2.723 to 3.479)
    3.879 (3.492 to 4.31)
        Leading to Hospitalisation
    0.238 (0.2 to 0.283)
    0.313 (0.268 to 0.365)
        Glucocorticosteroids and/or Antibiotics treatment
    0.794 (0.716 to 0.88)
    0.929 (0.847 to 1.019)
        Moderate or Severe and/or treated with Antibiotics
    1.012 (0.922 to 1.11)
    1.21 (1.115 to 1.313)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Moderate COPD Exacerbations Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2875 [4]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.914
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.775
         upper limit
    1.078
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0771
    Notes
    [4] - Level of significance: 5% 2-sided Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mild, Moderate or Severe COPD Exacerbations Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [5]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.794
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.675
         upper limit
    0.933
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0654
    Notes
    [5] - Level of significance: 5% 2-sided Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    COPD Exacerbations treated with Glucocorticosteroids and/or Antibiotics Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0262 [7]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.854
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.744
         upper limit
    0.982
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0605
    Notes
    [6] - Level of significance: 5% 2-sided
    [7] - Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Moderate or Severe COPD Exacerbations and/or treated with Antibiotics Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0047 [8]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.837
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.739
         upper limit
    0.947
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0528
    Notes
    [8] - Level of significance: 5% 2-sided Poisson regression model (estimates of exacerbation rates using time in trial as model offset).
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Leading to Hospitalisation Estimation Comments: A rate ratio of < 1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0209 [9]
    Method
    Generalized Linear Regression
    Parameter type
    Rate ratio
    Point estimate
    0.761
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.604
         upper limit
    0.96
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0899
    Notes
    [9] - Level of significance: 5% 2-sided. Negative binomial regression model (estimates of exacerbation rates)

    Secondary: Percentage of Participants Experiencing at Least 1 COPD Exacerbation

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    End point title
    Percentage of Participants Experiencing at Least 1 COPD Exacerbation
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of participants
        number (not applicable)
    55.2
    60.5
    No statistical analyses for this end point

    Secondary: Time to First COPD Exacerbation All Categories

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    End point title
    Time to First COPD Exacerbation All Categories
    End point description
    Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for all events: mild, moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (confidence interval 95%)
    218 (189 to 259)
    180 (147 to 200)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1461 [10]
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.917
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.815
         upper limit
    1.031
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0549
    Notes
    [10] - Level of significance: 5% 2-sided.

    Secondary: Time to Second Moderate or Severe COPD Exacerbation

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    End point title
    Time to Second Moderate or Severe COPD Exacerbation
    End point description
    Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy. Result Comment: 99999=Not Available (NA). Roflumilast arm: 95% confidence interval upper limit not estimated. Placebo arm: parameters not estimated-data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 weeks [some participants extended treatment beyond 52 Weeks and are included in the analysis]
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (confidence interval 95%)
    421 (413 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazard ratio of <1 represents a favourable outcome for the test treatment
    Comparison groups
    Placebo v Roflumilast 500 µg
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.027 [11]
    Method
    Wei-Lin-Weissfeld Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.641
         upper limit
    0.974
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0842
    Notes
    [11] - Level of significance: 5% 2-sided

    Secondary: Time to Third Moderate or Severe COPD Exacerbation

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    End point title
    Time to Third Moderate or Severe COPD Exacerbation
    End point description
    Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy. Result Comment: 99999=Not Available (NA). Parameters not estimated-data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazard ratio of <1 represents a favourable outcome for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0731 [12]
    Method
    Wei-Lin-Weissfeld Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.749
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.546
         upper limit
    1.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1209
    Notes
    [12] - Level of significance: 5% 2-sided

    Secondary: Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived from Exacerbation per Patient per Year

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    End point title
    Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived from Exacerbation per Patient per Year
    End point description
    The number needed to treat (NNT) analysis is a simple, concise method to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. Risk reduction: Rate(Placebo)— Rate (Roflumilast 500 μg), Number needed to treat for benefit (NNTB): 1/(Risk reduction). A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: exacerbation per patient per year
        number (not applicable)
    0.805
    0.927
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    NNTB
    Point estimate
    9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4
         upper limit
    31

    Secondary: Number of Moderate or Severe COPD Exacerbation Days

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    End point title
    Number of Moderate or Severe COPD Exacerbation Days
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. The number of exacerbation days per patient is the sum of durations (stop date of exacerbation — start date of exacerbation + 1) of all exacerbations within the category.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    380
    432
    Units: days
        arithmetic mean (standard deviation)
    26.9 ± 23.09
    30.9 ± 29.49
    No statistical analyses for this end point

    Secondary: Duration of Moderate or Severe COPD Exacerbations Per Participant

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    End point title
    Duration of Moderate or Severe COPD Exacerbations Per Participant
    End point description
    A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    380
    432
    Units: days
        arithmetic mean (standard deviation)
    15.9 ± 10.59
    16.6 ± 14.49
    No statistical analyses for this end point

    Secondary: Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)

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    End point title
    Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)
    End point description
    Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    928
    941
    Units: liters
        least squares mean (standard error)
    0.036 ± 0.0114
    -0.057 ± 0.0111
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1869
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [13]
    Method
    Repeated measurement model
    Parameter type
    Least Square Mean Difference
    Point estimate
    0.092
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.061
         upper limit
    0.124
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0159
    Notes
    [13] - Level of significance: 5% 2-sided. Unstructured covariance structure and restricted maximum likelihood (REML).

    Secondary: Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)

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    End point title
    Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)
    End point description
    Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    928
    941
    Units: liters/second
        least squares mean (standard error)
    0.035 ± 0.0044
    0.009 ± 0.0043
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1869
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [14]
    Method
    Repeated measurement model
    Parameter type
    LS Mean Difference
    Point estimate
    0.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.013
         upper limit
    0.038
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0062
    Notes
    [14] - Level of significance: 5% 2-sided. Unstructured covariance structure and REML.

    Secondary: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)

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    End point title
    Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)
    End point description
    FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    924
    937
    Units: liters
        least squares mean (standard error)
    0.061 ± 0.0093
    -0.033 ± 0.0091
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1861
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [15]
    Method
    Repeated measurement model
    Parameter type
    LS Mean Difference
    Point estimate
    0.094
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.069
         upper limit
    0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0131
    Notes
    [15] - Level of significance: 5% 2-sided. Unstructured covariance structure and REML.

    Secondary: Change From Baseline in Post-Bronchodilator FEV1/FVC

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    End point title
    Change From Baseline in Post-Bronchodilator FEV1/FVC
    End point description
    The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    701
    780
    Units: percent
        arithmetic mean (standard deviation)
    1.17 ± 7.0339
    0.58 ± 6.8405
    No statistical analyses for this end point

    Secondary: Change From Baseline in Use of Rescue Medication From Daily Diary

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    End point title
    Change From Baseline in Use of Rescue Medication From Daily Diary
    End point description
    Salbutamol metered dose inhaler was available as rescue medication during the study. The participant recorded the use of rescue medication in a daily diary. A negative change from Baseline indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    848
    896
    Units: puffs per day
        least squares mean (standard error)
    -0.109 ± 0.0676
    0.173 ± 0.0654
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1744
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0027 [16]
    Method
    Repeated measurement model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.283
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.467
         upper limit
    -0.098
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0941
    Notes
    [16] - Level of significance: 5% 2-sided. Compound symmetry covariance structure and REML.

    Secondary: Change From Baseline in COPD Symptom Score From Daily Diary

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    End point title
    Change From Baseline in COPD Symptom Score From Daily Diary
    End point description
    Participants recorded COPD symptoms cough and sputum production in a daily diary. Cough was assessed using a 4-point scale where 0=No cough to 3=severe cough and sputum was assessed using a 4-point scale where 0=no sputum production to 3=severe sputum production. Least-squares means from ANCOVA including treatment by time interaction. A negative change from Baseline indicates improvement. Total symptom score is the sum of cough and sputum scores, ranging from 0 (best possible outcome) to 6 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    897
    932
    Units: score on a scale
        least squares mean (standard error)
    -0.412 ± 0.0315
    -0.398 ± 0.0306
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1829
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7392 [17]
    Method
    Repeated measurement model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.101
         upper limit
    0.071
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0439
    Notes
    [17] - Level of significance: 5% 2-sided. Compound symmetry covariance structure and REML.

    Secondary: Percentage of Symptom-Free Days

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    End point title
    Percentage of Symptom-Free Days
    End point description
    Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of days
        arithmetic mean (standard deviation)
    7.09 ± 17.119
    6.88 ± 16.185
    No statistical analyses for this end point

    Secondary: Percentage of Rescue Medication-Free Days

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    End point title
    Percentage of Rescue Medication-Free Days
    End point description
    Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of days
        arithmetic mean (standard deviation)
    23.25 ± 33.734
    22.77 ± 33.141
    No statistical analyses for this end point

    Secondary: Change From Baseline in COPD Assessment Test (CAT) Total Score

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    End point title
    Change From Baseline in COPD Assessment Test (CAT) Total Score
    End point description
    Participants completed the CAT questionnaire at Baseline and after 52 Weeks of Treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from Baseline indicates improvement. Least-squares means from ANCOVA including treatment by time interaction.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    924
    940
    Units: score on a scale
        arithmetic mean (standard error)
    -1.27 ± 0.1556
    -0.985 ± 0.1518
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1864
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1909 [18]
    Method
    Repeated measurement model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.285
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.711
         upper limit
    0.142
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2175
    Notes
    [18] - Level of significance: 5% 2-sided. Unstructured covariance structure and REML.

    Secondary: Percentage of Participants With Improvement in CAT

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    End point title
    Percentage of Participants With Improvement in CAT
    End point description
    Participants completed the CAT questionnaire at Baseline and after 52 Weeks of treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. Improvement was defined as a CAT Total Score reduction from Baseline > 1.6.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of participants
        number (not applicable)
    71.2
    72.5
    No statistical analyses for this end point

    Secondary: Time to Mortality Due to Any Reason During the Treatment Period Score

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    End point title
    Time to Mortality Due to Any Reason During the Treatment Period Score
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day. Result Comment: 99.99999=Not Available (NA). Data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99.99999 (44 to 381)
    99.99999 (21 to 293)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9414 [19]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.528
         upper limit
    1.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3468
    Notes
    [19] - Level of significance: 5% 2-sided.

    Secondary: Time to Mortality Due to COPD Exacerbation During the Treatment Period

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    End point title
    Time to Mortality Due to COPD Exacerbation During the Treatment Period
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day. Result Comment: 99.99999=Not Available (NA). Data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99.99999 (44 to 322)
    99.99999 (25 to 293)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8876 [20]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.078
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.378
         upper limit
    3.075
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5765
    Notes
    [20] - Level of significance: 5% 2-sided.

    Secondary: Time to Withdrawal During the Treatment Period

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    End point title
    Time to Withdrawal During the Treatment Period
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    420 (5 to 428)
    444 (1 to 444)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [21]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.529
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.268
         upper limit
    1.845
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1463
    Notes
    [21] - Level of significance: 5% 2-sided.

    Secondary: Time to Withdrawal Due to COPD Exacerbation During the Treatment Period

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    End point title
    Time to Withdrawal Due to COPD Exacerbation During the Treatment Period
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day. Result Comment: 99.99999=Not Available (NA). Data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99.99999 (25 to 371)
    99.99999 (12 to 319)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3477 [22]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.695
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.326
         upper limit
    1.484
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2691
    Notes
    [22] - Level of significance: 5% 2-sided.

    Secondary: Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period

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    End point title
    Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period
    End point description
    Composite MACE is a combined endpoint (cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of participants
        number (not applicable)
    1.7
    1.7
    No statistical analyses for this end point

    Secondary: Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period

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    End point title
    Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period
    End point description
    Composite MACE is a combined endpoint(cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke). Time to event was calculated as date of onset of event — date of first intake of double-blind study drug + 1 day. Result Comment: 99.99999=Not Available (NA). Data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99.99999 (52 to 415)
    99.99999 (50 to 365)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Estimation Comments: A hazards ratio of < 1 represents a lower hazard for the test treatment.
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8208 [23]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.083
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.542
         upper limit
    2.167
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3832
    Notes
    [23] - Level of significance: 5% 2-sided.

    Secondary: Percentage of Participant With All-Cause Hospitalisation During the Treatment Period

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    End point title
    Percentage of Participant With All-Cause Hospitalisation During the Treatment Period
    End point description
    Percentage of patients with at least one hospital admission due to any cause.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: percentage of participants
        number (not applicable)
    24.9
    29.3
    No statistical analyses for this end point

    Secondary: Time to First Hospitalisation Due to Any Cause During the Treatment Period

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    End point title
    Time to First Hospitalisation Due to Any Cause During the Treatment Period
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (confidence interval 95%)
    400 (387 to 415)
    408 (391 to 420)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roflumilast 500 µg v Placebo
    Number of subjects included in analysis
    1935
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7943 [24]
    Method
    Cox-proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.977
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.821
         upper limit
    1.162
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0865
    Notes
    [24] - Level of significance: 5% 2-sided.

    Secondary: Time to Trial Withdrawal Due to an Adverse Event

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    End point title
    Time to Trial Withdrawal Due to an Adverse Event
    End point description
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day. Result Comment: 99.99999=Not Available (NA). Data did not reach the median.
    End point type
    Secondary
    End point timeframe
    52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    969
    966
    Units: days
        median (full range (min-max))
    99.99999 (7 to 420)
    99.99999 (13 to 444)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)

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    End point title
    Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) [25]
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
    End point type
    Secondary
    End point timeframe
    52 weeks
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subject Analysis Set Placebo was used for this endpoint and includes all participants who received at least one dose of placebo.
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    968
    967
    Units: percentage of participants
        number (not applicable)
    66.9
    59.2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight

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    End point title
    Change From Baseline in Body Weight
    End point description
    Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    938
    944
    Units: kilograms (kg)
        least squares mean (standard error)
    -2.66 ± 0.13
    -0.14 ± 0.13
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI)

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    End point title
    Change From Baseline in Body Mass Index (BMI)
    End point description
    Body mass index (BMI) is a measure of body fat based on height and weight. Least Square Means was from an ANCOVA model including LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Roflumilast 500 µg Placebo
    Number of subjects analysed
    938
    944
    Units: kg/m^2
        least squares mean (standard error)
    -0.94 ± 0.046
    -0.04 ± 0.046
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    52 Weeks
    Adverse event reporting additional description
    Safety Population included all randomized participants who received at least one dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Roflumilast 500 µg
    Reporting group description
    Roflumilast 500 µg tablet, orally, once daily for 52 weeks (following a 4 week placebo run-in period) and concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Reporting group title
    Placebo
    Reporting group description
    Placebo-matching roflumilast tablet, orally, once daily for 52 weeks (following a 4 week placebo run-in period) and concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

    Serious adverse events
    Roflumilast 500 µg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    249 / 968 (25.72%)
    285 / 967 (29.47%)
         number of deaths (all causes)
    21
    24
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic occlusion
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    3 / 968 (0.31%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 968 (0.21%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Alcohol detoxification
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign lung neoplasm
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder adenocarcinoma stage unspecified
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder neoplasm
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 968 (0.10%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon neoplasm
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid tumour
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 968 (0.10%)
    4 / 967 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    4 / 968 (0.41%)
    4 / 967 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal neoplasm
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 968 (0.31%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Drug ineffective
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 968 (0.21%)
    3 / 967 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal obstruction
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant evaluation
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    4 / 968 (0.41%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 968 (0.21%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 968 (0.10%)
    5 / 967 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 968 (0.62%)
    6 / 967 (0.62%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 968 (0.21%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 968 (0.31%)
    5 / 967 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 968 (0.41%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve stenosis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 968 (0.31%)
    5 / 967 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Congenital, familial and genetic disorders
    Accessory auricle
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitello-intestinal duct remnant
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 968 (0.21%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    144 / 968 (14.88%)
    184 / 967 (19.03%)
         occurrences causally related to treatment / all
    0 / 186
    1 / 259
         deaths causally related to treatment / all
    0 / 8
    0 / 7
    Chronic respiratory failure
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 968 (0.31%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum disorder
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    5 / 968 (0.52%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 968 (0.10%)
    3 / 967 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid sinus syndrome
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 968 (0.31%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder due to a general medical condition
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 968 (0.10%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 968 (0.41%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 968 (0.21%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal angiodysplasia haemorrhagic
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 968 (0.10%)
    3 / 967 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    3 / 968 (0.31%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal mass
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perivascular dermatitis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 968 (0.10%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyrotoxic crisis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 968 (0.21%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    3 / 968 (0.31%)
    7 / 967 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 968 (0.00%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 968 (0.21%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngitis
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid abscess
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    33 / 968 (3.41%)
    37 / 967 (3.83%)
         occurrences causally related to treatment / all
    0 / 35
    0 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 6
    Pneumonia moraxella
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 968 (0.10%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 968 (0.21%)
    2 / 967 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 968 (0.10%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tracheobronchitis
         subjects affected / exposed
    2 / 968 (0.21%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 968 (0.00%)
    1 / 967 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection viral
         subjects affected / exposed
    1 / 968 (0.10%)
    0 / 967 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Roflumilast 500 µg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 968 (23.55%)
    114 / 967 (11.79%)
    Investigations
    Weight decreased
         subjects affected / exposed
    84 / 968 (8.68%)
    27 / 967 (2.79%)
         occurrences all number
    86
    27
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    97 / 968 (10.02%)
    33 / 967 (3.41%)
         occurrences all number
    108
    35
    Nausea
         subjects affected / exposed
    55 / 968 (5.68%)
    15 / 967 (1.55%)
         occurrences all number
    59
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    52 / 968 (5.37%)
    52 / 967 (5.38%)
         occurrences all number
    68
    59

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2012
    Protocol Amendment 1 • MACE included as an additional efficacy endpoint • Re-enrollment allowed of patients not presenting with postbronchodilator FEV1 ≤50% of predicted after at least 4 weeks • LABA and ICS pretreatment fixed combinations at a constant (maximum) dose were only required for 3 months instead of 12 months. • Physical exercise maintenance was allowed during the trial. • Rate of severe exacerbations per patient per year is a key secondary endpoint. • PK samples were to be analysed at PPD. Update in changes in drug safety and trial management responsibilities and labelling of rescue medication.
    17 Oct 2012
    Protocol Amendment 2 Nycomed GmbH merged with Takeda Pharma and assumed sponsorship of the study from 30 November 2012.
    12 Sep 2013
    Protocol Amendment 3 • Clarification of AE and SAE reporting. • Clarification that European Medicines Agency Guidelines, ‘no special storage requirements’ for roflumilast = 15°C to 30°C. • Clarification for analysis of plasma PK samples.

    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.
    Please Note: At this time the EudraCT system does not recognize "NA" as a viable result for an Endpoint. When this system error is corrected the results will be re-submitted with the proper data.
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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