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    Clinical Trial Results:
    A 12-week Phase IIa, Double-blind, Placebo-controlled, Randomised Study to Investigate the Efficacy and Safety of AZD7624 in COPD Patients with a History of Frequent Acute Exacerbations while on Maintenance Therapy

    Summary
    EudraCT number
    		 2014-001053-16
    Trial protocol
    		 NL  
    Global end of trial date
    04 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2017
    First version publication date
    19 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D2550C00005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Stockholm, Sweden, 151 85
    Public contact
    Ziad Taib, AstraZeneca AB, 46 708 46 73 56, ziad.taib@astrazeneca.com
    Scientific contact
    Ziad Taib, AstraZeneca AB, 46 708 46 73 56, ziad.taib@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
    03 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of AZD7624 versus placebo on the time to first event of moderate or severe COPD exacerbations or early drop-out related to worsening of COPD symptoms (i.e., composite endpoint referred to as “ExDo”) in patients with COPD on maintenance treatment with at least ICS and LABA.
    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 the International Council for Harmonisation (ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. Each subject was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study and it was ensured that the Informed Consent Form (ICF) was signed and dated before any study specific procedure was performed. Opportunity was given to ask questions and subjects were allowed time to consider the information provided. Subjects were also notified that they were free to discontinue from the study at any time. A copy of the signed ICF was provided to the subjects. Written informed consent was obtained from all healthy subjects prior to initiation of the study.
    Background therapy
    		 Stable COPD maintenance treatment with at least inhaled corticosteroids (ICS) and long-acting beta agonist (LABA) for at least 2 months prior to enrolment (Visit 1), to be continued unchanged during the study.
    Evidence for comparator
    		 A placebo comparator was used in this study.
    Actual start date of recruitment
    28 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 80
    Country: Number of subjects enrolled
    United States: 74
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Peru: 19
    Country: Number of subjects enrolled
    South Africa: 13
    Worldwide total number of subjects
    213
    EEA total number of subjects
    13
    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)
    104
    From 65 to 84 years
    109
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the total 327 patients enrolled into the study, 114 were not randomised. The majority of these were due to screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 327 [1]
    Number of subjects completed
    		 213

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 6
    Reason: Number of subjects
    		 not specified: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 10
    Reason: Number of subjects
    		 Protocol deviation: 97
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The country of the subject was only databased and tabulated for subjects randomized into the study. The country for screening failures is not included in the table of Subject number per country.
    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZD7624 1.0 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD7624
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution, Inhalation solution
    Routes of administration
    Inhalation use, Inhalation use
    Dosage and administration details
    2 x 0.5 mg inhalation once daily

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations once daily

    Number of subjects in period 1
    		AZD7624 1.0 mg Placebo
    Started
    108
    105
    Completed
    93
    91
    Not completed
    15
    14
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    7
         Adverse event, non-fatal
    7
    3
         Lost to follow-up
    1
    1
         Protocol deviation
    1
    2
         not specified
    2
    -
         completion status not recorded
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period Total
    Number of subjects
    		 213 213
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 104 104
        From 65-84 years
    		 109 109
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.8 ( 8.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 76 76
        Male
    		 137 137
    Race
    Units: Subjects
        White
    		 173 173
        Black or African American
    		 9 9
        American Indian or Alaska Native
    		 7 7
        Other
    		 23 23
        Unknown
    		 1 1
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.74 ( 5.641 ) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The FAS was used as the primary population for reporting efficacy data and to summarise baseline characteristics. This set comprised all patients randomised into the study who received at least 1 inhalation of investigational product and was analysed according to randomised treatment (intention-to-treat principle).

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    212
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    103
        From 65-84 years
    109
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    64.8 ( 8.7 )
    Gender Categorical
    Units: Subjects
        Female
    76
        Male
    136
    Race
    Units: Subjects
        White
    173
        Black or African American
    9
        American Indian or Alaska Native
    7
        Other
    23
        Unknown
    0
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.74 ( 5.641 )

    End points

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    End points reporting groups
    Reporting group title
    AZD7624 1.0 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The FAS was used as the primary population for reporting efficacy data and to summarise baseline characteristics. This set comprised all patients randomised into the study who received at least 1 inhalation of investigational product and was analysed according to randomised treatment (intention-to-treat principle).

    Primary: Time to first ExDo event

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    End point title
    		 Time to first ExDo event
    End point description
    the time to first event of moderate or severe COPD exacerbation or early drop-out related to worsening of COPD symptoms (ie, composite endpoint referred to as “ExDo”)
    End point type
    Primary
    End point timeframe
    up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106 [1]
    105
    Units: Days
        median (not applicable)
    -99 ( -99 )
    118 ( -99 )
    Notes
    [1] - There were too few events to estimate median using Kaplan Meier methodology
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    Hazard ratios, 95% CIs for hazard ratios, and p-values are estimated using a Cox regression model with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex as covariates
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.2371
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.4
    Notes
    [2] - A hazard ratio greater than 1 indicates a higher rate of incidence in the first of the two groups.

    Secondary: Time to first moderate or severe COPD exacerbation or early drop-out

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    End point title
    		 Time to first moderate or severe COPD exacerbation or early drop-out
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106 [3]
    105
    Units: Days
        median (not applicable)
    -99 ( -99 )
    118 ( -99 )
    Notes
    [3] - There were too few events to estimate median using Kaplan Meier methodology
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    Hazard ratio, 95% CI for hazard ratio, and p-value are estimated using a Cox regression model with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.1261
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.5
    Notes
    [4] - A hazard ratio greater than 1 indicates a higher rate of incidence in the first of the two groups.

    Secondary: Time to first moderate or severe COPD exacerbation

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    End point title
    		 Time to first moderate or severe COPD exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106 [5]
    105 [6]
    Units: Days
        median (not applicable)
    -99 ( -99 )
    -99 ( -99 )
    Notes
    [5] - There were too few events to estimate median using Kaplan Meier methodology
    [6] - There were too few events to estimate median using Kaplan Meier methodology
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    Hazard ratio, 95% CI for hazard ratio, and p-value are estimated using a Cox regression model with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1529
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.76
    Notes
    [7] - A hazard ratio greater than 1 indicates a higher rate of incidence in the first of the two groups.

    Secondary: Time to first moderate or severe COPD exacerbation (Anthonisens criteria)

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    End point title
    		 Time to first moderate or severe COPD exacerbation (Anthonisens criteria)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106 [8]
    105 [9]
    Units: Days
        median (not applicable)
    -99 ( -99 )
    -99 ( -99 )
    Notes
    [8] - There were too few events to estimate median using Kaplan Meier methodology
    [9] - There were too few events to estimate median using Kaplan Meier methodology
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    Hazard ratio, 95% CI for hazard ratio, and p-value are estimated using a Cox regression model with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.8543
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 2.01
    Notes
    [10] - A hazard ratio greater than 1 indicates a higher rate of incidence in the first of the two groups.

    Secondary: Time to first symptom defined COPD exacerbation (EXACT daily diary)

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    End point title
    		 Time to first symptom defined COPD exacerbation (EXACT daily diary)
    End point description
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106 [11]
    105 [12]
    Units: Days
        median (not applicable)
    -99 ( -99 )
    -99 ( -99 )
    Notes
    [11] - There were too few events to estimate median using Kaplan Meier methodology
    [12] - There were too few events to estimate median using Kaplan Meier methodology
    Statistical analysis title
    		 Cox regression analysis
    Statistical analysis description
    Hazard ratios, 95% CIs for Hazard ratios, and p-values are estimated using a Cox regression model with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.5381
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.38
    Notes
    [13] - A hazard ratio greater than 1 indicates a higher rate of incidence in the first of the two groups.

    Secondary: Frequency of ExDo events

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    End point title
    		 Frequency of ExDo events
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106
    105
    Units: Events / year
        least squares mean (standard error)
    2.16 ( 0.8 )
    1.62 ( 0.63 )
    Statistical analysis title
    		 Frequency of ExDo events, negative binomial model
    Statistical analysis description
    Analysis model: rates, rate ratios, and p-value are from a negative binomial regression analysis, with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex included in the model as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.249
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33

    Secondary: Frequency of moderate or severe COPD exacerbations or early drop-out

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    End point title
    		 Frequency of moderate or severe COPD exacerbations or early drop-out
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106
    105
    Units: Exacerbations / year
        least squares mean (standard error)
    2.17 ( 0.8 )
    1.55 ( 0.6 )
    Statistical analysis title
    		 negative binomial model
    Statistical analysis description
    Analysis model: rates, rate ratios, and p-value are from a negative binomial regression analysis, with treatment, LAMA maintenance treatment, age group, baseline FEV1 and sex included in the model as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.157
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33

    Secondary: Frequency of moderate or severe COPD exacerbations

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    End point title
    		 Frequency of moderate or severe COPD exacerbations
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106
    105
    Units: Exacerbations / year
        least squares mean (standard error)
    2.12 ( 0.78 )
    1.42 ( 0.56 )
    Statistical analysis title
    		 Negative binomial model
    Statistical analysis description
    Analysis model: rates, rate ratios, and p-value are from a negative binomial regression analysis, with treatment, country, LAMA maintenance treatment, age group, baseline FEV1 and sex included in the model as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.129
    Method
    		 Negative binomial regression
    Parameter type
    		 Risk ratio
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Frequency of moderate or severe COPD exacerbations (Anthonisens criteria)

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    End point title
    		 Frequency of moderate or severe COPD exacerbations (Anthonisens criteria)
    End point description
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    107
    105
    Units: exacerbations / year
        least squares mean (standard error)
    1.23 ( 0.39 )
    1.09 ( 0.56 )
    Statistical analysis title
    		 Negative binomial model
    Statistical analysis description
    Analysis model: rates, rate ratios, and p-value are from a negative binomial regression analysis, with treatment, LAMA maintenance treatment and sex included in the model as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.751
    Method
    		 negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 2.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41

    Secondary: Frequency of symptom defined COPD exacerbations (EXACT daily diary)

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    End point title
    		 Frequency of symptom defined COPD exacerbations (EXACT daily diary)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106
    105
    Units: exacerbations / year
        least squares mean (standard error)
    1.96 ( 0.54 )
    2.33 ( 0.64 )
    Statistical analysis title
    		 Negative binomial model
    Statistical analysis description
    Analysis model: rates, rate ratios, and p-value are from a negative binomial regression analysis, with treatment, LAMA maintenance treatment, baseline FEV1 and sex included in the model as covariates.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19

    Secondary: Transitional Dyspnoea Index - Total Daily Score

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    End point title
    		 Transitional Dyspnoea Index - Total Daily Score
    End point description
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    102
    100
    Units: Score
        least squares mean (standard error)
    1.29 ( 0.43 )
    1.58 ( 0.44 )
    Statistical analysis title
    		 Mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit and treatment by visit interaction as fixed effects, patient as a random effect and baseline assessment as a continuous covariate. An unstructured covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.3468
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.32
    Notes
    [14] - Positive values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Secondary: St George Respiratory Questionnaire for COPD patients (SGRQ-C)

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    End point title
    		 St George Respiratory Questionnaire for COPD patients (SGRQ-C)
    End point description
    Change from pre study-treatment baseline in Health related quality of life (as assessed by St George Respiratory Questionnaire for COPD patients [SGRQ-C] total score)
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    99
    102
    Units: Score
        least squares mean (standard error)
    -5.7 ( 2.43 )
    -6.65 ( 2.48 )
    Statistical analysis title
    		 Mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit and treatment by visit interaction as fixed effects, patient as a random effect and baseline assessment as a continuous covariate. An unstructured covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.5909
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 4.43
    Notes
    [15] - Negative values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Secondary: Spirometry assessments - FEV1

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    End point title
    		 Spirometry assessments - FEV1
    End point description
    Pulmonary function measured as changes from baseline (post bronchodilator at Visit 3) in trough Forced Expiratory Volume in 1 second (FEV1)
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    103
    104
    Units: Litres
        least squares mean (standard error)
    -0.07 ( 0.04 )
    -0.08 ( 0.04 )
    Statistical analysis title
    		 mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit, sex, smoking history and treatment by visit interaction as fixed effects, patient as a random effect, and baseline assessment, age, BMI and height as continuous covariates. A compound symetry covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.5144
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.07
    Notes
    [16] - Positive values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Secondary: Spirometry Assessments - FVC

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    End point title
    		 Spirometry Assessments - FVC
    End point description
    Pulmonary function measured as changes from baseline (post bronchodilator at Visit 3) in trough Forced Vital Capacity (FVC)
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    103
    104
    Units: Litres
        least squares mean (standard error)
    -0.07 ( 0.05 )
    -0.05 ( 0.06 )
    Statistical analysis title
    		 Mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit, sex, smoking history and treatment by visit interaction as fixed effects, patient as a random effect, and baseline assessment, age, BMI and height as continuous covariates. A compound symmetry covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.5416
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.05
    Notes
    [17] - Positive values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Secondary: Spirometry assessments - FEV1/FVC

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    End point title
    		 Spirometry assessments - FEV1/FVC
    End point description
    Pulmonary function measured as changes from baseline (post bronchodilator at Visit 3) in trough FEV1/FVC
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    103
    104
    Units: L / L
        least squares mean (standard error)
    -0.01 ( 0.01 )
    -0.01 ( 0.01 )
    Statistical analysis title
    		 Mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit, sex, smoking history and treatment by visit interaction as fixed effects, patient as a random effect, and baseline assessment, age, BMI and height as continuous covariates. A compound symetry covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.1965
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.02
    Notes
    [18] - Positive values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Secondary: EXACT for Respiratory Symptoms (E-RS)

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    End point title
    		 EXACT for Respiratory Symptoms (E-RS)
    End point description
    Symptoms of COPD (using the EXACT for Respiratory Symptoms [E-RS] Total Score, a subset of items from the EXACT diary)
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 AZD7624 1.0 mg Placebo
    Number of subjects analysed
    106
    105
    Units: Score
        least squares mean (standard error)
    -0.21 ( 0.88 )
    0.17 ( 0.91 )
    Statistical analysis title
    		 Mixed model repeated measures analysis
    Statistical analysis description
    Results obtained from mixed model repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit and treatment by visit interaction as fixed effects, patient as a random effect and baseline assessment as a continuous covariate. An unstructured covariance matrix has been used.
    Comparison groups
    AZD7624 1.0 mg v Placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.5474
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 0.85
    Notes
    [19] - Negative values for a difference show AZD7624 to have a favourable outcome compared to Placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events occurring during the treatment period or 2-week follow-up period are reported
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    AZD7624 1.0 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Total
    Reporting group description
    		 -

    Serious adverse events
    		 AZD7624 1.0 mg Placebo Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 108 (10.19%)
    11 / 105 (10.48%)
    22 / 213 (10.33%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 105 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Coronary artery occlusion
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 105 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 105 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 108 (6.48%)
    6 / 105 (5.71%)
    13 / 213 (6.10%)
         occurrences causally related to treatment / all
    2 / 10
    0 / 8
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 105 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 105 (0.95%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 105 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 AZD7624 1.0 mg Placebo Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 108 (65.74%)
    48 / 105 (45.71%)
    119 / 213 (55.87%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 105 (1.90%)
    5 / 213 (2.35%)
         occurrences all number
    3
    2
    5
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    5 / 108 (4.63%)
    1 / 105 (0.95%)
    6 / 213 (2.82%)
         occurrences all number
    6
    2
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 105 (0.00%)
    3 / 213 (1.41%)
         occurrences all number
    3
    0
    3
    Asthenia
         subjects affected / exposed
    2 / 108 (1.85%)
    4 / 105 (3.81%)
    6 / 213 (2.82%)
         occurrences all number
    2
    5
    7
    Oedema peripheral
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 105 (2.86%)
    3 / 213 (1.41%)
         occurrences all number
    0
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    31 / 108 (28.70%)
    23 / 105 (21.90%)
    54 / 213 (25.35%)
         occurrences all number
    40
    30
    70
    Cough
         subjects affected / exposed
    8 / 108 (7.41%)
    2 / 105 (1.90%)
    10 / 213 (4.69%)
         occurrences all number
    8
    2
    10
    Dyspnoea
         subjects affected / exposed
    8 / 108 (7.41%)
    4 / 105 (3.81%)
    2 / 213 (0.94%)
         occurrences all number
    11
    5
    16
    Productive cough
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 105 (0.00%)
    3 / 213 (1.41%)
         occurrences all number
    3
    0
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 105 (0.95%)
    5 / 213 (2.35%)
         occurrences all number
    4
    1
    5
    Pain in extremity
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 105 (2.86%)
    3 / 213 (1.41%)
         occurrences all number
    0
    3
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 108 (4.63%)
    3 / 105 (2.86%)
    8 / 213 (3.76%)
         occurrences all number
    5
    3
    8
    Bronchitis
         subjects affected / exposed
    4 / 108 (3.70%)
    2 / 105 (1.90%)
    6 / 213 (2.82%)
         occurrences all number
    4
    2
    6
    Nasopharyngitis
         subjects affected / exposed
    4 / 108 (3.70%)
    4 / 105 (3.81%)
    8 / 213 (3.76%)
         occurrences all number
    4
    4
    8
    Sinusitis
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 105 (2.86%)
    4 / 213 (1.88%)
         occurrences all number
    2
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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