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    Clinical Trial Results:
    A phase IIa, randomised, multi-centre, double-blind, placebo-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
    		 2016-002863-32
    Trial protocol
    		 GB   DE  
    Global end of trial date
    18 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2018
    First version publication date
    01 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D6640C00004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    2 Kingdom Street, London, United Kingdom, W2 6BD
    Public contact
    Study Information Centre, AstraZeneca Clinical, Information.centre@astrazeneca.com
    Scientific contact
    Dr Ioannis Psallidas, MD, PhD, AstraZeneca, Information.centre@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
    22 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study was to assess the efficacy, safety and pharmacokinetics (PK) of AZD8871 after a 14-day treatment period at 2 different doses 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 Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements and the AstraZeneca policy on Bioethics. Informed consent was given freely after the subject was informed of the nature, significance, implications and risks of the study; and consent was evidenced in writing, dated and signed, or otherwise marked, by that person so as to indicate his / her consent, prior to the start of participation in the study. The nature of the informed consent complied with the current version of the Declaration of Helsinki, the current requirements of GCP (CPMP/ICH/135/95) and local regulation whichever provided the greater subject protection. Additional informed consent was obtained from the subset of patients enrolled for the PK analysis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2016
    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
    Germany: 17
    Country: Number of subjects enrolled
    United Kingdom: 25
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    24
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at two centres, one each in Germany and the UK. The first patient was enrolled in December 2016 and the last patient last visit was in August 2017.

    Pre-assignment
    Screening details
    		 A total of 103 patients were screened. The screening period (lasting up to 28 days) consisted of a Screening Visit (Visit 1), Visit 2 and a run-in period (14–28 days) to assess clinical stability; 42 patients were eligible to participate and were randomised.

    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
    Blinding implementation details
    This study was performed in a double-blind manner. All IPs were supplied in identical packaging. Placebo-containing DPI devices were presented with the same external appearance and the same composition as the AZD8871-containing devices, except for the active ingredient. Supplies of salbutamol and ipratropium were open-label.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 AZD8871 100 µg
    Arm description
    		 The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD8871
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    100 μg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Arm title
    		 AZD8871 600 µg
    Arm description
    		 The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD8871
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    600 μg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Arm title
    		 Placebo
    Arm description
    		 The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    AZD8871
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo once daily by DPI device via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

    Number of subjects in period 1
    		AZD8871 100 µg AZD8871 600 µg Placebo
    Started
    34
    39
    36
    Completed
    33
    32
    33
    Not completed
    1
    7
    3
         Adverse event, non-fatal
    1
    2
    2
         Development of study-specific withdrawal criteria
    -
    4
    -
         Protocol deviation
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 42 42
    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)
    		 24 24
        From 65-84 years
    		 18 18
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.6 ± 6.6 -
    Sex/Gender, Customized
    Units: Subjects
        Female
    		 14 14
        Male
    		 28 28
    Subject analysis sets

    Subject analysis set title
    Overall study population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants who received at least one dose of investigational product.

    Subject analysis sets values
    		 Overall study population
    Number of subjects
    42
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    24
        From 65-84 years
    18
        85 years and over
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    63.6 ± 6.6
    Sex/Gender, Customized
    Units: Subjects
        Female
    14
        Male
    28

    End points

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    End points reporting groups
    Reporting group title
    AZD8871 100 µg
    Reporting group description
    		 The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Reporting group title
    AZD8871 600 µg
    Reporting group description
    		 The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

    Subject analysis set title
    Overall study population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomised participants who received at least one dose of investigational product.

    Primary: Change from baseline in trough forced expiratory volume in 1 second (FEV1)

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    End point title
    		 Change from baseline in trough forced expiratory volume in 1 second (FEV1)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in trough FEV1 on Day 15
    End point type
    Primary
    End point timeframe
    On Day 15
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    38
    35
    Units: Litres
        least squares mean (standard error)
    0.168 ± 0.037
    0.267 ± 0.035
    0.007 ± 0.036
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.161
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.075
         upper limit
    		 0.246
    Notes
    [1] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.176
         upper limit
    		 0.343
    Notes
    [2] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.099
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.182
    Notes
    [3] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose)

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    End point title
    		 Observed maximum plasma (Cmax) of AZD8871 and its metabolites (single dose)
    End point description
    Observed maximum concentration, taken directly from the individual concentration-time curve, on Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [4]
    18 [5]
    0 [6]
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    61.05 ± 47.47
    290.8 ± 36.30
    ±
        LAS191861|
    7.796 ± 38.67
    33.87 ± 33.05
    ±
        LAS34850|
    187.7 ± 55.41
    1016 ± 50.72
    ±
    Notes
    [4] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=16
    [5] - AZD8871 n=18 LAS191861 n=18 LAS34850 n=18
    [6] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14)

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    End point title
    		 Observed maximum plasma (Cmax) of AZD8871 and its metabolites (multiple doses, Day 14)
    End point description
    Observed maximum concentration, taken directly from the individual concentration-time curve, on Day 14 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [7]
    18 [8]
    0 [9]
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    72.52 ± 45.69
    381.8 ± 36.09
    ±
        LAS191861|
    11.89 ± 39.41
    63.17 ± 38.23
    ±
        LAS34850|
    221.4 ± 69.96
    1152 ± 55.11
    ±
    Notes
    [7] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=16
    [8] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [9] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose)

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    End point title
    		 Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (single dose)
    End point description
    Time to reach maximum concentration taken directly from the individual concentration-time curve on Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [10]
    18 [11]
    0 [12]
    Units: hours
    median (full range (min-max))
        AZD8871|
    0.93 (0.42 to 2.00)
    1.46 (0.48 to 2.03)
    ( to )
        LAS191861|
    1.92 (0.93 to 4.83)
    2.02 (1.00 to 4.03)
    ( to )
        LAS34850|
    3.94 (1.92 to 6.00)
    3.98 (3.92 to 6.03)
    ( to )
    Notes
    [10] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=16
    [11] - AZD8871 n=18 LAS191861 n=18 LAS34850 n=18
    [12] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14)

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    End point title
    		 Time to reach maximum plasma concentration (tmax) of AZD8871 and its metabolites (multiple doses, Day 14)
    End point description
    Time to reach maximum concentration taken directly from the individual concentration-time curve on Day 14 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [13]
    18 [14]
    0 [15]
    Units: hours
    median (full range (min-max))
        AZD8871|
    0.93 (0.42 to 1.00)
    1.00 (0.50 to 2.22)
    ( to )
        LAS191861|
    1.96 (0.98 to 3.95)
    2.00 (0.98 to 3.98)
    ( to )
        LAS34850|
    3.92 (0.00 to 4.00)
    4.02 (3.90 to 6.05)
    ( to )
    Notes
    [13] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=16
    [14] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [15] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: AUClast of AZD8871 and its metabolites (single dose)

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    End point title
    		 AUClast of AZD8871 and its metabolites (single dose)
    End point description
    Area under the plasma concentration-curve from time zero to the last quantifiable time point (24 hours post-dose) calculated on Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [16]
    18 [17]
    0 [18]
    Units: pg.h/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    301.0 ± 54.52
    1777 ± 40.93
    ±
        LAS191861|
    60.06 ± 94.87
    358.5 ± 32.60
    ±
        LAS34850|
    1414 ± 69.31
    9299 ± 53.88
    ±
    Notes
    [16] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=14
    [17] - AZD8871 n=18 LAS191861 n=18 LAS34850 n=18
    [18] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: AUClast of AZD8871 and its metabolites (multiple doses, Day 14)

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    End point title
    		 AUClast of AZD8871 and its metabolites (multiple doses, Day 14)
    End point description
    Area under the plasma concentration-curve from time zero to the last quantifiable time point (24 hours post-dose) calculated on Day 14 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [19]
    18 [20]
    0 [21]
    Units: pg.h/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    539.2 ± 51.23
    3156 ± 42.51
    ±
        LAS191861|
    160.2 ± 64.39
    935.9 ± 46.56
    ±
        LAS34850|
    1964 ± 93.81
    13050 ± 52.49
    ±
    Notes
    [19] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=15
    [20] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [21] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: AUC0-24 of AZD8871 and its metabolites (single dose)

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    End point title
    		 AUC0-24 of AZD8871 and its metabolites (single dose)
    End point description
    Area under the plasma concentration-curve from time zero to 24 hours post-dose calculated on Day 1 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [22]
    18 [23]
    0 [24]
    Units: pg.h/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    326.1 ± 49.18
    1776 ± 40.95
    ±
        LAS191861|
    135.6 ± 25.79
    358.1 ± 32.56
    ±
        LAS34850|
    0 ± 0
    10440 ± 49.47
    ±
    Notes
    [22] - AZD8871 n=14 LAS191861 n=7 LAS34850 n=1
    [23] - AZD8871 n=18 LAS191861 n=18 LAS34850 n=15
    [24] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14)

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    End point title
    		 AUC0-24 of AZD8871 and its metabolites (multiple doses, Day 14)
    End point description
    Area under the plasma concentration-curve from time zero to 24 hours post-dose calculated on Day 14 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [25]
    18 [26]
    0 [27]
    Units: pg.h/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    538.4 ± 51.16
    3152 ± 42.53
    ±
        LAS191861|
    179.4 ± 38.81
    933.8 ± 46.65
    ±
        LAS34850|
    3281 ± 66.13
    13030 ± 52.51
    ±
    Notes
    [25] - AZD8871 n=16 LAS191861 n=15 LAS34850 n=7
    [26] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [27] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14)

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    End point title
    		 Accumulation ratio for Cmax (RacCmax) of AZD8871 and its metabolites (Day 14)
    End point description
    Accumulation ratio for Cmax estimated as (Cmax on Day 14 / Cmax on Day 1) in each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [28]
    18 [29]
    0 [30]
    Units: pg/mL
    arithmetic mean (full range (min-max))
        AZD8871|
    1.263 (0.765 to 2.30)
    1.385 (0.700 to 1.90)
    ( to )
        LAS191861|
    1.594 (0.946 to 2.86)
    1.968 (0.929 to 2.74)
    ( to )
        LAS34850|
    1.257 (0.757 to 3.388)
    1.133 (0.545 to 1.64)
    ( to )
    Notes
    [28] - AZD8871 n=16 LAS191861 n=16 LAS34850 n=16
    [29] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [30] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14)

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    End point title
    		 Accumulation ratio for AUC0-24 (RacAUC[0-24]) of AZD8871 and its metabolites (Day 14)
    End point description
    Accumulation ratio for AUC(0-24) estimated as (AUC0-24 on Day 14 / AUC0-24 on Day 1 in each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [31]
    18 [32]
    0 [33]
    Units: pg*h/mL
    arithmetic mean (full range (min-max))
        AZD8871|
    1.893 (1.06 to 3.86)
    1.878 (1.09 to 2.87)
    ( to )
        LAS191861|
    1.576 (1.10 to 2.44)
    2.721 (1.41 to 3.55)
    ( to )
        LAS34850|
    1.24 (1.24 to 1.24)
    1.326 (0.713 to 1.77)
    ( to )
    Notes
    [31] - AZD8871 n=14 LAS191861 n=7 LAS34850 n=1
    [32] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=15
    [33] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Cavg of AZD8871 and its metabolites during a dosing interval (Day 14)

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    End point title
    		 Cavg of AZD8871 and its metabolites during a dosing interval (Day 14)
    End point description
    Average plasma concentration during a dosing interval calculated on Day 14 of each treatment period.
    End point type
    Secondary
    End point timeframe
    On Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    16 [34]
    18 [35]
    0 [36]
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        AZD8871|
    22.44 ± 51.13
    131.4 ± 42.49
    ±
        LAS191861|
    7.478 ± 38.81
    38.94 ± 46.62
    ±
        LAS34850|
    136.7 ± 66.11
    543.3 ± 52.44
    ±
    Notes
    [34] - AZD8871 n=16 LAS191861 n=15 LAS34850 n=7
    [35] - AZD8871 n=17 LAS191861 n=17 LAS34850 n=17
    [36] - Not included in the pharmacokinetic analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in trough FEV1 at Day 1 (single dose)

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    End point title
    		 Change from baseline in trough FEV1 at Day 1 (single dose)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in trough FEV1 on Day 1
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.092 ± 0.029
    0.161 ± 0.027
    0.006 ± 0.028
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.032
         upper limit
    		 0.14
    Notes
    [37] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.103
         upper limit
    		 0.207
    Notes
    [38] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.069
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.017
         upper limit
    		 0.121
    Notes
    [39] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in trough FEV1 at Day 8 (pre-dose)

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    End point title
    		 Change from baseline in trough FEV1 at Day 8 (pre-dose)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in trough FEV1 on Day 8 (pre-dose)
    End point type
    Secondary
    End point timeframe
    on Day 8 (pre-dose)
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.180 ± 0.033
    0.232 ± 0.030
    0.032 ± 0.031
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.148
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.067
         upper limit
    		 0.229
    Notes
    [40] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.121
         upper limit
    		 0.278
    Notes
    [41] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.201
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.028
         upper limit
    		 0.131
    Notes
    [42] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in trough FEV1 over the treatment duration (Days 1-15)

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    End point title
    		 Change from baseline in trough FEV1 over the treatment duration (Days 1-15)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in trough FEV1 over the treatment duration from Day 1 to Day 15
    End point type
    Secondary
    End point timeframe
    Days 1-15
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.146 ± 0.029
    0.215 ± 0.027
    0.016 ± 0.027
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.071
         upper limit
    		 0.19
    Notes
    [43] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.199
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.141
         upper limit
    		 0.257
    Notes
    [44] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.069
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.011
         upper limit
    		 0.127
    Notes
    [45] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in Peak FEV1 at Day 1 (single dose)

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    End point title
    		 Change from baseline in Peak FEV1 at Day 1 (single dose)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Peak FEV1
    End point type
    Secondary
    End point timeframe
    on Day 1
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.376 ± 0.026
    0.469 ± 0.025
    0.076 ± 0.025
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.251
         upper limit
    		 0.35
    Notes
    [46] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.394
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.346
         upper limit
    		 0.442
    Notes
    [47] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.093
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.045
         upper limit
    		 0.141
    Notes
    [48] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in Peak FEV1 at Day 8

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    End point title
    		 Change from baseline in Peak FEV1 at Day 8
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Peak FEV1
    End point type
    Secondary
    End point timeframe
    on Day 8
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.486 ± 0.040
    0.556 ± 0.037
    0.136 ± 0.038
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.349
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.266
         upper limit
    		 0.433
    Notes
    [49] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [50]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.338
         upper limit
    		 0.501
    Notes
    [50] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.092
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.012
         upper limit
    		 0.152
    Notes
    [51] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in Peak FEV1 at Day 14

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    End point title
    		 Change from baseline in Peak FEV1 at Day 14
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Peak FEV1
    End point type
    Secondary
    End point timeframe
    on Day 14
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    38
    36
    Units: Litres
        least squares mean (standard error)
    0.476 ± 0.037
    0.522 ± 0.035
    0.095 ± 0.036
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [52]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.294
         upper limit
    		 0.467
    Notes
    [52] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.427
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.342
         upper limit
    		 0.511
    Notes
    [53] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.279
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.13
    Notes
    [54] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)

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    End point title
    		 Change from baseline in Peak FEV1 over the treatment duration (Days 1-15)
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Peak FEV1
    End point type
    Secondary
    End point timeframe
    over the treatment duration (Days 1-15)
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Litres
        least squares mean (standard error)
    0.438 ± 0.028
    0.511 ± 0.027
    0.102 ± 0.028
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.336
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.297
         upper limit
    		 0.375
    Notes
    [55] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [56]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.409
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.371
         upper limit
    		 0.447
    Notes
    [56] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.035
         upper limit
    		 0.111
    Notes
    [57] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment

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    End point title
    		 Change from baseline in BCSS questionnaire Total Score from Day 1 to Day 8 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Total score of the Breathlessness, Cough Sputum Scale (BCSS) questionnaire
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 8 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Score points
        least squares mean (standard error)
    -0.416 ± 0.216
    -0.920 ± 0.198
    -0.071 ± 0.205
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 = 0.205
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.345
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.882
         upper limit
    		 0.193
    Notes
    [58] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.849
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.368
         upper limit
    		 -0.33
    Notes
    [59] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 = 0.06
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.505
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.031
         upper limit
    		 0.022
    Notes
    [60] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment

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    End point title
    		 Change from baseline in BCSS questionnaire Total Score from Day 9 to Day 14 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD was assessed by measuring the change from baseline in Total score of the Breathlessness, Cough Sputum Scale (BCSS) questionnaire
    End point type
    Secondary
    End point timeframe
    From Day 9 to Day 14 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Score points
        least squares mean (standard error)
    -0.491 ± 0.237
    -1.191 ± 0.219
    -0.030 ± 0.226
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 = 0.111
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.461
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.032
         upper limit
    		 0.109
    Notes
    [61] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [62]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.162
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.713
         upper limit
    		 -0.61
    Notes
    [62] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.259
         upper limit
    		 -0.142
    Notes
    [63] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment

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    End point title
    		 Change from baseline in cough individual domain score from Day 1 to Day 8 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire cough individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 8 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: Score points
        least squares mean (standard error)
    -0.186 ± 0.091
    -0.287 ± 0.084
    -0.134 ± 0.087
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [64]
    P-value
    		 = 0.621
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.263
         upper limit
    		 0.158
    Notes
    [64] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.138
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.153
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.357
         upper limit
    		 0.05
    Notes
    [65] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [66]
    P-value
    		 = 0.333
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.101
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.307
         upper limit
    		 0.105
    Notes
    [66] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment

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    End point title
    		 Change from baseline in cough individual domain score from Day 9 to Day 14 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire cough individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 9 to Day 14 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: points
        least squares mean (standard error)
    -0.160 ± 0.096
    -0.445 ± 0.088
    -0.123 ± 0.091
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 = 0.748
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.263
         upper limit
    		 0.19
    Notes
    [67] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [68]
    P-value
    		 = 0.005
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.321
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.103
    Notes
    [68] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [69]
    P-value
    		 = 0.013
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.285
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.506
         upper limit
    		 -0.063
    Notes
    [69] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment

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    End point title
    		 Change from baseline in breathlessness individual domain score from Day 1 to Day 8 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire breathlessness individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 8 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: points
        least squares mean (standard error)
    -0.122 ± 0.097
    -0.377 ± 0.089
    0.099 ± 0.092
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [70]
    P-value
    		 = 0.064
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.221
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.455
         upper limit
    		 0.013
    Notes
    [70] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [71]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.702
         upper limit
    		 -0.25
    Notes
    [71] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [72]
    P-value
    		 = 0.03
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.255
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.484
         upper limit
    		 -0.026
    Notes
    [72] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment

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    End point title
    		 Change from baseline in breathlessness individual domain score from Day 9 to Day 14 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire breathlessness individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 9 to Day 14 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: points
        least squares mean (standard error)
    -0.202 ± 0.108
    -0.453 ± 0.100
    0.106 ± 0.103
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [73]
    P-value
    		 = 0.018
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.308
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.561
         upper limit
    		 -0.055
    Notes
    [73] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [74]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.559
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.804
         upper limit
    		 -0.314
    Notes
    [74] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [75]
    P-value
    		 = 0.047
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.499
         upper limit
    		 -0.003
    Notes
    [75] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment

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    End point title
    		 Change from baseline in sputum individual domain score from Day 1 to Day 8 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire sputum individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 8 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: points
        least squares mean (standard error)
    -0.100 ± 0.070
    -0.255 ± 0.064
    -0.035 ± 0.066
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [76]
    P-value
    		 = 0.477
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.065
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.245
         upper limit
    		 0.116
    Notes
    [76] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [77]
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.219
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.393
         upper limit
    		 -0.046
    Notes
    [77] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [78]
    P-value
    		 = 0.084
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.331
         upper limit
    		 0.022
    Notes
    [78] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Secondary: Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment

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    End point title
    		 Change from baseline in sputum individual domain score from Day 9 to Day 14 post-treatment
    End point description
    The efficacy of inhaled AZD8871 in patients with moderate to severe COPD will be assessed by measuring the change from baseline in BCSS questionnaire sputum individual domain scores
    End point type
    Secondary
    End point timeframe
    From Day 9 to Day 14 post-treatment
    End point values
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Number of subjects analysed
    34
    39
    36
    Units: points
        least squares mean (standard error)
    -0.122 ± 0.078
    -0.297 ± 0.073
    -0.011 ± 0.075
    Statistical analysis title
    		 AZD8871 100 µg vs Placebo
    Comparison groups
    AZD8871 100 µg v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [79]
    P-value
    		 = 0.213
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.286
         upper limit
    		 0.065
    Notes
    [79] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs Placebo
    Comparison groups
    AZD8871 600 µg v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [80]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.456
         upper limit
    		 -0.116
    Notes
    [80] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.
    Statistical analysis title
    		 AZD8871 600 µg vs AZD8871 100 µg
    Comparison groups
    AZD8871 100 µg v AZD8871 600 µg
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [81]
    P-value
    		 = 0.046
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.175
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.347
         upper limit
    		 -0.003
    Notes
    [81] - Analysis conducted in overall study population, 42 subjects. Subjects in this analysis field should be ignored due to reporting system limitations for statistical analysis of cross-over studies.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to Follow-up/early termination Visit, 28 to 35 days after the last administration of investigational product (IP)
    Adverse event reporting additional description
    All reported AEs, date of onset/resolution, intensity, severity, outcome, action taken and relationship to IP were listed. Non-Treatment-emergent AE (non-TEAE): Any AE occurring before first dose, or >30 days after last dose of IP TEAE: any AE occurring after first dose or present prior to the first dose, but increasing in severity after IP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    AZD8871 100 µg
    Reporting group description
    		 The subjects received AZD8871 100 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Reporting group title
    AZD8871 600 µg
    Reporting group description
    		 The subjects received AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo was administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient received one inhaled dose from placebo DPI provided to him/her on each day of the treatment period.

    Serious adverse events
    		 AZD8871 100 µg AZD8871 600 µg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 39 (2.56%)
    1 / 36 (2.78%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease exacerbation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 39 (2.56%)
    0 / 36 (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
    Abdominal wall abscess
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 39 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 39 (0.00%)
    1 / 36 (2.78%)
         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 100 µg AZD8871 600 µg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 34 (14.71%)
    7 / 39 (17.95%)
    5 / 36 (13.89%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 39 (7.69%)
    4 / 36 (11.11%)
         occurrences all number
    5
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 39 (7.69%)
    0 / 36 (0.00%)
         occurrences all number
    2
    3
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 39 (5.13%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    Infections and infestations
    Viral upper respiratory tract infections
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 39 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2016
    High dose level was changed from 900 μg to 600 μg, based on exposure levels seen in the Phase I Study D6640C00003 (Sections 1.2, 1.4, 3.5, 7.1, 7.2.2, 8.2, 8.5.3). Dosage form for 300 μg removed and 2 Dry powder inhalers/administration changed to 1/administration (Section 7.1). New data from D6640C00003 added (Section 1.2). Update to serious adverse event reporting process (Section 6.3.6). Clarification of timing of taste assessment (Section 4.2.3).
    16 Dec 2016
    Update to exclusion criteria (Section 3.2) to exclude patients who had 2 or more exacerbations of COPD in the year prior to Screening and patients who were placed in an institution due to a regulatory or court order. Addition of study-specific withdrawal criteria (based on measurable parameters for vital signs, laboratory results, electrocardiograms, lung function, and worsening of COPD)(section 3.9). Appendix C updated to align with Section 3.9.

    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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