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    Clinical Trial Results:
    A Randomized, Double-Blind, Chronic Dosing (24 Weeks), Placebo-Controlled, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate to Very Severe COPD, Compared with Placebo

    Summary
    EudraCT number
    		 2014-004712-10
    Trial protocol
    		 DE   CZ   PL   HU  
    Global end of trial date
    31 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2018
    First version publication date
    07 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PT003014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02343458
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pearl Therapeutics Inc.
    Sponsor organisation address
    200 Cardinal Way, Redwood City, United States, 94063
    Public contact
    Colin Reisner, Pearl Therapeutics Inc., 1 6503052600, creisner@pearltherapeutics.com
    Scientific contact
    Colin Reisner, Pearl Therapeutics Inc., 1 6503052600, creisner@pearltherapeutics.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
    31 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the efficacy of treatment with GFF MDI, FF MDI, and GP MDI to Placebo MDI and to compare the efficacy of GFF MDI to its components on lung function using trough forced expiratory volume in 1 second (FEV1) in subjects with moderate to very severe COPD.
    Protection of trial subjects
    For subjects who were on ICS LABA, the ICS LABA was discontinued, however, then prescribed an ICS Monotherapy at an equivalent dosing regimen for the duration of the study. Subjects were also given sponsor provided Ventolin HFA as rescue medication.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Mar 2015
    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
    China: 466
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    Germany: 126
    Country: Number of subjects enrolled
    United Kingdom: 56
    Country: Number of subjects enrolled
    Hungary: 82
    Country: Number of subjects enrolled
    Japan: 150
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 73
    Country: Number of subjects enrolled
    Poland: 164
    Country: Number of subjects enrolled
    Russian Federation: 70
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    United States: 494
    Worldwide total number of subjects
    1740
    EEA total number of subjects
    476
    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)
    868
    From 65 to 84 years
    872
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 175 sites in the United States, United Kingdom, Taiwan (TW),South Korea (SK), Russia, Poland, Hungary, Germany, Czech Republic, China, and Japan from April 2015 to August 2017. The entire study period was scheduled to take approximately 30 weeks for each individual subject from the time of screening.

    Pre-assignment
    Screening details
    		 Subjects were randomized in a 7:6:6:3 scheme (GFF MDI, FF MDI, GP MDI, and Placebo MDI). Randomization was stratified by reversibility to Ventolin HFA and COPD disease severity (moderate vs severe or very severe) to ensure a similar distribution of treatment arms across stratum.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GFF MDI 14.4/9.6 ug
    Arm description
    		 Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    GFF MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 Inhalations BID

    Arm title
    		 FF MDI 9.6 ug
    Arm description
    		 Formoterol Fumarate, Metered Dose Inhalation 9.6 ug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    FF MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Arm title
    		 GP MDI 14.4 ug
    Arm description
    		 Glycopyrronium 14.4 ug Metered Dose Inhalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium MDI
    Investigational medicinal product code
    Other name
    GP MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Arm title
    		 Placebo MDI
    Arm description
    		 Placebo Metered Dose Inhalation
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Placebo MDI
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Number of subjects in period 1
    		GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Started
    551
    480
    474
    235
    Completed
    491
    415
    412
    197
    Not completed
    60
    65
    62
    38
         Physician decision
    1
    4
    2
    2
         Subject Discretion
    18
    17
    23
    14
         Adverse event, non-fatal
    15
    14
    15
    3
         Protocol Specified Criteria
    17
    12
    13
    8
         Lost to follow-up
    5
    5
    3
    1
         Lack of efficacy
    3
    8
    4
    8
         Protocol deviation
    1
    5
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GFF MDI 14.4/9.6 ug
    Reporting group description
    		 Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate, Metered Dose Inhalation 9.6 ug

    Reporting group title
    GP MDI 14.4 ug
    Reporting group description
    		 Glycopyrronium 14.4 ug Metered Dose Inhalation

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Reporting group values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI Total
    Number of subjects
    		 551 480 474 235 1740
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 261 240 248 119 868
        From 65-84 years
    		 290 240 226 116 872
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.7 ( 7.4 ) 64.1 ( 7.6 ) 64.0 ( 8.1 ) 63.9 ( 7.5 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 143 115 128 64 450
        Male
    		 408 365 346 171 1290
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 0 1
        Asian
    		 223 204 181 92 700
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 12 16 18 6 52
        White
    		 315 260 275 137 987
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    GFF MDI 14.4/9.6 ug
    Reporting group description
    		 Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate, Metered Dose Inhalation 9.6 ug

    Reporting group title
    GP MDI 14.4 ug
    Reporting group description
    		 Glycopyrronium 14.4 ug Metered Dose Inhalation

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Primary: Change from baseline in morning pre-dose trough FEV1 at week 24 of treatment (US/China approach)

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    End point title
    		 Change from baseline in morning pre-dose trough FEV1 at week 24 of treatment (US/China approach)
    End point description
    For the US/China approach, the primary endpoint was the change from baseline in morning pre-dose trough FEV1 at Week 24 of treatment
    End point type
    Primary
    End point timeframe
    at week 24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    488
    413
    412
    196
    Units: mL
        least squares mean (confidence interval 95%)
    120 (102 to 138)
    47 (28 to 67)
    60 (41 to 80)
    -45 (-73 to -17)
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) at Week 24
    Comparison groups
    GFF MDI 14.4/9.6 ug v Placebo MDI
    Number of subjects included in analysis
    684
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.132
         upper limit
    		 0.198
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) at Week 24
    Comparison groups
    FF MDI 9.6 ug v Placebo MDI
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.058
         upper limit
    		 0.126
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) at Week 24
    Comparison groups
    GP MDI 14.4 ug v Placebo MDI
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.071
         upper limit
    		 0.14
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) at Week 24
    Comparison groups
    GFF MDI 14.4/9.6 ug v FF MDI 9.6 ug
    Number of subjects included in analysis
    901
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.046
         upper limit
    		 0.099
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) at Week 24
    Comparison groups
    GFF MDI 14.4/9.6 ug v GP MDI 14.4 ug
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.033
         upper limit
    		 0.086

    Primary: Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach

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    End point title
    		 Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    End point description
    Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    End point type
    Primary
    End point timeframe
    over weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    517
    436
    437
    205
    Units: mL
        least squares mean (confidence interval 95%)
    128 (113 to 143)
    54 (38 to 71)
    74 (58 to 91)
    -25 (-49 to -1)
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over weeks 12-24, Japan approach
    Comparison groups
    GFF MDI 14.4/9.6 ug v Placebo MDI
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.125
         upper limit
    		 0.181
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    Comparison groups
    FF MDI 9.6 ug v Placebo MDI
    Number of subjects included in analysis
    641
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.109
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    Comparison groups
    GP MDI 14.4 ug v Placebo MDI
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.128
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    Comparison groups
    GFF MDI 14.4/9.6 ug v FF MDI 9.6 ug
    Number of subjects included in analysis
    953
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.051
         upper limit
    		 0.096
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 over weeks 12-24, Japan approach
    Comparison groups
    GFF MDI 14.4/9.6 ug v GP MDI 14.4 ug
    Number of subjects included in analysis
    954
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.031
         upper limit
    		 0.076

    Primary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.

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    End point title
    		 Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    End point description
    Change from baseline in morning pre-dose trough FEV1 over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    End point type
    Primary
    End point timeframe
    over 24 weeks
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    541
    467
    465
    225
    Units: mL
        least squares mean (confidence interval 95%)
    135 (121 to 149)
    63 (48 to 78)
    80 (65 to 94)
    -20 (-41 to 2)
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    Comparison groups
    GFF MDI 14.4/9.6 ug v Placebo MDI
    Number of subjects included in analysis
    766
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.129
         upper limit
    		 0.18
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    Comparison groups
    FF MDI 9.6 ug v Placebo MDI
    Number of subjects included in analysis
    692
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.057
         upper limit
    		 0.109
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    Comparison groups
    GP MDI 14.4 ug v Placebo MDI
    Number of subjects included in analysis
    690
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.073
         upper limit
    		 0.125
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    Comparison groups
    GFF MDI 14.4/9.6 ug v FF MDI 9.6 ug
    Number of subjects included in analysis
    1008
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.052
         upper limit
    		 0.092
    Statistical analysis title
    		 Change from baseline in AM pre-dose trough FEV1
    Statistical analysis description
    Change from baseline in morning pre-dose trough FEV1 (Liters) over 24 weeks. Primary endpoint, EU/SK/TW approach, Secondary endpoint US/China approach.
    Comparison groups
    GFF MDI 14.4/9.6 ug v GP MDI 14.4 ug
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.035
         upper limit
    		 0.076

    Secondary: TDI focal score over 24 weeks, US/China and EU/SK/TW Approach

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    End point title
    		 TDI focal score over 24 weeks, US/China and EU/SK/TW Approach
    End point description
    TDI Focal Score over 24 weeks, US/China and EU/SK/TW Approach
    End point type
    Secondary
    End point timeframe
    over 24 Weeks
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    532
    458
    457
    217
    Units: Score
        least squares mean (confidence interval 95%)
    1.6 (1.4 to 1.8)
    1.5 (1.3 to 1.7)
    1.3 (1.1 to 1.5)
    0.8 (0.5 to 1.1)
    No statistical analyses for this end point

    Secondary: TDI focal score over Weeks 12-24 Japan approach

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    End point title
    		 TDI focal score over Weeks 12-24 Japan approach
    End point description
    TDI Focal Score over Weeks 12-24 Japan approach
    End point type
    Secondary
    End point timeframe
    over Weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    515
    434
    436
    205
    Units: Scores
        least squares mean (confidence interval 95%)
    1.7 (1.5 to 1.9)
    1.5 (1.3 to 1.7)
    1.4 (1.2 to 1.6)
    0.8 (0.5 to 1.1)
    No statistical analyses for this end point

    Secondary: TDI focal score over 24 weeks - US/China and EU/SK/TW approaches -Symptomatic Population

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    End point title
    		 TDI focal score over 24 weeks - US/China and EU/SK/TW approaches -Symptomatic Population
    End point description
    TDI Focal Score – Secondary Endpoints, US/China and EU/SK/TW approaches
    End point type
    Secondary
    End point timeframe
    over 24 Weeks
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    244
    217
    228
    108
    Units: Scores
        least squares mean (confidence interval 95%)
    1.5 (1.2 to 1.7)
    1.3 (1.0 to 1.6)
    1.1 (0.8 to 1.3)
    0.7 (0.3 to 1.2)
    No statistical analyses for this end point

    Secondary: TDI focal score over weeks 12-24 - Japan approach - Symptomatic Population

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    End point title
    		 TDI focal score over weeks 12-24 - Japan approach - Symptomatic Population
    End point description
    TDI Focal Score – Secondary Endpoint, Japan approach
    End point type
    Secondary
    End point timeframe
    over weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    237
    200
    218
    97
    Units: Scores
        least squares mean (confidence interval 95%)
    1.5 (1.2 to 1.8)
    1.4 (1.0 to 1.7)
    1.1 (0.8 to 1.4)
    0.7 (0.2 to 1.2)
    No statistical analyses for this end point

    Secondary: Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach

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    End point title
    		 Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach
    End point description
    Peak change from baseline in FEV1 within 2 hours post-dosing at Week 24 US/China approach
    End point type
    Secondary
    End point timeframe
    at week 24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    490
    413
    412
    196
    Units: mL
        least squares mean (confidence interval 95%)
    358 (338 to 378)
    247 (226 to 269)
    214 (192 to 235)
    55 (24 to 87)
    No statistical analyses for this end point

    Secondary: Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach

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    End point title
    		 Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach
    End point description
    Peak change from baseline in FEV1 within 2 hours post-dosing over weeks 12-24 Japan approach
    End point type
    Secondary
    End point timeframe
    over weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    516
    436
    436
    205
    Units: mL
        least squares mean (confidence interval 95%)
    368 (350 to 386)
    255 (236 to 274)
    228 (209 to 248)
    70 (42 to 98)
    No statistical analyses for this end point

    Secondary: Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach

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    End point title
    		 Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach
    End point description
    Peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks EU/SK/TW approach
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    550
    480
    474
    235
    Units: mL
        least squares mean (confidence interval 95%)
    375 (360 to 389)
    277 (261 to 293)
    234 (218 to 250)
    82 (58 to 105)
    No statistical analyses for this end point

    Secondary: Change from Baseline in SGRQ Total Score at week 24, US/China approach

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    End point title
    		 Change from Baseline in SGRQ Total Score at week 24, US/China approach
    End point description
    Change from Baseline in SGRQ Total Score at week 24, US/China approach
    End point type
    Secondary
    End point timeframe
    at week 24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    489
    415
    412
    196
    Units: Units
        least squares mean (confidence interval 95%)
    -5.3 (-6.4 to -4.2)
    -5.6 (-6.8 to -4.4)
    -3.7 (-4.8 to -2.5)
    -0.9 (-2.6 to 0.8)
    No statistical analyses for this end point

    Secondary: Change from Baseline in SGRQ Total Score over weeks 12-24 , Japan & EU/SK/TW approach

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    End point title
    		 Change from Baseline in SGRQ Total Score over weeks 12-24 , Japan & EU/SK/TW approach
    End point description
    Change from Baseline in SGRQ Total Score over weeks 12-24 , Japan & EU/SK/TW approach
    End point type
    Secondary
    End point timeframe
    over weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    516
    436
    436
    205
    Units: Units
        least squares mean (confidence interval 95%)
    -5.2 (-6.1 to -4.3)
    -5.0 (-5.9 to -4.0)
    -3.6 (-4.6 to -2.6)
    -1.7 (-3.1 to -0.3)
    No statistical analyses for this end point

    Secondary: Change from Baseline in SGRQ Total Score at week 24 in Symptomatic Population, US/China approach

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    End point title
    		 Change from Baseline in SGRQ Total Score at week 24 in Symptomatic Population, US/China approach
    End point description
    Change from Baseline in SGRQ Total Score at week 24 in Symptomatic Population, US/China approach
    End point type
    Secondary
    End point timeframe
    at week 24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    220
    189
    202
    92
    Units: Units
        least squares mean (confidence interval 95%)
    -6.9 (-8.6 to -5.2)
    -7.8 (-9.7 to -5.9)
    -3.8 (-5.6 to -2.0)
    -1.6 (-4.3 to 1.1)
    No statistical analyses for this end point

    Secondary: Change from Baseline in SGRQ Total Score over weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW approach

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    End point title
    		 Change from Baseline in SGRQ Total Score over weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW approach
    End point description
    Change from Baseline in SGRQ Total Score over weeks 12-24, in Symptomatic Population, Japan & EU/SK/TW approach
    End point type
    Secondary
    End point timeframe
    over weeks 12-24
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    237
    200
    218
    97
    Units: Units
        least squares mean (confidence interval 95%)
    -6.9 (-8.4 to -5.4)
    -7.3 (-8.9 to -5.6)
    -3.9 (-5.5 to -2.4)
    -3.1 (-5.4 to -0.8)
    No statistical analyses for this end point

    Secondary: Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches

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    End point title
    		 Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches
    End point description
    Change from baseline in average daily rescue Ventolin use over 24 weeks in RVU population, all approaches
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    256
    232
    225
    109
    Units: Puffs/day
        least squares mean (confidence interval 95%)
    -1.4 (-1.7 to -1.1)
    -1.0 (-1.3 to -0.7)
    -0.6 (-0.9 to -0.3)
    -0.4 (-0.8 to -0.0)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 5 Minutes Post-Dose, all approaches

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    End point title
    		 Time to onset of action on Day 1 - 5 Minutes Post-Dose, all approaches
    End point description
    Time to onset of action on Day 1 - 5 Minutes Post-Dose, all approaches
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    464
    406
    403
    197
    Units: mL
        least squares mean (confidence interval 95%)
    202 (191 to 212)
    186 (175 to 197)
    59 (48 to 70)
    22 (6 to 38)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 15 Minutes Post-Dose, all approaches

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    End point title
    		 Time to onset of action on Day 1 - 15 Minutes Post-Dose, all approaches
    End point description
    Time to onset of action on Day 1 - 15 Minutes Post-Dose, all approaches
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Number of subjects analysed
    530
    458
    453
    229
    Units: mL
        least squares mean (confidence interval 95%)
    241 (230 to 252)
    220 (208 to 231)
    105 (93 to 117)
    33 (16 to 50)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time the subject signed consent throughout the four treatment periods of 24 weeks and up to 10 days following the last dose of study drug.
    Adverse event reporting additional description
    The Safety Population was defined as all subjects who were randomized to treatment regardless and received at least one dose of study treatment. Serious adverse events collected from the time the subject signed consent up to 14 days following the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    GFF MDI 14.4/9.6 ug
    Reporting group description
    		 Glycopyrronium, Formoterol Fumarate, Metered Dose Inhalation 14.4/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate, Metered Dose Inhalation 9.6 ug

    Reporting group title
    GP MDI 14.4 ug
    Reporting group description
    		 Glycopyrronium 14.4 ug Metered Dose Inhalation

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Serious adverse events
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 551 (9.62%)
    40 / 480 (8.33%)
    34 / 474 (7.17%)
    19 / 235 (8.09%)
         number of deaths (all causes)
    1
    1
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer metastatic
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Breast neoplasm
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac myxoma
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemangiopericytoma
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 551 (0.36%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    16 / 551 (2.90%)
    13 / 480 (2.71%)
    12 / 474 (2.53%)
    7 / 235 (2.98%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 13
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma-chronic obstructive pulmonary disease overlap syndrome
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerous fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    2 / 474 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 480 (0.42%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 551 (0.18%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery disease
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypoglycemic coma
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudoradicular syndrome
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Angel closure glaucoma
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    2 / 474 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischemic
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorroids thrombosed
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    7 / 551 (1.27%)
    2 / 480 (0.42%)
    3 / 474 (0.63%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 551 (0.54%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 551 (0.00%)
    2 / 480 (0.42%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Borrelia Infection
         subjects affected / exposed
    0 / 551 (0.00%)
    1 / 480 (0.21%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes melitus
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    1 / 474 (0.21%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 551 (0.18%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 551 (0.00%)
    0 / 480 (0.00%)
    0 / 474 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 GFF MDI 14.4/9.6 ug FF MDI 9.6 ug GP MDI 14.4 ug Placebo MDI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 551 (30.13%)
    123 / 480 (25.63%)
    128 / 474 (27.00%)
    61 / 235 (25.96%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    16 / 551 (2.90%)
    13 / 480 (2.71%)
    12 / 474 (2.53%)
    7 / 235 (2.98%)
         occurrences all number
    16
    13
    12
    7
    Cough
         subjects affected / exposed
    13 / 551 (2.36%)
    8 / 480 (1.67%)
    10 / 474 (2.11%)
    2 / 235 (0.85%)
         occurrences all number
    14
    8
    11
    3
    Dyspnoea
         subjects affected / exposed
    11 / 551 (2.00%)
    7 / 480 (1.46%)
    6 / 474 (1.27%)
    7 / 235 (2.98%)
         occurrences all number
    11
    7
    8
    7
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    15 / 551 (2.72%)
    5 / 480 (1.04%)
    7 / 474 (1.48%)
    1 / 235 (0.43%)
         occurrences all number
    16
    5
    7
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    50 / 551 (9.07%)
    46 / 480 (9.58%)
    44 / 474 (9.28%)
    16 / 235 (6.81%)
         occurrences all number
    56
    52
    55
    17
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 551 (6.72%)
    29 / 480 (6.04%)
    33 / 474 (6.96%)
    20 / 235 (8.51%)
         occurrences all number
    44
    34
    40
    24
    Pneumonia
         subjects affected / exposed
    9 / 551 (1.63%)
    5 / 480 (1.04%)
    5 / 474 (1.05%)
    6 / 235 (2.55%)
         occurrences all number
    9
    5
    5
    6
    Bronchitis
         subjects affected / exposed
    4 / 551 (0.73%)
    6 / 480 (1.25%)
    8 / 474 (1.69%)
    5 / 235 (2.13%)
         occurrences all number
    5
    7
    8
    5
    Pharyngitis
         subjects affected / exposed
    11 / 551 (2.00%)
    4 / 480 (0.83%)
    3 / 474 (0.63%)
    0 / 235 (0.00%)
         occurrences all number
    11
    4
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2014
    Updated registration approaches to Include Japan. Updated inclusion/exclusion criteria. Clarification of COP exacerbation.
    08 Apr 2015
    Updated inclusion criteria.
    20 Apr 2015
    Updated number of estimated number of sites. Clarification of approaches. Clarify and standardize reporting of COPD language. Update of statistical methods in synopsis.
    01 May 2015
    Updated inclusion criteria, specifications for EU specific text.
    20 Jan 2017
    Revised sponsor contact name. Clarified use of ITT population vs symptomatic and rescue ventolin user populations. Clarified TDI language. Updated endpoints.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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