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    Clinical Trial Results:
    A Phase IIa, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety and Efficacy of 28 Day Oral Administration of BAY 85-8501 in Patients with non-Cystic Fibrosis Bronchiectasis

    Summary
    EudraCT number
    		 2012-004491-18
    Trial protocol
    		 GB   ES   IT  
    Global end of trial date
    13 Jun 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Sep 2016
    First version publication date
    24 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY85-8501 / 16359
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01818544
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    22 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of 28 day oral administration of BAY 85-8501 versus placebo in subjects with non-Cystic Fibrosis (CF) Bronchiectasis (BE).
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Italy: 54
    Worldwide total number of subjects
    94
    EEA total number of subjects
    94
    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)
    29
    From 65 to 84 years
    65
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 27 sites in 4 countries between 22 April 2013 (first subject first visit) and 13 June 2014 (last subject last visit).

    Pre-assignment
    Screening details
    		 Of 139 subjects screened, 94 subjects were randomized to the study. The reason for 45 screen failures was non-fulfilment of the inclusion or exclusion and subject withdrawal criteria.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAY85-8501
    Arm description
    		 Daily oral dose of 1 milligram (mg) BAY85-8501 tablets for 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY85-8501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily oral dose of 1 mg BAY85-8501 tablets for 28 days.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to BAY85-8501 for 28 days.
    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 matched to BAY85-8501 for 28 days.

    Number of subjects in period 1
    		BAY85-8501 Placebo
    Started
    47
    47
    Treated
    45
    47
    Completed
    37
    45
    Not completed
    10
    2
         Consent withdrawn by subject
    1
    -
         Protocol violation
    2
    -
         Adverse event
    6
    1
         Unspecified
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAY85-8501
    Reporting group description
    		 Daily oral dose of 1 milligram (mg) BAY85-8501 tablets for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to BAY85-8501 for 28 days.

    Reporting group values
    		 BAY85-8501 Placebo Total
    Number of subjects
    		 47 47 94
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.1 ( 12.21 ) 68.6 ( 8.04 ) -
    Gender categorical
    Units: Subjects
        Female
    		 22 22 44
        Male
    		 25 25 50

    End points

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    End points reporting groups
    Reporting group title
    BAY85-8501
    Reporting group description
    		 Daily oral dose of 1 milligram (mg) BAY85-8501 tablets for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to BAY85-8501 for 28 days.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population (N= 92) was defined as all subjects who received at least one dose of study medication.

    Subject analysis set title
    Full Analysis Set (FAS) Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS population (N= 94) was defined as all randomized subjects.

    Primary: Number Of Subjects Who Need To Discontinue Study Medication Due To Findings In Physical Examination

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    End point title
    		 Number Of Subjects Who Need To Discontinue Study Medication Due To Findings In Physical Examination [1]
    End point description
    End point type
    Primary
    End point timeframe
    From start of study treatment up to follow-up visit (28 days after last dose)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [2]
    47 [3]
    Units: Subjects
    4
    1
    Notes
    [2] - Safety population
    [3] - Safety population
    No statistical analyses for this end point

    Primary: Change From Baseline in Systolic Blood Pressure At Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Systolic Blood Pressure At Days 7, 14, 21, 28, 56 [4]
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [5]
    47 [6]
    Units: millimeter of mercury
    arithmetic mean (standard deviation)
        Baseline (N= 45, 47)
    134.6 ( 21.48 )
    133.1 ( 16.94 )
        Change at Day 7 (N= 43, 47)
    1.1 ( 13.75 )
    0.8 ( 12.68 )
        Change at Day 14 (N= 42, 46)
    -1.4 ( 14.64 )
    -1.1 ( 14.34 )
        Change at Day 21 (N= 42, 47)
    -3.4 ( 15.93 )
    -1 ( 13.03 )
        Change at Day 28 (N= 44, 47)
    -3.6 ( 13.13 )
    -2.9 ( 16.21 )
        Change at Day 56 (N= 39, 46)
    -3 ( 15.37 )
    -2 ( 13.17 )
    Notes
    [5] - Safety population
    [6] - Safety population
    No statistical analyses for this end point

    Primary: Change From Baseline in Diastolic Blood Pressure At Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Diastolic Blood Pressure At Days 7, 14, 21, 28, 56 [7]
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [8]
    47 [9]
    Units: millimeter of mercury
    arithmetic mean (standard deviation)
        Baseline (N= 45, 47)
    76.9 ( 10.81 )
    77.3 ( 11.32 )
        Change at Day 7 (N= 43, 47)
    -0.7 ( 8.39 )
    -3.6 ( 9.29 )
        Change at Day 14 (N= 42, 46)
    -2.4 ( 10.19 )
    -2.3 ( 8.67 )
        Change at Day 21 (N= 42, 47)
    -1.1 ( 8.43 )
    -2 ( 9.14 )
        Change at Day 28 (N= 44, 47)
    -2 ( 7.99 )
    -3.7 ( 9.43 )
        Change at Day 56 (N= 39, 46)
    -2.5 ( 9.67 )
    -3.8 ( 8.97 )
    Notes
    [8] - Safety population
    [9] - Safety population
    No statistical analyses for this end point

    Primary: Change From Baseline in Heart Rate At Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Heart Rate At Days 7, 14, 21, 28, 56 [10]
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [11]
    47 [12]
    Units: beats per minute
    arithmetic mean (standard deviation)
        Baseline (N= 45, 47)
    74.6 ( 10.82 )
    74.5 ( 10.6 )
        Change at Day 7 (N= 43, 47)
    0.5 ( 9.35 )
    -0.4 ( 11.06 )
        Change at Day 14 (N= 42, 46)
    -2.2 ( 8.28 )
    0.2 ( 9.5 )
        Change at Day 21 (N= 42, 47)
    0.2 ( 10.93 )
    1.5 ( 10.96 )
        Change at Day 28 (N= 44, 47)
    -0.7 ( 10.09 )
    1 ( 10.8 )
        Change at Day 56 (N= 39, 46)
    -1.9 ( 12.46 )
    1.7 ( 8.57 )
    Notes
    [11] - Safety population
    [12] - Safety population
    No statistical analyses for this end point

    Primary: Number of Subjects With new Abnormal (Pathologic) Electrocardiogram (ECG) Findings From Baseline to Day 28

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    End point title
    		 Number of Subjects With new Abnormal (Pathologic) Electrocardiogram (ECG) Findings From Baseline to Day 28 [13]
    End point description
    ECG abnormalities that were considered clinically significant (CS) or clinically insignificant (CI) by the investigator were reported. Parameters analyzed included ventricular rate, PR duration, QRS duration, and QT duration to the subjects.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [14]
    47 [15]
    Units: Subjects
        Baseline: Abnormal, CI
    6
    14
        Baseline: Abnormal, CS
    0
    0
        Change at Day 7: Abnormal, CI
    4
    12
        Change at Day 7: Abnormal, CS
    0
    0
        Change at Day 14: Abnormal, CI
    6
    16
        Change at Day 14: Abnormal, CS
    0
    1
        Change at Day 21: Abnormal, CI
    5
    14
        Change at Day 21: Abnormal, CS
    0
    0
        Change at Day 28: Abnormal, CI
    7
    13
        Change at Day 28: Abnormal, CS
    0
    0
    Notes
    [14] - Safety population
    [15] - Safety population
    No statistical analyses for this end point

    Primary: Number of Subjects who Show Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Bilirubin (TB) Abnormalities in Their Safety Lab Assessment

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    End point title
    		 Number of Subjects who Show Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Bilirubin (TB) Abnormalities in Their Safety Lab Assessment [16]
    End point description
    The pre-specified laboratory abnormalities included ALT and AST greater than or equal to (>=) 3 times upper limit of normal (ULN) and total bilirubin with an increase of 200% from baseline.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [17]
    45 [18]
    Units: Subjects
        Baseline (ALT)
    1
    0
        Change at Day 7 (ALT)
    0
    0
        Change at Day 14 (ALT)
    0
    0
        Change at Day 21 (ALT)
    0
    0
        Change at Day 28 (ALT)
    0
    1
        Change at Day 56 (ALT)
    0
    0
        Baseline (AST)
    0
    0
        Change at Day 7 (AST)
    0
    1
        Change at Day 14 (AST)
    0
    0
        Change at Day 21 (AST)
    0
    0
        Change at Day 28 (AST)
    0
    0
        Change at Day 56 (AST)
    0
    0
        Change at Day 7 (TB)
    0
    1
        Change at Day 14 (TB)
    0
    0
        Change at Day 21 (TB)
    1
    0
        Change at Day 28 (TB)
    0
    1
        Change at Day 56 (TB)
    0
    0
    Notes
    [17] - Safety Population
    [18] - Safety population
    No statistical analyses for this end point

    Primary: Number of Subjects With Drug-Related Adverse Events as a Measure of Safety And Tolerability

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    End point title
    		 Number of Subjects With Drug-Related Adverse Events as a Measure of Safety And Tolerability [19]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the start of study drug administration.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    45 [20]
    47 [21]
    Units: Subjects
        Any Study Drug Related TEAE
    11
    12
        Any Study Drug Related Serious TEAE
    0
    0
    Notes
    [20] - Safety population
    [21] - Safety population
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulmonary Function Test Forced Expired Volume in 1 Second (FEV1) At Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Pulmonary Function Test Forced Expired Volume in 1 Second (FEV1) At Days 7, 14, 21, 28, 56
    End point description
    FEV1 is a pulmonary function test, defined as the amount of air expelled in 1 second, included pre-bronchodilator (BD) and post-bronchodilator (BD) tests. The pre-BDs were performed prior to administration of any BD where as post-BDs were obtained within at least 15 minutes and no more than 30 minutes after administration of standard dose of BD. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [22]
    47 [23]
    Units: liters
    arithmetic mean (standard deviation)
        Baseline Pre-bronchodialator (BD) (N= 39, 44)
    1.631 ( 0.6687 )
    1.448 ( 0.4387 )
        Baseline Post-BD (N= 44, 47)
    1.705 ( 0.5875 )
    1.522 ( 0.4489 )
        Change at Day 7: Pre-BD (N= 37, 44)
    -0.01 ( 0.1331 )
    -0.007 ( 0.1153 )
        Change at Day 7: Post-BD (N= 43, 47)
    0.01 ( 0.1526 )
    0.004 ( 0.1343 )
        Change at Day 14: Pre-BD (N= 36, 43)
    0.018 ( 0.1617 )
    -0.03 ( 0.1528 )
        Change at Day 14: Post-BD (N= 42, 46)
    0.035 ( 0.1698 )
    -0.028 ( 0.1798 )
        Change at Day 21: Pre-BD (N= 36, 44)
    -0.024 ( 0.1534 )
    -0.075 ( 0.156 )
        Change at Day 21: Post-BD (N= 42, 47)
    0.016 ( 0.137 )
    -0.032 ( 0.1637 )
        Change at Day 28: Pre-BD (N= 37, 44)
    -0.004 ( 0.1552 )
    -0.078 ( 0.1986 )
        Change at Day 28: Post-BD (N= 42, 47)
    0.026 ( 0.1924 )
    -0.051 ( 0.197 )
        Change at Day 56: Pre-BD (N= 34, 43)
    -0.014 ( 0.1541 )
    -0.063 ( 0.2214 )
        Change at Day 56: Post-BD (N= 39, 45)
    -0.026 ( 0.174 )
    -0.073 ( 0.2101 )
    Notes
    [22] - FAS population
    [23] - FAS population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    FEV1 was analyzed by an analysis of covariance (ANCOVA) with baseline as a covariate and treatment as a factor. Adjusted means (least square [LS] means) for treatment, as well as the difference in LS means between treatment groups, and the corresponding 95% confidence intervals were calculated.
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0558
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0021
         upper limit
    		 0.1653

    Secondary: Change From Baseline in Pulmonary Function Test Forced Vital Capacity (FVC) at Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Pulmonary Function Test Forced Vital Capacity (FVC) at Days 7, 14, 21, 28, 56
    End point description
    FVC is defined as the total amount of air exhaled during the lung function test. FVC is a pulmonary function test included pre-bronchodilator and post-bronchodilator tests. The pre-BDs were performed prior to administration of any BD where as post-BDs were obtained within at least 15 minutes and no more than 30 minutes after administration of standard dose of BD. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [24]
    47 [25]
    Units: liters
    arithmetic mean (standard deviation)
        Baseline Pre-BD (N= 39, 44)
    2.733 ( 1.0127 )
    2.46 ( 0.7168 )
        Baseline Post-BD (N= 44, 47)
    2.819 ( 0.9748 )
    2.529 ( 0.673 )
        Change at Day 7: Pre-BD (N= 37, 44)
    0.008 ( 0.2387 )
    -0.003 ( 0.2294 )
        Change at Day 7: Post-BD (N= 43, 47)
    0.031 ( 0.2422 )
    0.007 ( 0.2397 )
        Change at Day 14: Pre-BD (N= 36, 43)
    0.026 ( 0.2193 )
    -0.044 ( 0.2678 )
        Change at Day 14: Post-BD (N= 42, 46)
    0.072 ( 0.257 )
    0 ( 0.1924 )
        Change at Day 21: Pre-BD (N= 36, 44)
    -0.01 ( 0.2658 )
    -0.073 ( 0.2227 )
        Change at Day 21: Post-BD (N= 42, 47)
    0.077 ( 0.2832 )
    -0.031 ( 0.2377 )
        Change at Day 28: Pre-BD (N= 37, 44)
    -0.009 ( 0.2997 )
    -0.06 ( 0.2495 )
        Change at Day 28: Post-BD (N= 42, 47)
    0.013 ( 0.3402 )
    -0.029 ( 0.2086 )
        Change at Day 56: Pre-BD (N= 34, 43)
    -0.04 ( 0.2676 )
    -0.04 ( 0.3101 )
        Change at Day 56: Post-BD (N= 39, 45)
    0.007 ( 0.3405 )
    -0.03 ( 0.2734 )
    Notes
    [24] - FAS population
    [25] - FAS population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    FVC was analyzed by an ANCOVA with baseline as a covariate and treatment as a factor. Adjusted means (LS means) for treatment, as well as the difference in LS means between treatment groups, and the corresponding 95% confidence intervals were calculated.
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3993
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    0.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0686
         upper limit
    		 0.1704

    Secondary: Change From Baseline in Pulmonary Function Test Forced Expiratory Flow Over the Middle Half of Subject’s Forced Vital Capacity (FVC) (FEF25-75) at Days 7, 14, 21, 28, 56

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    End point title
    		 Change From Baseline in Pulmonary Function Test Forced Expiratory Flow Over the Middle Half of Subject’s Forced Vital Capacity (FVC) (FEF25-75) at Days 7, 14, 21, 28, 56
    End point description
    FEF 25 Percent (%)-75% measurement describes the amount of air expelled from the lungs during the middle half (25% - 75%) of the forced vital capacity test. FEF25-75 is a pulmonary function test included pre-BD and post-BDs. The pre-BDs were performed prior to administration of any BD where as post-BDs were obtained within at least 15 minutes and no more than 30 minutes after administration of standard dose of BD. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7, 14, 21, 28, 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [26]
    47 [27]
    Units: liter per second
    arithmetic mean (standard deviation)
        Baseline: Pre-BD (N= 37, 43)
    0.927 ( 0.7019 )
    0.79 ( 0.4473 )
        Baseline: Post-BD (N= 41, 46)
    0.96 ( 0.6376 )
    0.858 ( 0.4768 )
        Change at Day 7: Pre-BD (N= 35, 43)
    -0.021 ( 0.1989 )
    -0.033 ( 0.1622 )
        Change at Day 7: Post-BD (N= 40, 46)
    0.045 ( 0.3017 )
    -0.004 ( 0.2318 )
        Change at Day 14: Pre-BD (N= 34, 42)
    0.028 ( 0.3661 )
    -0.03 ( 0.2288 )
        Change at Day 14: Post-BD (N= 39, 45)
    0.064 ( 0.4494 )
    -0.023 ( 0.3312 )
        Change at Day 21: Pre-BD (N= 34, 43)
    -0.019 ( 0.2114 )
    -0.088 ( 0.2813 )
        Change at Day 21: Post-BD (N= 39, 46)
    -0.058 ( 0.3483 )
    -0.06 ( 0.2851 )
        Change at Day 28: Pre-BD (N= 35, 43)
    -0.045 ( 0.3533 )
    -0.103 ( 0.3242 )
        Change at Day 28: Post-BD (N= 39, 46)
    0.081 ( 0.4294 )
    -0.038 ( 0.3975 )
        Change at Day 56: Pre-BD (N= 32, 42)
    0.07 ( 0.3323 )
    -0.068 ( 0.3002 )
        Change at Day 56: Post-BD (N= 36, 44)
    -0.066 ( 0.5485 )
    -0.077 ( 0.4097 )
    Notes
    [26] - FAS population
    [27] - FAS population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    FEF25-75 was analyzed by an ANCOVA with baseline as a covariate and treatment as a factor. Adjusted means (LS means) for treatment, as well as the difference in LS means between treatment groups, and the corresponding 95% confidence intervals were calculated.
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1159
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    0.138
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0348
         upper limit
    		 0.3114

    Secondary: Change From Baseline in Total Score on St. George's Respiratory Questionnaire (SGRQ) at Day 28 and 56

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    End point title
    		 Change From Baseline in Total Score on St. George's Respiratory Questionnaire (SGRQ) at Day 28 and 56
    End point description
    SGRQ has been developed to measure the impact of respiratory disease on health status. The SGRQ scoring was done 0-100% with 0 being no impairment of quality of life. This was scored separately for each of 3 sections (Activity, Impact and Symptom) of the questionnaire and a summary score utilizing responses to all items was the total SGRQ score. This total score ranged from zero to 100%. Score range of change from baseline between -4 to +4 points indicate "no clinical relevant change"; less than (<) 4 points indicate "improvement"; greater than (>) 4 points indicate "deterioration". In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [28]
    47 [29]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Baseline (N= 42, 46)
    43.18 ( 20.159 )
    39.68 ( 14.546 )
        Change at Day 28 (N= 40, 45)
    0.36 ( 9.051 )
    0.18 ( 11.715 )
        Change at Day 56 (N= 36, 44)
    -0.87 ( 6.851 )
    1.54 ( 10.874 )
    Notes
    [28] - FAS population
    [29] - FAS population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Baseline value was defined as the last non-missing assessment prior to the first dose of study drug. Adjusted means was defined as LS means. Data at the EOT (Week 4/Day 28) visit analyzed by the ANCOVA with baseline as a covariate and treatment as a factor (BAY85-8501 versus placebo).
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7028
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    0.862
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6172
         upper limit
    		 5.3412

    Secondary: Change From Baseline in 24 Hours Sputum Weight at Day 28

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    End point title
    		 Change From Baseline in 24 Hours Sputum Weight at Day 28
    End point description
    In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 28
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [30]
    47 [31]
    Units: gram(s)
    arithmetic mean (standard deviation)
        Baseline (N= 45, 47)
    22.14 ( 19.8151 )
    25.431 ( 24.4686 )
        Change at Day 28 (N= 40, 44)
    -0.126 ( 14.3549 )
    -3.398 ( 11.4987 )
    Notes
    [30] - FAS population
    [31] - FAS population
    No statistical analyses for this end point

    Secondary: Change From Baseline of Biomarkers in Sputum at Days 14, 28, 56: Alpha-1 Antitrypsin Human Neutrophil Elastase (A1AH-NE) Complex, Interleukin-8 (IL-8)

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    End point title
    		 Change From Baseline of Biomarkers in Sputum at Days 14, 28, 56: Alpha-1 Antitrypsin Human Neutrophil Elastase (A1AH-NE) Complex, Interleukin-8 (IL-8)
    End point description
    Sputum biomarker assessments were taken from induced sputum. Inflammatory markers, included IL-8, A1AH-NE complex were recorded. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [32]
    47 [33]
    Units: microgram per liter
    arithmetic mean (standard deviation)
        Baseline: A1AH-NE (N= 44, 47)
    22.558 ( 19.408 )
    23 ( 37.4346 )
        Change at Day 14: A1AH-NE (N= 38, 45)
    0.62 ( 13.338 )
    13.482 ( 62.8838 )
        Change at Day 28: A1AH-NE (N= 40, 45)
    -4.805 ( 17.3091 )
    -1.803 ( 24.2774 )
        Change at Day 56: A1AH-NE ( N= 34, 42)
    -1.985 ( 17.5933 )
    10.17 ( 43.4871 )
        Baseline: IL-8 (N= 44, 47)
    105.5 ( 112.305 )
    95.7 ( 91.279 )
        Change at Day 14: IL-8 (N= 38, 45)
    9.19 ( 59.909 )
    -6.73 ( 52.883 )
        Change at Day 28: IL-8 (N= 40, 46)
    13.14 ( 58.059 )
    -12.19 ( 51.165 )
        Change at Day 56: IL-8 (N= 34, 42)
    20.66 ( 62.955 )
    -1.42 ( 73.201 )
    Notes
    [32] - FAS population
    [33] - FAS population
    Statistical analysis title
    		 Alpha-1-antitrypsin Human NE Complex in Sputum
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.311
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -2.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.475
         upper limit
    		 2.732
    Statistical analysis title
    		 Interleukin-8 in Sputum
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0215
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    27.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.093
         upper limit
    		 50.021

    Secondary: Change From Baseline of Biomarkers in Sputum at Days 14, 28, 56: Neutrophil cell Count

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    End point title
    		 Change From Baseline of Biomarkers in Sputum at Days 14, 28, 56: Neutrophil cell Count
    End point description
    Sputum biomarker assessments were taken from induced sputum. Inflammatory markers, included neutrophil cell count. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [34]
    47 [35]
    Units: giga per liter
    arithmetic mean (standard deviation)
        Baseline (N= 41, 39)
    17.76 ( 21.3226 )
    20.107 ( 25.2439 )
        Change at Day 14 (N= 32, 34)
    -0.301 ( 17.1693 )
    -0.11 ( 16.0611 )
        Change at Day 28 (N= 36, 36)
    -3.446 ( 12.6294 )
    0.786 ( 27.9962 )
        Change at Day 56 (N= 25, 34)
    -0.513 ( 12.5183 )
    -2.067 ( 23.12 )
    Notes
    [34] - FAS population
    [35] - FAS population
    Statistical analysis title
    		 Neutrophil cell Count in Sputum
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3704
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.463
         upper limit
    		 5.46

    Secondary: Change From Baseline of Human Neutrophil Elastase (NE) Activity in Sputum at Days 14, 28, 56

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    End point title
    		 Change From Baseline of Human Neutrophil Elastase (NE) Activity in Sputum at Days 14, 28, 56
    End point description
    Neutrophil elastase activity in sputum was performed to treatment group for each scheduled visit. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [36]
    47 [37]
    Units: units per liter
    arithmetic mean (standard deviation)
        Baseline (N= 44, 47)
    213.21 ( 229.235 )
    250.21 ( 296.335 )
        Change at Day 14 (N= 38, 45)
    34.62 ( 170.219 )
    -22.29 ( 137.516 )
        Change at Day 28 (N= 40, 46)
    -6.76 ( 169.055 )
    -24.84 ( 155.737 )
        Change at Day 56 (N= 34, 42)
    11.89 ( 162.026 )
    -41 ( 216.065 )
    Notes
    [36] - FAS population
    [37] - FAS population
    No statistical analyses for this end point

    Secondary: Change From Baseline of Human Neutrophil Elastase (NE) Concentration in Sputum at Days 14, 28, 56

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    End point title
    		 Change From Baseline of Human Neutrophil Elastase (NE) Concentration in Sputum at Days 14, 28, 56
    End point description
    Neutrophil elastase concentration in sputum was performed to treatment group for each scheduled visit. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [38]
    47 [39]
    Units: microgram per liter
    arithmetic mean (standard deviation)
        Baseline (N= 44, 47)
    24.567 ( 37.7496 )
    39.215 ( 120.0264 )
        Change at Day 14 (N= 38, 45)
    21.261 ( 20.4157 )
    32.79 ( 91.6294 )
        Change at Day 28 (N= 40, 44)
    -7.59 ( 33.8392 )
    -12.523 ( 112.9358 )
        Change at Day 56 (N= 34, 42)
    -2.282 ( 35.3634 )
    16.033 ( 190.0303 )
    Notes
    [38] - FAS population
    [39] - FAS population
    No statistical analyses for this end point

    Secondary: Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: C-reactive Protein

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    End point title
    		 Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: C-reactive Protein
    End point description
    Biomarkers in blood that were analyzed included C-reactive protein (hCRP). hCRP is an acute phase reactant protein. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome. CRP is an acute phase reactant protein
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [40]
    47 [41]
    Units: microgram per liter
    arithmetic mean (standard deviation)
        Baseline (N= 45, 45)
    7.47 ( 7.325 )
    11.66 ( 14.582 )
        Change at Day 14 (N= 42, 44)
    -0.45 ( 4.584 )
    0.52 ( 8.834 )
        Change at Day 28 (N= 44, 45)
    2.9 ( 22.077 )
    2.46 ( 19.309 )
        Change at Day 56 (N= 38, 42)
    -0.62 ( 8.329 )
    4.96 ( 19.868 )
    Notes
    [40] - FAS population
    [41] - FAS population
    Statistical analysis title
    		 Biomarkers in Blood: Creactive Protein
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.927
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.539
         upper limit
    		 9.367

    Secondary: Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: Interleukin-8 (IL-8)

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    End point title
    		 Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: Interleukin-8 (IL-8)
    End point description
    Biomarkers in blood that were analyzed included IL-8. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [42]
    47 [43]
    Units: nanogram per liter
    arithmetic mean (standard deviation)
        Baseline (N= 45, 45)
    46.97 ( 185.099 )
    18.86 ( 12.88 )
        Change at Day 14 (N= 42, 45)
    14.8 ( 109.806 )
    10.34 ( 51.355 )
        Change at Day 28 (N= 44, 45)
    -29.85 ( 181.546 )
    7.68 ( 32.687 )
        Change at Day 56 (N= 38, 43)
    -35.19 ( 191.115 )
    3.42 ( 39.332 )
    Notes
    [42] - FAS population
    [43] - FAS population
    Statistical analysis title
    		 Biomarkers in Blood: Interleukin-8
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0771
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -9.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.188
         upper limit
    		 1.063

    Secondary: Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: Neutrophil cell Count

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    End point title
    		 Change From Baseline of Biomarkers in Blood at Days 14, 28, 56: Neutrophil cell Count
    End point description
    Biomarkers in blood that were analyzed included neutrophil cell count. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [44]
    47 [45]
    Units: giga per liter
    arithmetic mean (standard deviation)
        Baseline (N= 45, 47)
    4.331 ( 1.2776 )
    4.338 ( 1.4379 )
        Change at Day 14 (N= 41, 45)
    -0.056 ( 0.9886 )
    -0.257 ( 1.2292 )
        Change at Day 28 (N= 44, 47)
    0.122 ( 1.0209 )
    -0.2 ( 1.4049 )
        Change at Day 56 (N= 39, 43)
    -0.037 ( 0.9817 )
    0.377 ( 1.2587 )
    Notes
    [44] - FAS population
    [45] - FAS population
    Statistical analysis title
    		 Biomarkers in Blood: Neutrophil cell Count
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.143
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.643
         upper limit
    		 4.371

    Secondary: Change From Baseline of Biomarkers in Urine At Days 14, 28, 56: Creatinine

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    End point title
    		 Change From Baseline of Biomarkers in Urine At Days 14, 28, 56: Creatinine
    End point description
    Biomarker assessments included creatinine in the urine. Concentrations of creatinine was measured and reported. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [46]
    47 [47]
    Units: micromole per liter
    arithmetic mean (standard deviation)
        Baseline (N= 42, 43)
    7328.1 ( 5135.68 )
    7153.7 ( 4273.61 )
        Change at Day 14 (N= 39, 41)
    1598.1 ( 6149.83 )
    363.8 ( 2890.06 )
        Change at Day 28 (N= 40, 39)
    1221.8 ( 5070.3 )
    1856.5 ( 4082.98 )
        Change at Day 56 (N= 37, 40)
    1064.9 ( 6227.38 )
    948 ( 4387.41 )
    Notes
    [46] - FAS population
    [47] - FAS population
    Statistical analysis title
    		 Biomarkers in Urine: Creatinine
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5255
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -585.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2413.24
         upper limit
    		 1242.474

    Secondary: Change From Baseline of Biomarkers in Urine at Days 14, 28, 56: Desmosine

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    End point title
    		 Change From Baseline of Biomarkers in Urine at Days 14, 28, 56: Desmosine
    End point description
    Biomarker assessments included elastin degradation product desmosine in the urine. Desmosine was measured and reported. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [48]
    47 [49]
    Units: nanogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (N= 42, 43)
    10.816 ( 7.797 )
    12.812 ( 8.8276 )
        Change at Day 14 (N= 39, 41)
    2.262 ( 7.677 )
    0.371 ( 4.5118 )
        Change at Day 28 (N= 40, 39)
    2.744 ( 8.1192 )
    3.617 ( 5.9407 )
        Change at Day 56 (N= 37, 40)
    1.316 ( 9.6672 )
    1.577 ( 8.5245 )
    Notes
    [48] - FAS population
    [49] - FAS population
    Statistical analysis title
    		 Biomarkers in Urine: Desmosine
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3605
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.545
         upper limit
    		 1.673

    Secondary: Change From Baseline of Biomarkers in Urine at Days 14, 28, 56: Normalized Desmosine Value to Creatinine

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    End point title
    		 Change From Baseline of Biomarkers in Urine at Days 14, 28, 56: Normalized Desmosine Value to Creatinine
    End point description
    Normalized desmosine value to creatinine is the ratio obtained by calculating assay of desmosine divided by assay of creatinine. In the categories listed below, “N” signifies the number of subjects evaluable for the outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, 28 and 56
    End point values
    		 BAY85-8501 Placebo
    Number of subjects analysed
    47 [50]
    47 [51]
    Units: nanogram per milligram
    arithmetic mean (standard deviation)
        Baseline (N= 42, 43)
    13.926 ( 5.4532 )
    15.674 ( 4.2885 )
        Change at Day 14 (N= 39, 41)
    0.227 ( 4.227 )
    0.081 ( 3.4887 )
        Change at Day 28 (N= 40, 39)
    0.609 ( 3.6745 )
    0.651 ( 2.9772 )
        Change at Day 56 (N= 37, 40)
    0.096 ( 4.1133 )
    0.03 ( 4.4286 )
    Notes
    [50] - FAS population
    [51] - FAS population
    Statistical analysis title
    		 Normalized Desmosine Value to Creatinine
    Comparison groups
    BAY85-8501 v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7666
    Method
    		 ANCOVA
    Parameter type
    		 LS-mean Difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.756
         upper limit
    		 1.299

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to follow-up visit (28 days after last dose)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    BAY85-8501
    Reporting group description
    		 Daily oral dose of 1 mg BAY85-8501 tablets for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo-matched to BAY85-8501 for 28 days.

    Serious adverse events
    		 BAY85-8501 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 47 (2.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Accelerated idioventricular rhythm
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 47 (2.13%)
         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
    Apnoeic attack
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 47 (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
    Bronchopneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 47 (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
    		 BAY85-8501 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 45 (40.00%)
    20 / 47 (42.55%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 47 (8.51%)
         occurrences all number
    9
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 47 (6.38%)
         occurrences all number
    1
    3
    Diarrhoea
         subjects affected / exposed
    4 / 45 (8.89%)
    3 / 47 (6.38%)
         occurrences all number
    6
    4
    Vomiting
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 47 (0.00%)
         occurrences all number
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 45 (8.89%)
    4 / 47 (8.51%)
         occurrences all number
    5
    4
    Sputum increased
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 47 (6.38%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 47 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 45 (4.44%)
    6 / 47 (12.77%)
         occurrences all number
    2
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 47 (2.13%)
         occurrences all number
    3
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2012
    Measurement of the concentration of neutrophil elastase in the sputum was added as a biomarker endpoint. This endpoint allowed direct measurement of NE concentration (in sputum) as a biomarker endpoint; it was inadvertently omitted in the final stage of protocol preparation.

    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.
    Decimal places were automatically truncated if last decimal equals zero.
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