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    Clinical Trial Results:
    Effects of ROFLUMILAST on markers of subclinical atherosclerosis In stable COPD; the ELASTIC-trial

    Summary
    EudraCT number
    		 2011-004152-19
    Trial protocol
    		 AT  
    Global end of trial date
    18 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Feb 2018
    First version publication date
    12 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ELASTIC2011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01630200
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology
    Sponsor organisation address
    Sanatoriumstrasse 2, Vienna, Austria, 1140
    Public contact
    Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, 0043 019106041007, matthias.urban@wienkav.at
    Scientific contact
    Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology, 0043 019106041007, matthias.urban@wienkav.at
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effects of ROFLUMILAST 500µg once daily on arterial stiffness in patients with COPD
    Protection of trial subjects
    Blood samples were taken at visit2 and 4 to rule a potential impairment of liver - or renal function During 6 minute walk test dyspnea scores were assessed to quantify patients subjective amount of dyspnea and excertion
    Background therapy
    		 not applicable
    Evidence for comparator
    		 not applicable
    Actual start date of recruitment
    02 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    40
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from an outpatient database of the Department of Respiratory and Critical Care Medicine in the Otto Wagner Hospital in Vienna. Recruitement started in April 2012 and lasted until July 2015.

    Pre-assignment
    Screening details
    		 A total of 240 patients were assessed for eligibility. Patients went through a 4 weeks run-in period to check for medication compliance. The primary reason for screening failure were comorbid diseases consistent with a predefined exclusion criteria. 80 patients were randomized to the study groups.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The study was conducted in a double-blinded manner. All responsible persons, those administering the interventions or assessing the outcomes, and elementally all experimental and control patients were blinded to group assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast arm
    Arm description
    		 After Randomization patients from the Roflumilast arm received the study medication (IMP: Roflumilast, 500µg, once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Roflumilast arm were equivalent to the Placebo arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    R03DX07
    Other name
    Daxas® (EU), Daliresp® (USA)
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500µg triangular coated tablet, administered oral once daily, in the morning

    Arm title
    		 Placebo arm
    Arm description
    		 After Randomization patients from the Placebo arm received Placebo (once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Placebo arm were equivalent to the Placebo arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    not applicable
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500µg triangular coated tablet, administered oral once daily, in the morning

    Number of subjects in period 1
    		Roflumilast arm Placebo arm
    Started
    40
    40
    Completed
    33
    34
    Not completed
    7
    6
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    2
    3
         Adverse event, non-fatal
    2
    2
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roflumilast arm
    Reporting group description
    		 After Randomization patients from the Roflumilast arm received the study medication (IMP: Roflumilast, 500µg, once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Roflumilast arm were equivalent to the Placebo arm.

    Reporting group title
    Placebo arm
    Reporting group description
    		 After Randomization patients from the Placebo arm received Placebo (once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Placebo arm were equivalent to the Placebo arm.

    Reporting group values
    		 Roflumilast arm Placebo arm Total
    Number of subjects
    		 40 40 80
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age of participants was evaluated on individual level at Visit 1 based on date of birth assessed via a survey
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64.5 (61 to 69.5) 64.5 (56 to 72) -
    Gender categorical
    Gender of participants was evaluated on individual level at Visit 1 based on anthropometric data
    Units: Subjects
        Female
    		 22 16 38
        Male
    		 18 24 42
    Ethnicity
    Units: Subjects
        Caucasian
    		 40 40 80
    Body Mass Index
    Body Mass Index of participants was evaluated on individual level at Visit 1 based on the equation: [Bodyweight in kilograms divided by height in meters squared]
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 26.5 (21.7 to 31.8) 26.8 (14.2 to 29.4) -
    Smoking History
    Smoking history of participants was evaluated on individual level at Visit 1 based on the equation: (number of cigarettes smoked per day/20) × number of years smoked
    Units: Pack Years
        median (inter-quartile range (Q1-Q3))
    		 50 (40 to 80) 50 (30 to 75) -
    Exacerbation rate
    Exacerbation Rate of participants was evaluated on individual level at Visit 1 based on the number of COPD-exacerbations during the last years, characterized as a worsing of respiratory symptoms exceeding the usual day-to-day variability and the demand for intensified administration of bronchodilatory medication plus oral corticosteroids and/or antibiotics.
    Units: counts
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 4) 3 (2 to 4) -
    CAT score
    CAT (COPD assessement test) of participants was assessed on individual level at Visit 1 via the standardised and validated questionnaire containing 8 questions to quantify subjects COPD related symptoms via a scoe ranging from 0-5
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 21 (15.5 to 26.5) 21 (13 to 26) -
    6-Minute Walk Test
    6-Minute Walk Test of participants was measured on individual level at Visit 1 based on the maximum distance walked on a 30 meters level ground during a time period of 6 minutes
    Units: meters
        median (inter-quartile range (Q1-Q3))
    		 428 (340 to 558) 456 (364 to 570) -
    FVC
    FVC (forced vital capacity) of participants was measured on individual level at baseline visit via standardized spirometry
    Units: percent of individual predicted value
        median (inter-quartile range (Q1-Q3))
    		 66.6 (58.5 to 79.2) 69.4 (59.5 to 75.1) -
    FEV1
    FEV1 (forced expiratory volume in 1 second) of participants was measured on individual level at baseline visit via standardized spirometry
    Units: percent of individual predicted value
        median (inter-quartile range (Q1-Q3))
    		 34.5 (25.5 to 48.6) 35.3 (27 to 46.8) -
    FEV1/FVC ratio
    FEV1FVC ratio: (forced expiratory volume in 1 second/forced vital capacity ratio) of participants was measured on individual level at baseline visit via standardized spirometry
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    		 42 (35.8 to 51) 40.6 (35.5 to 53) -
    Cholesterol
    Cholesterol of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    		 216 (190 to 246) 218 (183 to 254) -
    Triglycerides
    Triglycerides of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    		 129 (95 to 184) 127 (85.5 to 163) -
    Blood Glucose
    Blood glucose of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    		 101 (92 to 115) 97.5 (91 to 122) -
    Creatinine
    Creatinine of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    		 0.8 (0.7 to 0.9) 0.8 (0.6 to 0.9) -
    Neutrophils
    Neutrophil counts were measured on individual level at baseline visit via collection of venous blood samples and and subsequent quantification in whole blood
    Units: Giga/l
        median (inter-quartile range (Q1-Q3))
    		 6.13 (5.22 to 8.18) 5.69 (4.99 to 7.05) -
    CRP
    CRP (C-reactive protein) of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: mg/dl
        median (inter-quartile range (Q1-Q3))
    		 5.2 (3.1 to 9.5) 3.85 (1.65 to 8.2) -
    IL-6
    IL6 (Interleukin-6) of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 10.9 (5.87 to 14.75) 8.9 (5.4 to 13.6) -
    TNF-alpha
    TNF-lpha (tumor necrosis factor alpha) of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    		 17.7 (13.8 to 22.6) 14.7 (12 to 20.9) -
    ADMA
    ADMA (asymmetric dimethylarginine) of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    		 0.71 (0.55 to 0.88) 0.71 (0.56 to 0.86) -
    MMP-9
    MMP-9 (matrix metalloproteinase-9) of participants was measured on individual level at baseline visit via collection of venous blood samples and quantification in serum
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    		 1575 (949 to 2179) 1443 (964 to 1887) -
    Systolic Blood Pressure
    Arterial Systolic Blood Pressure of participants was measured on individual level at baseline visit via a sphygmomanometric cuff at the right upper arm
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 139 (128 to 150) 138 (125 to 156) -
    Diastolic Blood Pressure
    Arterial Diastolic Blood Pressure of participants was measured on individual level at baseline visit via a sphygmomanometric cuff at the right upper arm
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 79 (72 to 86) 79.5 (73 to 88.5) -
    Heart Rate
    Heart Rate of participants was measured on individual level at baseline visit via a 12-lead electrocardiogramm
    Units: beets per minute
        median (inter-quartile range (Q1-Q3))
    		 90 (77.5 to 99.5) 78.5 (71 to 90) -
    AIx
    AIx (Augmentation Index) of participants was measured on individual level at baseline visit via applanation tonometry at the radial artery of the right arm
    Units: percent
        median (inter-quartile range (Q1-Q3))
    		 23 (19 to 33) 27 (17 to 36) -
    RHI
    RHI (Reactive Hyperemia Index) of participants was measured on individual level at baseline visit via the validated plethysmographic Endopat device at patients right arm
    Units: index
        median (inter-quartile range (Q1-Q3))
    		 1.56 (1.38 to 2.32) 1.64 (1.46 to 2) -
    PWV
    PWV (carotid-femoral pulse wave velocity) of participants was measured on individual level at baseline visit via ECG-gated applanation tonometry at the right carotid and femoral artery
    Units: m/s
        median (inter-quartile range (Q1-Q3))
    		 9.7 (8.4 to 11.2) 9.8 (8.05 to 11.05) -

    End points

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    End points reporting groups
    Reporting group title
    Roflumilast arm
    Reporting group description
    		 After Randomization patients from the Roflumilast arm received the study medication (IMP: Roflumilast, 500µg, once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Roflumilast arm were equivalent to the Placebo arm.

    Reporting group title
    Placebo arm
    Reporting group description
    		 After Randomization patients from the Placebo arm received Placebo (once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Placebo arm were equivalent to the Placebo arm.

    Primary: Change in Pulse Wave Velocity between Baseline and Final Visit

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    End point title
    		 Change in Pulse Wave Velocity between Baseline and Final Visit
    End point description
    Difference in the change of log Pulse Wave Velocity between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Primary
    End point timeframe
    Measurement of Pulse Wave Velocity was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: m/s
        least squares mean (confidence interval 95%)
    1.07 (0.98 to 1.17)
    0.99 (0.91 to 1.08)
    Statistical analysis title
    		 Intergroup comparison of primary endpoint
    Statistical analysis description
    Primary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of cf-PWV from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of cf-PWV the analysis were calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 5
    Method
    		 ANCOVA
    Confidence interval

    Secondary: change from baseline RHI

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    End point title
    		 change from baseline RHI
    End point description
    Difference in the change of Reactive Hyperemia Index between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Reactive Hyperemia Index was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: units
        least squares mean (confidence interval 95%)
    0.99 (0.88 to 1.11)
    1.02 (0.91 to 1.15)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of RHI from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of RHI the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: change from baseline AIx

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    End point title
    		 change from baseline AIx
    End point description
    Difference in the change of Augmentation Index between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Augmentation Index was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: percent
        least squares mean (confidence interval 95%)
    -1.11 (-5.33 to 3.11)
    -1.99 (-6.12 to 2.14)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of AIx from final visit for baseline as well as for GOLD stage. Due to a normal distribution of AIx the analysis was calculated unlogarythmised, resulting in an absolute difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline MMP-9

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    End point title
    		 Change from baseline MMP-9
    End point description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of MMP-9 from final visit for baseline as well as for GOLD stage. Due to a normal distribution of AIx the analysis was calculated unlogarythmised, resulting in an absolute difference.
    End point type
    Secondary
    End point timeframe
    Measurement of Matrix Metalloproteinase-9 was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: ng/ml
        least squares mean (confidence interval 95%)
    -143 (-370 to 84.6)
    -77 (-301 to 146)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of MMP-9 from final visit for baseline as well as for GOLD stage. Due to a normal distribution of MMP-9 the analysis was calculated unlogarythmised, resulting in an absolute difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline ADMA

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    End point title
    		 Change from baseline ADMA
    End point description
    Difference in the change of Asymmetric Dimethyarginine between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Asymmetric Dimethyarginine was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: µmol/l
        least squares mean (confidence interval 95%)
    0.97 (0.88 to 1.06)
    0.91 (0.83 to 1)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of ADMA from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of ADMA the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline TNF-alpha

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    End point title
    		 Change from baseline TNF-alpha
    End point description
    Difference in the change of Tumor Necrosis Factor-alpha between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Tumor Necrosis Factor-alpha was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: pg/ml
        least squares mean (confidence interval 95%)
    0.95 (0.82 to 1.08)
    1.06 (0.92 to 1.22)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of TNF-alpha from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of TNF-alpha the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline IL-6

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    End point title
    		 Change from baseline IL-6
    End point description
    Difference in the change of Interleukin-6 between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Interleukin-6 was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: pg/ml
        least squares mean (confidence interval 95%)
    1.22 (1.01 to 1.47)
    1.03 (0.85 to 1.25)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of IL-6 from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of IL-6 the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline CRP

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    End point title
    		 Change from baseline CRP
    End point description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of CRP from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of CRP the analysis was calculated under a log-scale, resulting in percentage difference.
    End point type
    Secondary
    End point timeframe
    Measurement of C-reactive Protein was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: mg/dl
        least squares mean (confidence interval 95%)
    0.83 (0.63 to 1.1)
    1.21 (0.92 to 1.6)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of CRP from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of CRP the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline FEV1

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    End point title
    		 Change from baseline FEV1
    End point description
    Difference in the change of FEV1 between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of Forced Espiratory Volume in 1 Seocnd was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: % predicted
        least squares mean (confidence interval 95%)
    1.02 (0.96 to 1.08)
    1.01 (0.96 to 1.07)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of FEV1 from final visit for baseline as well as for GOLD stage. Due to a right-skewed distribution of FEV1 the analysis was calculated under a log-scale, resulting in percentage difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline 6MWT

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    End point title
    		 Change from baseline 6MWT
    End point description
    Difference in the change of 6-Minute Walk Test between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of 6-Minute Walk Test was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: meter
        least squares mean (confidence interval 95%)
    59.2 (18.3 to 100)
    0.69 (-39.7 to 42.1)
    Statistical analysis title
    		 Change from baseline 6MWT
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of 6MWT from final visit for baseline as well as for GOLD stage. Due to a normal distribution of 6MWT the analysis was calculated unlogarythmised, resulting in an absolute difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change from baseline CAT

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    End point title
    		 Change from baseline CAT
    End point description
    Difference in the change of CAT between the study groups (Roflumilast versus Placebo) after the 24 weeks study period
    End point type
    Secondary
    End point timeframe
    Measurement of COPD Assessment Test was conducted firstly at the intial visit (following randomisation) and secondly after a study period of 24 weeks
    End point values
    		 Roflumilast arm Placebo arm
    Number of subjects analysed
    40
    40
    Units: points
        least squares mean (confidence interval 95%)
    0.42 (-1.36 to 2.19)
    1.2 (-0.57 to 2.98)
    Statistical analysis title
    		 Intergroup comparison of secondary endpoint
    Statistical analysis description
    Secondary endpoint was calculated via analysis of covariance (ANCOVA) with adjustment of the intergroup comparison of CAT from final visit for baseline as well as for GOLD stage. Due to a normal distribution of CAT the analysis was calculated unlogarythmised, resulting in an absolute difference.
    Comparison groups
    Roflumilast arm v Placebo arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported during the 24 weeks active study phase starting with randomization and ending with the final visit.
    Adverse event reporting additional description
    Adverse events were collected routinely during every study visit. Moreover, patients were instructed to appraise the study team about potential adverse events intermittently via phone calls.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Roflumilast arm
    Reporting group description
    		 After Randomization patients from the Roflumilast arm received the study medication (IMP: Roflumilast, 500µg, once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Roflumilast arm were equivalent to the Placebo arm.

    Reporting group title
    Placebo arm
    Reporting group description
    		 After Randomization patients from the Placebo arm received Placebo (once daily, oral administration) in a double-blinded manner for a period of 24 weeks. Apart from the study medication, study related procedures in Placebo arm were equivalent to the Placebo arm.

    Serious adverse events
    		 Roflumilast arm Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 40 (32.50%)
    9 / 40 (22.50%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic macroangiopathy
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (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
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Insomnia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
    Additional description: death of unknown etiology (pat was found dead at home)
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polypectomy
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchoscopic lung volume reduction
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchoscopy
    Additional description: Assessment of previously diagnosed bronchiectasis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnic coma
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 40 (7.50%)
    5 / 40 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    Additional description: Acute exacerbation of COPD
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (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: 0%
    Non-serious adverse events
    		 Roflumilast arm Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 40 (67.50%)
    22 / 40 (55.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    Tremor
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Weight decreased
         subjects affected / exposed
    6 / 40 (15.00%)
    0 / 40 (0.00%)
         occurrences all number
    6
    0
    Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Appetite disorder
    Additional description: Loss of appetite
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 40 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Pulmonary embolism
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Chronic obstructive pulmonary disease
    Additional description: acute exacerbation of COPD
         subjects affected / exposed
    14 / 40 (35.00%)
    16 / 40 (40.00%)
         occurrences all number
    19
    24
    Pneumonia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Convulsions local
    Additional description: Muscular cramps of the upper or lower extremities
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Influenza like illness
         subjects affected / exposed
    5 / 40 (12.50%)
    4 / 40 (10.00%)
         occurrences all number
    6
    6
    Insomnia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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