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    Clinical Trial Results:
    A Randomised, Double-Blind, Double-Dummy, Multicentre, Parallel Group Study to Assess the Efficacy and Safety of Glycopyrronium/Formoterol Fumarate Fixed-dose Combination Relative to Umeclidinium/Vilanterol Fixed-dose Combination Over 24 Weeks in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (AERISTO)

    Summary
    EudraCT number
    		 2016-004655-75
    Trial protocol
    		 FR   BG  
    Global end of trial date
    04 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 May 2019
    First version publication date
    16 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5970C00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03162055
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, 43183
    Public contact
    Vice President, Inhalation and Oral Respiratory, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Vice President, Inhalation and Oral Respiratory, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of glycopyrronium/formoterol fumarate (GFF) relative to umeclidinium/vilanterol (UV) on lung function as measured by trough forced expiratory volume in 1 second (FEV1) and peak FEV1 in participants with moderate to very severe chronic obstructive pulmonary disease (COPD).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 Participants were provided albuterol/salbutamol metered dose inhaler (MDI) for use as rescue medication for worsening of COPD symptoms during the study. The following maintenance treatments were allowed provided stable dosing prior to Visit 1 and throughout the study: • In participants who were steroid dependent systemic steroids equivalent of 5 milligrams (mg) prednisone per day or 10 mg every other day. • Theophylline ≤200 mg twice daily (BD). • Phosphodiesterase-4 Inhibitors. • Leukotriene antagonists. • Cromoglicate.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 164
    Country: Number of subjects enrolled
    Canada: 93
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Hungary: 178
    Country: Number of subjects enrolled
    Russian Federation: 303
    Country: Number of subjects enrolled
    Ukraine: 195
    Country: Number of subjects enrolled
    United States: 165
    Worldwide total number of subjects
    1119
    EEA total number of subjects
    363
    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)
    570
    From 65 to 84 years
    543
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 110 centers in 7 countries (Russia, Bulgaria, Ukraine, United States of America, Canada, Hungary and France) between 25 May 2017 and 04 May 2018. Participants with moderate to very severe COPD were recruited in this study.

    Pre-assignment
    Screening details
    		 The study had a screening period, followed by a 24-week double-blind and double-dummy treatment period. A total of 1445 participants were screened. Of which, 1119 participants were enrolled and randomized to study treatment.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Glycopyrronium/Formoterol Fumarate
    Arm description
    		 Participants were randomized to receive 2 inhalations of glycopyrronium/formoterol fumarate (GFF) fixed-dose combination 7.2/4.8 micrograms (mcg) per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to umeclidinium/vilanterol (UV) administered once daily in the morning by dry powder inhaler (DPI) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium/Formoterol Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered by MDI.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 inhalation of placebo matched to the UV administered by DPI.

    Arm title
    		 Umeclidinium/Vilanterol
    Arm description
    		 Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of placebo matched to the GFF administered by MDI.

    Investigational medicinal product name
    Umeclidinium/Vilanterol
    Investigational medicinal product code
    Other name
    Anoro Ellipta
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered by DPI.

    Number of subjects in period 1
    		Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Started
    559
    560
    Received treatment
    557
    560
    Safety analysis set
    552
    552
    Full analysis set (FAS)
    552
    552
    Per protocol (PP) analysis set
    506
    510 [1]
    Completed
    497
    517
    Not completed
    62
    43
         Adverse event, serious fatal
    3
    3
         Consent withdrawn by subject
    17
    2
         Adverse event, non-fatal
    6
    5
         Study-specific withdrawal criteria
    22
    14
         Unspecified
    8
    15
         Did not receive treatment
    2
    -
         Lost to follow-up
    -
    1
         Incorrect randomization
    4
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The PP analysis set is a subset of the FAS, deducting participants with important protocol deviations which may affect efficacy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glycopyrronium/Formoterol Fumarate
    Reporting group description
    		 Participants were randomized to receive 2 inhalations of glycopyrronium/formoterol fumarate (GFF) fixed-dose combination 7.2/4.8 micrograms (mcg) per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to umeclidinium/vilanterol (UV) administered once daily in the morning by dry powder inhaler (DPI) for 24 weeks.

    Reporting group title
    Umeclidinium/Vilanterol
    Reporting group description
    		 Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.

    Reporting group values
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol Total
    Number of subjects
    		 559 560 1119
    Age, Customized
    Units: Subjects
        <65 years
    		 276 294 570
        65 - 74 years
    		 227 218 445
        75 - 84 years
    		 53 45 98
        >=85 years
    		 3 3 6
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.3 ( 7.99 ) 63.9 ( 8.05 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 145 161 306
        Male
    		 414 399 813
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 13 10 23
        White
    		 545 550 1095
        More than one race
    		 0 0 0
        Other
    		 1 0 1
    Subject analysis sets

    Subject analysis set title
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks. The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy.

    Subject analysis set title
    PP Analysis Set: Umeclidinium/Vilanterol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks. The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy.

    Subject analysis sets values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects
    506
    510
    Age, Customized
    Units: Subjects
        <65 years
    249
    274
        65 - 74 years
    205
    197
        75 - 84 years
    49
    36
        >=85 years
    3
    3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    64.3 ( 8.0 )
    63.6 ( 8.0 )
    Sex: Female, Male
    Units: Subjects
        Female
    126
    145
        Male
    380
    365
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
        Black or African American
    11
    8
        White
    495
    502
        More than one race
    0
    0
        Other
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Glycopyrronium/Formoterol Fumarate
    Reporting group description
    		 Participants were randomized to receive 2 inhalations of glycopyrronium/formoterol fumarate (GFF) fixed-dose combination 7.2/4.8 micrograms (mcg) per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to umeclidinium/vilanterol (UV) administered once daily in the morning by dry powder inhaler (DPI) for 24 weeks.

    Reporting group title
    Umeclidinium/Vilanterol
    Reporting group description
    		 Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.

    Subject analysis set title
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks. The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy.

    Subject analysis set title
    PP Analysis Set: Umeclidinium/Vilanterol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks. The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy.

    Primary: Mean Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks

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    End point title
    		 Mean Change From Baseline in Morning Pre-dose Trough FEV1 Over 24 Weeks
    End point description
    To assess the effects of GFF relative to UV on lung function as measured by change from baseline in morning pre-dose trough FEV1 is defined as the average of the -60 and -30 minute pre-dose values at each visit minus baseline using spirometry. Baseline is defined as the mean of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    474
    489
    Units: milliliter (mL)
        least squares mean (standard error)
    82.4 ( 11.2 )
    169.6 ( 11.2 )
    Statistical analysis title
    		 Treatment difference: Morning pre-dose FEV1
    Statistical analysis description
    Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.9974 [2]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -87.2
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -117
         upper limit
    		 -57.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.3
    Notes
    [1] - Change from baseline = Treatment + baseline FEV1 + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
    [2] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.

    Primary: Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population

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    End point title
    		 Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in PP Analysis Set Population
    End point description
    To assess the effects of GFF relative to UV on lung function as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the average of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    506
    509
    Units: mL
        least squares mean (standard error)
    293.5 ( 10.2 )
    296.9 ( 10.3 )
    Statistical analysis title
    		 Treatment difference:FEV1 within 2 hours post-dose
    Statistical analysis description
    Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1015
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.0002 [4]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -3.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -32.8
         upper limit
    		 25.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.1
    Notes
    [3] - Change from baseline = Treatment + baseline FEV1 + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
    [4] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.

    Primary: Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population

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    End point title
    		 Mean Peak Change From Baseline in FEV1 Within 2 Hours Post-dosing Over 24 Weeks in FAS Population
    End point description
    To assess the effects of GFF relative to UV on lung function as measured by peak change from baseline in FEV1 is defined as the maximum of the FEV1 assessments within the 2 hours post-dosing time windows at each visit minus baseline using spirometry. Baseline is defined as the average of the non-missing -60 and -30 minute values obtained prior to dosing at randomization (Day 1). The FAS included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).
    End point type
    Primary
    End point timeframe
    From Baseline (Day 1) up to 24 weeks
    End point values
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Number of subjects analysed
    552
    552
    Units: mL
        least squares mean (standard error)
    299.1 ( 9.9 )
    300.8 ( 9.9 )
    Statistical analysis title
    		 Treatment difference:FEV1 within 2 hours post-dose
    Statistical analysis description
    Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    Glycopyrronium/Formoterol Fumarate v Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.5516
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -30.3
         upper limit
    		 27
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.8
    Notes
    [5] - Change from baseline = Treatment + baseline FEV1 + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.

    Secondary: Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1

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    End point title
    		 Percentage of Participants With Increase of FEV1 of >=100 mL From Baseline at 5 Minutes Post-dosing on Day 1
    End point description
    The percentage of participants with an increase in FEV1 of >=100 mL from baseline at 5 minutes post-dosing on Day 1 was determined to assess the early onset of action. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1). Only data assigned to the 5 minute window was used to determine response. Participants with missing data were considered non-responders for the analysis. The FAS analysis set included all randomized participants who received at least 1 inhalation of IP from the GFF or UV inhaler (active or placebo).
    End point type
    Secondary
    End point timeframe
    5 minutes post-dose on Day 1
    End point values
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Number of subjects analysed
    552
    552
    Units: Percentage of participants
        number (not applicable)
    60.1
    40.8
    Statistical analysis title
    		 Treatment difference: FEV1 >=100 mL at 5 minutes
    Statistical analysis description
    Estimate of the log odds of being a responder in the GFF treatment group compared to the UV treatment group using a logistic regression.
    Comparison groups
    Glycopyrronium/Formoterol Fumarate v Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.79
         upper limit
    		 2.95
    Notes
    [6] - ln (1/(1-p)) = Treatment + baseline FEV1 + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region. p=percentage of participants with increase of >=100 mL.

    Secondary: Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks

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    End point title
    		 Mean Peak Change From Baseline in Inspiratory Capacity (IC) Within 2 Hours Post-dosing Over 24 Weeks
    End point description
    Peak change from baseline in IC is defined as the maximum of the IC assessments within the 2 hours post-dosing time windows at each visit minus baseline. Baseline is defined as the average of available evaluable -60 and -30 minute pre-dose assessments conducted at randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    496
    501
    Units: mL
        least squares mean (standard error)
    363.1 ( 15.5 )
    378.3 ( 15.6 )
    Statistical analysis title
    		 Treatment difference: IC within 2 hours post-dose
    Statistical analysis description
    Estimate of the mean peak change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    997
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 = 0.0371 [8]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -15.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.4
         upper limit
    		 22.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.4
    Notes
    [7] - Change from baseline = Treatment + baseline IC + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
    [8] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin -50 mL.

    Secondary: Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks

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    End point title
    		 Mean Transition Dyspnea Index (TDI) Focal Score Over 24 Weeks
    End point description
    The baseline dyspnea index (BDI) and TDI consist of 3 individual components: functional impairment, magnitude of task, and magnitude of effort. For the BDI, each of these 3 components were rated in 5 grades from 0 (very severe) to 4 (no impairment), and were summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea were rated for each component by 7 grades from -3 (major deterioration) to +3 (major improvement), and were added to form a TDI focal score from -9 to +9. Baseline is defined as the latest BDI assessment within 7 days before or at randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day -7 or 1) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    500
    507
    Units: Units on a scale
        least squares mean (standard error)
    1.23 ( 0.10 )
    1.60 ( 0.10 )
    Statistical analysis title
    		 Treatment difference: TDI score
    Statistical analysis description
    Estimate of the mean TDI focal score over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1007
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [9] - TDI focal score = Treatment + Baseline Dyspnea Index + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
    [10] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin -1.0 unit.

    Secondary: Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks

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    End point title
    		 Mean Change From Baseline in Early Morning Symptoms of COPD Instrument (EMSCI) Over 24 Weeks
    End point description
    Change from baseline in the 6-item EMSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The EMSCI collected data about the frequency and severity of early morning symptoms and the impact of COPD symptoms on early morning activity in participants with COPD. Participants completed a daily electronic patient-reported outcome (ePRO) questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day -7) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    502
    508
    Units: Units on a scale
        least squares mean (standard error)
    -0.142 ( 0.018 )
    -0.176 ( 0.018 )
    Statistical analysis title
    		 Treatment difference: EMSCI score
    Statistical analysis description
    Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.0017 [12]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.034
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.011
         upper limit
    		 0.078
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023
    Notes
    [11] - Change from baseline = Treatment + baseline EMSCI score + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + time interval + treatment by time interval.
    [12] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.

    Other pre-specified: Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks

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    End point title
    		 Mean Change From Baseline in Night-Time Symptoms of COPD Instrument (NiSCI) Over 24 Weeks
    End point description
    Change from baseline in the 6-item NiSCI Symptom Severity Score was derived by averaging the responses from a participant on the 6 item-level symptom scores (scored on a 4-point scale from 1 to 4, whereas 1= mild and 4= very severe). The NiSCI collected data about the frequency and severity of night-time symptoms and the impact of COPD symptoms on night-time awakenings in participants with COPD. Participants completed a daily ePRO questionnaire for their COPD symptoms. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline (Day -7) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    502
    508
    Units: Units on a scale
        least squares mean (standard error)
    -0.165 ( 0.019 )
    -0.207 ( 0.019 )
    Statistical analysis title
    		 Treatment difference: NiSCI score
    Statistical analysis description
    Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1010
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 = 0.0088 [14]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.024
    Notes
    [13] - Change from baseline = Treatment + baseline NiSCI score + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + time interval + treatment by time interval.
    [14] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin 0.1 unit.

    Other pre-specified: Mean Change From Baseline in Daily Rescue (albuterol/salbutamol MDI) Use Over 24 Weeks

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    End point title
    		 Mean Change From Baseline in Daily Rescue (albuterol/salbutamol MDI) Use Over 24 Weeks
    End point description
    The number of inhalations of rescue albuterol/salbutamol MDI was recorded in the participant ePRO in the morning and evening. Baseline is defined as the average of the non-missing values from the ePRO data collected in the last 7 days before the randomization (Day 1). The rescue medication user analysis set included all participants in the FAS with average baseline rescue albuterol/salbutamol MDI use of >=1 inhalation/day. Only participants with data available for analysis are presented.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline (Day -7) up to 24 weeks
    End point values
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Number of subjects analysed
    450
    450
    Units: Puffs/day
        least squares mean (standard error)
    -1.70 ( 0.16 )
    -2.35 ( 0.16 )
    Statistical analysis title
    		 Treatment difference: Daily rescue use
    Statistical analysis description
    Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    Glycopyrronium/Formoterol Fumarate v Umeclidinium/Vilanterol
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.9995
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [15] - Change from baseline =Treatment + baseline rescue albuterol/salbutamol MDI use + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + time interval + treatment by time interval.

    Other pre-specified: Mean Change From Baseline in CAT Score Over 24 Weeks

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    End point title
    		 Mean Change From Baseline in CAT Score Over 24 Weeks
    End point description
    The CAT is used to quantify the impact of COPD symptoms on health status. The CAT has a scoring range of 0-40, and it is calculated as the sum of the responses given for each of the 8 items (scored on a 6-point scale from 0 to 5), with higher scores indicating a higher impact of COPD symptoms on health status. If the response to 1 of the 8 items is missing, the missing item was considered equal to the average of the 7 non-missing items for that participant. If more than 1 item is missing the score was considered missing. Baseline is defined as the latest assessment within 7 days before or at randomization (Day 1). The PP analysis set included the subset of the FAS containing participants with post-randomization data obtained prior to important protocol deviations which may have affected efficacy. Only participants with data available for analysis are presented.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline (Day -7 or 1) up to 24 weeks
    End point values
    		 PP Analysis Set: Glycopyrronium/Formoterol Fumarate PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects analysed
    500
    506
    Units: Units on a scale
        least squares mean (standard error)
    -2.97 ( 0.21 )
    -3.56 ( 0.22 )
    Statistical analysis title
    		 Treatment difference: CAT score
    Statistical analysis description
    Estimate of the mean change from baseline over 24 weeks in the GFF treatment group is compared to the UV treatment group using a repeated measures analysis.
    Comparison groups
    PP Analysis Set: Glycopyrronium/Formoterol Fumarate v PP Analysis Set: Umeclidinium/Vilanterol
    Number of subjects included in analysis
    1006
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    P-value
    		 < 0.0001 [17]
    Method
    		 Repeated measures analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 1.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [16] - Change from baseline = Treatment + baseline CAT score + bronchodilator responsiveness to albuterol/salbutamol MDI + stratification factor (prior treatment) + region + visit + treatment by visit.
    [17] - Non-inferiority p-value is calculated corresponding to the non-inferiority margin 2.0 unit.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day 1) up to 14 days after last IP dose, approximately 26 weeks.
    Adverse event reporting additional description
    The safety analysis set included all participants who received at least 1 inhalation of the randomized active IP that they were assigned.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Glycopyrronium/Formoterol Fumarate
    Reporting group description
    		 Participants were randomized to receive 2 inhalations of GFF fixed-dose combination 7.2/4.8 mcg per actuation administered in the morning and evening by MDI for 24 weeks. Participants also received 1 inhalation of placebo matched to UV administered once daily in the morning by DPI for 24 weeks.

    Reporting group title
    Umeclidinium/Vilanterol
    Reporting group description
    		 Participants were randomized to receive 1 inhalation of UV fixed-dose combination 62.5/25 mcg per actuation administered once daily in the morning by DPI for 24 weeks. Participants also received 2 inhalations of placebo matched to the GFF administered twice daily in the morning and evening by MDI for 24 weeks.

    Serious adverse events
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 552 (5.80%)
    40 / 552 (7.25%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post thrombotic syndrome
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 552 (0.18%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Incarcerated hernia
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    16 / 552 (2.90%)
    10 / 552 (1.81%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 552 (0.00%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 552 (0.18%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 552 (0.18%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 552 (0.18%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 552 (0.00%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial infarction
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 552 (0.00%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 552 (0.18%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 552 (0.54%)
    3 / 552 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 552 (0.18%)
    2 / 552 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 552 (0.18%)
    0 / 552 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 552 (0.00%)
    1 / 552 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Glycopyrronium/Formoterol Fumarate Umeclidinium/Vilanterol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 552 (23.37%)
    153 / 552 (27.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 552 (2.36%)
    7 / 552 (1.27%)
         occurrences all number
    16
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 552 (6.16%)
    41 / 552 (7.43%)
         occurrences all number
    52
    55
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 552 (0.91%)
    6 / 552 (1.09%)
         occurrences all number
    6
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 552 (0.72%)
    7 / 552 (1.27%)
         occurrences all number
    4
    8
    Constipation
         subjects affected / exposed
    1 / 552 (0.18%)
    7 / 552 (1.27%)
         occurrences all number
    1
    7
    Diarrhoea
         subjects affected / exposed
    7 / 552 (1.27%)
    13 / 552 (2.36%)
         occurrences all number
    8
    15
    Dry mouth
         subjects affected / exposed
    2 / 552 (0.36%)
    6 / 552 (1.09%)
         occurrences all number
    2
    6
    Toothache
         subjects affected / exposed
    1 / 552 (0.18%)
    6 / 552 (1.09%)
         occurrences all number
    1
    6
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    20 / 552 (3.62%)
    20 / 552 (3.62%)
         occurrences all number
    22
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 552 (0.18%)
    6 / 552 (1.09%)
         occurrences all number
    1
    7
    Back pain
         subjects affected / exposed
    12 / 552 (2.17%)
    9 / 552 (1.63%)
         occurrences all number
    13
    9
    Pain in extremity
         subjects affected / exposed
    1 / 552 (0.18%)
    7 / 552 (1.27%)
         occurrences all number
    1
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 552 (5.43%)
    36 / 552 (6.52%)
         occurrences all number
    32
    42
    Sinusitis
         subjects affected / exposed
    4 / 552 (0.72%)
    6 / 552 (1.09%)
         occurrences all number
    4
    8
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 552 (1.81%)
    10 / 552 (1.81%)
         occurrences all number
    13
    13
    Viral upper respiratory tract infection
         subjects affected / exposed
    17 / 552 (3.08%)
    26 / 552 (4.71%)
         occurrences all number
    18
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2017
    Primary and secondary objective tables updated by moving the peak change from baseline in FEV1 within 2 hours post-dosing over 24 weeks from secondary endpoint to become a primary endpoint, and statistical methods, including hierarchical testing procedures, updated accordingly. Section 1.3 (benefit/risk and ethical assessment) updated to add clarification on the chest x-ray. Inclusion criterion 9 updated with clarification on chest x-ray requirements. Exclusion criteria 2, 3 and 10 updated with clarifications and to correct an omission. Requirements for screening/enrolment and treatment period visits clarified in Section 4. Section 5.1.1 updated to clarify timing and acceptable manoeuvres for spirometry assessments. Section 5.1.2 updated to clarify when certain assessments should not be done. Table 8 on prohibited COPD medications: use of the ICS/LABA combination clarified and triple therapy removed.

    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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