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    Clinical Trial Results:
    A Phase IIa, Randomised, Multi-centre, Double-blind, Placebo and Active-controlled, 3 Periods, Crossover Study to Investigate the Efficacy, Pharmacokinetics, Safety and Tolerability of Inhaled AZD8871 Administered Once Daily for 2 Weeks in Patients with Moderate to Severe COPD

    Summary
    EudraCT number
    		 2018-001722-25
    Trial protocol
    		 GB   DE  
    Global end of trial date
    07 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2020
    First version publication date
    12 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D6640C00006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03645434
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    AstraZeneca AB, AstraZeneca AB, 001 18774004656, clinicaltrialtransparency@astrazeneca.com
    Scientific contact
    AstraZeneca AB, AstraZeneca AB, 001 18774004656, 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
    17 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe 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 (ICH)/Good Clinical Practice (GCP), applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 2018
    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
    United Kingdom: 31
    Country: Number of subjects enrolled
    Germany: 42
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    28
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects who met all the inclusion and none of the exclusion criteria were enrolled at 3 sites in Germany and 2 sites in the United Kingdom (UK).

    Pre-assignment
    Screening details
    		 Subjects attended Screening Visit within a 14 to 28-days Screening Period, before receiving their first dose of AZD8871. All subjects underwent inclusion exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures.

    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
    Arm title
    		 All participants
    Arm description
    		 Subjects received AZD8871 inhalation powder 600 μg, 1 inhalation per day; umeclidinium 55 μg / vilanterol 22 μg as oral inhalation once per day; Placebo to AZD8871 via oral inhalation, 1 inhalation per day and Placebo to Anoro® Ellipta® via oral inhalation, 1 inhalation per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD8871 600 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received AZD8871 (as saccharinate) inhalation powder 600 μg, 1 inhalation per day.

    Investigational medicinal product name
    Anoro® Ellipta®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received umeclidinium 55 μg / vilanterol 22 μg. as oral inhalation once per day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Placebo to AZD8871via oral inhalation, 1 inhalation per day

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Placebo to Anoro® Ellipta® via oral inhalation, 1 inhalation per day.

    Number of subjects in period 1
    		All participants
    Started
    73
    Completed
    66
    Not completed
    7
         Adverse event, non-fatal
    1
         COPD exacerbation
    1
         Participant did not meet FEV1 stability check
    1
         Stability criteria not met
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Subjects received AZD8871 inhalation powder 600 μg, 1 inhalation per day; umeclidinium 55 μg / vilanterol 22 μg as oral inhalation once per day; Placebo to AZD8871 via oral inhalation, 1 inhalation per day and Placebo to Anoro® Ellipta® via oral inhalation, 1 inhalation per day.

    Reporting group values
    		 All participants Total
    Number of subjects
    		 73 73
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 28 28
        From 65-84 years
    		 45 45
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.0 ( 7.6 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 23 23
        Male
    		 50 50
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 73 73
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Subjects received AZD8871 inhalation powder 600 μg, 1 inhalation per day; umeclidinium 55 μg / vilanterol 22 μg as oral inhalation once per day; Placebo to AZD8871 via oral inhalation, 1 inhalation per day and Placebo to Anoro® Ellipta® via oral inhalation, 1 inhalation per day.

    Subject analysis set title
    AZD8871 600 μg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received AZD8871 (as saccharinate) inhalation powder 600 μg, 1 inhalation per day.

    Subject analysis set title
    Anoro® Ellipta®
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received umeclidinium 55 μg / vilanterol 22 μg. as oral inhalation once per day.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received Placebo to AZD8871via oral inhalation, 1 inhalation per day

    Primary: Change from baseline in Trough FEV1

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    End point title
    		 Change from baseline in Trough FEV1
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
    End point type
    Primary
    End point timeframe
    Day 15
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
        arithmetic mean (standard deviation)
    0.1904 ( 0.2052 )
    0.2260 ( 0.2275 )
    -0.0222 ( 0.1404 )
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.151
         upper limit
    		 0.253
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0746
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.097
         upper limit
    		 0.005
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.248
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.197
         upper limit
    		 0.3

    Primary: Change from baseline in chronic obstructive pulmonary disease (COPD) assessment test (CAT)

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    End point title
    		 Change from baseline in chronic obstructive pulmonary disease (COPD) assessment test (CAT)
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. At each visit, patients are asked to evaluate the impact of COPD on their wellbeing and daily life on a 6-point Likert scale ranging from 0 to 5, with higher scores indicating a higher impact of COPD. The CAT is expressed as a total score, which is a sum of the 8 questions, ranging from 0 to 40.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Total Score
    arithmetic mean (standard deviation)
        Day 1 to Day 8
    -2.11 ( 4.34 )
    -2.78 ( 4.34 )
    -0.57 ( 4.69 )
        Day 9 to Day 14
    -2.87 ( 5.01 )
    -3.29 ( 4.94 )
    -0.52 ( 5.06 )
        Day 1 to Day 14
    -2.42 ( 4.49 )
    -3.01 ( 4.51 )
    -0.59 ( 4.81 )
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2049
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.637
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.352
         upper limit
    		 1.626
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.208
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.212
         upper limit
    		 -1.203
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0022
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.571
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.563
         upper limit
    		 -0.579
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5317
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.369
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.795
         upper limit
    		 1.533
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.755
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.924
         upper limit
    		 -1.585
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.386
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.541
         upper limit
    		 -1.23
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2906
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.546
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.472
         upper limit
    		 1.565
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.459
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.482
         upper limit
    		 -1.435
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.912
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.923
         upper limit
    		 -0.901

    Secondary: Area under the curve for the change in FEV1 from baseline to 4h, normalised by the time window(FEV1 AUC(0-4)/4h)

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    End point title
    		 Area under the curve for the change in FEV1 from baseline to 4h, normalised by the time window(FEV1 AUC(0-4)/4h)
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1, Day 8, and Day 14.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1
    0.3604 ( 0.1753 )
    0.2912 ( 0.1677 )
    0.0430 ( 0.0783 )
        Day 8
    0.4296 ( 0.2197 )
    0.3796 ( 0.2133 )
    0.0808 ( 0.2117 )
        Day 14
    0.4060 ( 0.2448 )
    0.3358 ( 0.2011 )
    0.0209 ( 0.1210 )
    No statistical analyses for this end point

    Secondary: Area under the curve for the change in FEV1 from baseline to 8h, normalised by the time window (FEV1 AUC(0-8)/8h)

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    End point title
    		 Area under the curve for the change in FEV1 from baseline to 8h, normalised by the time window (FEV1 AUC(0-8)/8h)
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1
    0.3072 ( 0.1565 )
    0.2798 ( 0.1695 )
    0.0230 ( 0.0923 )
        Day 14
    0.3394 ( 0.2462 )
    0.3102 ( 0.1998 )
    0.0021 ( 0.1204 )
    No statistical analyses for this end point

    Secondary: Area under the curve for the change in FEV1 from baseline to 12h, normalised by the time window (FEV1 AUC(0-12)/12h)

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    End point title
    		 Area under the curve for the change in FEV1 from baseline to 12h, normalised by the time window (FEV1 AUC(0-12)/12h)
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1
    0.2668 ( 0.1494 )
    0.2720 ( 0.1697 )
    0.0096 ( 0.0946 )
        Day 14
    0.3024 ( 0.2141 )
    0.2919 ( 0.2027 )
    -0.0032 ( 0.1150 )
    No statistical analyses for this end point

    Secondary: Area under the curve for the change in FEV1 from baseline to 24h, normalised by the time window (FEV1 AUC(0-24)/24h)

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    End point title
    		 Area under the curve for the change in FEV1 from baseline to 24h, normalised by the time window (FEV1 AUC(0-24)/24h)
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1
    0.1832 ( 0.1399 )
    0.2333 ( 0.1742 )
    -0.0132 ( 0.0920 )
        Day 14
    0.2223 ( 0.2154 )
    0.2417 ( 0.2012 )
    -0.0324 ( 0.1104 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Trough FEV1 on Day 2, and Day 8.

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    End point title
    		 Change from baseline in Trough FEV1 on Day 2, and Day 8.
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    Day 2 and Day 8.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 2
    0.1359 ( 0.1672 )
    0.2249 ( 0.1897 )
    0.0339 ( 0.1139 )
        Day 8
    0.2161 ( 0.1613 )
    0.2748 ( 0.1894 )
    0.0121 ( 0.1240 )
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 2
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.139
         upper limit
    		 -0.044
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 2
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.142
         upper limit
    		 0.237
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 2
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.098
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.051
         upper limit
    		 0.146
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 8
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0066
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.065
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.111
         upper limit
    		 -0.018
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 8
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.213
         upper limit
    		 0.306
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 8
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.195
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.148
         upper limit
    		 0.242

    Secondary: Change from baseline in Peak FEV1 on Day 1, Day 8 and Day 14.

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    End point title
    		 Change from baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1, Day 8, and Day 14.
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1
    0.403 ( 0.182 )
    0.333 ( 0.176 )
    0.092 ( 0.086 )
        Day 8
    0.511 ( 0.240 )
    0.454 ( 0.227 )
    0.120 ( 0.130 )
        Day 14
    0.464 ( 0.255 )
    0.391 ( 0.215 )
    0.066 ( 0.131 )
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0012
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.027
         upper limit
    		 0.107
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.239
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.199
         upper limit
    		 0.279
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.306
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.266
         upper limit
    		 0.346
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 8
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0734
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0.096
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 8
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.328
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.278
         upper limit
    		 0.379
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 8
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.374
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.324
         upper limit
    		 0.425
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0385
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.062
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.003
         upper limit
    		 0.121
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.326
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.266
         upper limit
    		 0.385
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.388
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.329
         upper limit
    		 0.447

    Secondary: Change from baseline in Breathlessness, Cough and Sputum Scale (BCSS) Total Score

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    End point title
    		 Change from baseline in Breathlessness, Cough and Sputum Scale (BCSS) Total Score
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. The BCSS questionnaire is a 3-item, patient-reported outcome (PRO) measure. On a daily basis, patients are asked to evaluate each of their 3 symptoms (breathlessness, cough, and sputum) on a 5-point Likert scale ranging from 0 to 4, with higher scores indicating a higher severity of the symptom. The BCSS questionnaire is expressed as a daily total score, which is the sum of the 3 symptom scores, ranging from 0 to 12.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Total Score
    arithmetic mean (standard deviation)
        Day 1 to Day 8
    -0.37 ( 1.27 )
    -0.61 ( 1.31 )
    0.16 ( 1.11 )
        Day 9 to Day 14
    -0.35 ( 1.58 )
    -0.63 ( 1.49 )
    0.53 ( 1.43 )
        Day 1 to Day 14
    -0.36 ( 1.33 )
    -0.63 ( 1.32 )
    0.36 ( 1.26 )
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1362
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.243
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.078
         upper limit
    		 0.563
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.794
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 -0.468
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.551
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.876
         upper limit
    		 -0.226
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.131
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.291
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.088
         upper limit
    		 0.669
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.157
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.539
         upper limit
    		 -0.776
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.867
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.248
         upper limit
    		 -0.486
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.096
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.049
         upper limit
    		 0.596
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.996
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.321
         upper limit
    		 -0.67
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1 to Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.722
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.047
         upper limit
    		 -0.397

    Secondary: Number of participants with adverse events.

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    End point title
    		 Number of participants with adverse events.
    End point description
    To evaluate the safety and tolerability of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    From Screening to folow-up or discontinuation (42 days after last study drug)
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Participants
        Any AE
    39
    38
    35
        Any AE with outcome=death
    0
    0
    0
        Any SAE (including events with outcome=death)
    0
    2
    2
        Any AE leading to discontinuation of treatment
    0
    1
    0
        Any AE leading to withdrawal from study
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Rescue medication use

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    End point title
    		 Rescue medication use
    End point description
    To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8 and Day 9 to Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: unit on a scale
    arithmetic mean (standard deviation)
        Day 1 to Day 8
    -1.00 ( 1.83 )
    -0.95 ( 2.03 )
    0.18 ( 2.13 )
        Day 9 to Day 14
    -0.78 ( 1.97 )
    -0.87 ( 1.96 )
    0.52 ( 1.80 )
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6566
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.578
         upper limit
    		 0.365
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.161
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.642
         upper limit
    		 -0.681
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 1 to Day 8
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.268
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.741
         upper limit
    		 -0.794
    Statistical analysis title
    		 AZD8871 600 μg vs Anoro® Ellipta®
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Anoro® Ellipta®
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.802
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.441
         upper limit
    		 0.569
    Statistical analysis title
    		 Anoro® Ellipta® vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    Anoro® Ellipta® v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.366
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.875
         upper limit
    		 -0.857
    Statistical analysis title
    		 AZD8871 600 μg vs Placebo
    Statistical analysis description
    Day 9 to Day 14
    Comparison groups
    AZD8871 600 μg v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.302
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.804
         upper limit
    		 -0.8

    Secondary: maximum plasma concentration (Cmax)

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    End point title
    		 maximum plasma concentration (Cmax)
    End point description
    To investigate the Cmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871 - Day 1
    310.4 ( 61.30 )
    0 ( 0 )
    0 ( 0 )
        AZD8871 - Day 14
    532.9 ( 46.58 )
    0 ( 0 )
    0 ( 0 )
        LAS191861- Day 1
    26.64 ( 53.33 )
    0 ( 0 )
    0 ( 0 )
        LAS191861- Day 14
    63.29 ( 52.12 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: time to reach maximum plasma concentration (Tmax)

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    End point title
    		 time to reach maximum plasma concentration (Tmax)
    End point description
    To investigate the Tmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Hours
    median (full range (min-max))
        AZD8871- Day 1
    0.99 (0.38 to 2.02)
    0 (0 to 0)
    0 (0 to 0)
        AZD8871- Day 14
    0.98 (0.45 to 2.05)
    0 (0 to 0)
    0 (0 to 0)
        LAS191861 - Day 1
    2.00 (0.98 to 4.00)
    0 (0 to 0)
    0 (0 to 0)
        LAS191861 - Day 14
    2.00 (0.98 to 4.03)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: time to reach last quantifiable plasma concentration (Tlast)

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    End point title
    		 time to reach last quantifiable plasma concentration (Tlast)
    End point description
    To investigate the Tlast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Hours
    median (full range (min-max))
        AZD8871 -Day 1
    23.93 (7.98 to 24.05)
    0 (0 to 0)
    0 (0 to 0)
        AZD8871-Day 14
    24.03 (23.90 to 24.37)
    0 (0 to 0)
    0 (0 to 0)
        LAS191861 - Day 1
    23.92 (1.97 to 24.05)
    0 (0 to 0)
    0 (0 to 0)
        LAS191861 - Day 14
    24.03 (23.90 to 24.37)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-curve from time 0 to the time of last quantifiable concentration (AUClast)

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    End point title
    		 Area under the plasma concentration-curve from time 0 to the time of last quantifiable concentration (AUClast)
    End point description
    To investigate the AUClast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: h*pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871- Day 1
    1655 ( 85.24 )
    0 ( 0 )
    0 ( 0 )
        AZD8871-Day 14
    4001 ( 55.64 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 -Day 1
    251.9 ( 97.81 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 -Day 14
    943.3 ( 63.08 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-curve from time 0 to 24 hours post-dose [AUC(0-24)]

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    End point title
    		 Area under the plasma concentration-curve from time 0 to 24 hours post-dose [AUC(0-24)]
    End point description
    To investigate the AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 1 and Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: h*pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871- Day 1
    1661 ( 83.55 )
    0 ( 0 )
    0 ( 0 )
        AZD8871- Day 14
    3996 ( 55.66 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 - Day 1
    289.5 ( 57.83 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 - Day 14
    941.7 ( 63.11 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Average plasma concentration during a dosing interval (Cavg)

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    End point title
    		 Average plasma concentration during a dosing interval (Cavg)
    End point description
    To investigate the Cavg of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871 -Day 14
    166.5 ( 55.63 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 - Day 14
    39.23 ( 63.06 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: Fluctuation index during a dosing interval (%Fluctuation)

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    End point title
    		 Fluctuation index during a dosing interval (%Fluctuation)
    End point description
    To investigate the %Fluctuation of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: percentage
    median (full range (min-max))
        AZD8871- Day 14
    273.1 (128 to 514)
    0 (0 to 0)
    0 (0 to 0)
        LAS191861 - Day 14
    91.03 (39.3 to 174)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Accumulation ratio for Cmax (Rac(Cmax))

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    End point title
    		 Accumulation ratio for Cmax (Rac(Cmax))
    End point description
    To investigate the Rac (Cmax) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Ratio
    geometric mean (geometric coefficient of variation)
        AZD8871 -Day 14
    1.725 ( 44.77 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 - Day 14
    2.377 ( 40.02 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Secondary: accumulation ratio for AUC(0-24) Rac(AUC(0-24))

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    End point title
    		 accumulation ratio for AUC(0-24) Rac(AUC(0-24))
    End point description
    To investigate the Rac(AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
    End point type
    Secondary
    End point timeframe
    At Day 14
    End point values
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Number of subjects analysed
    70
    69
    68
    Units: Ratio
    geometric mean (geometric coefficient of variation)
        AZD8871 - Day 14
    2.406 ( 50.37 )
    0 ( 0 )
    0 ( 0 )
        LAS191861 -Day 14
    3.443 ( 47.15 )
    0 ( 0 )
    0 ( 0 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to follow-up visit or treatment discontinuation (48 days after last dose)
    Adverse event reporting additional description
    An adverse event was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition might be symptoms, signs or the abnormal results of an investigation.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    AZD8871 600 μg
    Reporting group description
    		 Subjects received AZD8871 (as saccharinate) inhalation powder 600 μg, 1 inhalation per day.

    Reporting group title
    Anoro® Ellipta®
    Reporting group description
    		 Subjects received umeclidinium 55 μg / vilanterol 22 μg. as oral inhalation once per day.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Placebo to AZD8871via oral inhalation, 1 inhalation per day

    Serious adverse events
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 69 (2.90%)
    2 / 68 (2.94%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Tooth abscess
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 69 (1.45%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 70 (0.00%)
    0 / 69 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AZD8871 600 μg Anoro® Ellipta® Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 70 (27.14%)
    19 / 69 (27.54%)
    17 / 68 (25.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 70 (20.00%)
    13 / 69 (18.84%)
    14 / 68 (20.59%)
         occurrences all number
    28
    22
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 70 (8.57%)
    8 / 69 (11.59%)
    3 / 68 (4.41%)
         occurrences all number
    7
    9
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2018
    Removal of reversibility criterion for study eligibility. Reversibility testing continued to take place but did not impact a patient’s eligibility for entering the study. The screening failure rate was revised downwards from 60% to 50%; the number of patients to be screened is revised downwards from 180 to 145 patients. The ipratropium dose was changed from 34 μg to 20 μg. The ECG parameters were updated to remove QRS complexes.
    08 Aug 2018
    Section 5.1: Inclusion criterion #12 Clarifications were added regarding true sexual abstinence under the contraception criterion. Section 6.3 Measures to minimise bias: randomisation and blinding Description of unblinding processes was revised as follows: In case of an emergency, the Investigator has the sole responsibility for determining if unblinding of a patient’s treatment assignment is warranted. Patient safety must always be the first consideration in making such a determination. If the Investigator decides that unblinding is warranted, the Investigator is asked to contact the Sponsor prior to unblinding a patient’s treatment assignment unless this could delay emergency treatment of the patient. The changes were made in response to MHRA feedback.
    13 Sep 2018
    The below changes were made in response to MHRA feedback. Section 5.1: Inclusion criterion #12 Clarifications were added regarding true sexual abstinence under the contraception criterion. Section 6.3 Measures to minimise bias: randomisation and blinding Description of unblinding processes was revised as follows: In case of an emergency, the Investigator has the sole responsibility for determining if unblinding of a patient’s treatment assignment is warranted. Patient safety must always be the first consideration in making such a determination. If the Investigator decides that unblinding is warranted, the Investigator is asked to contact the Sponsor prior to unblinding a patient’s treatment assignment unless this could delay emergency treatment of the patient. The below changes were made in response to BfArM feedback. Section 5.2: Exclusion criteria #12 Maximum heart rate was lowered from >120 to >100 bpm. Section 5.2: Exclusion criteria #13 Maximum blood pressure was lowered from >180 to >160 mmHg. Section 7.3: Withdrawal from the study Description of processes to withdraw patients enrolled in error was revised as follows: Any patient that has been initiated on treatment and subsequently found not to meet all the eligibility criteria must stop the treatment and be excluded from the study.
    11 Dec 2018
    Clarification was added that heart rate for pre-dose timepoints on visits 4, 7 and 10 was to be taken from vital signs. Clarification was added that ECGs were to be done as single measurements and not as triplicates. Description of triple ECGs was removed. Clarification was added that ECGs and vital signs were to be measured after 5-minute rest in a supine position. Clarification was added that vital signs were to be done as single measurements and not as triplicates. Clinical Stability Check was added in the schedule of activities at Visit 6 and Visit 9. Clarification was added that screening results for drugs of abuse and alcohol were to be used to determine exclusion criterion #21 prior to randomisation due to the logistically accessibility of the results. Clarification was added regarding the timing of Cough Monitoring for home and site assessments. The following clinical safety laboratory parameters were added:• aPTT,• INR,• PTT. The following clarification was made: For Placebo and active comparator treatments immediately following an AZD8871 treatment period, only Day 1 pre-dose samples will be analysed unless specified. For any other Placebo and active comparator treatments, samples will not be analysed unless specified. Hy’s law SOP updated. Pregnancy test was added to Follow-Up Visit.

    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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