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    Clinical Trial Results:
    A randomised, double-blind, placebo controlled, parallel study to assess the benefits of aclidinium bromide in the relief of COPD symptoms including cough when administered to patients with COPD

    Summary
    EudraCT number
    		 2014-004715-37
    Trial protocol
    		 DE   GB   HU   IT   ES  
    Global end of trial date
    17 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2016
    First version publication date
    12 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M-34273-46
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02375724
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alternative sponsor identifier: D6560C00001
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    2 Kingdom St, London, United Kingdom, W2 6BD
    Public contact
    Study Director, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Study Director, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the effect of aclidinium bromide 400 μg administered twice a day on COPD symptoms including cough and on cough-related quality of life measures in patients with moderate COPD compared to placebo
    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/Good Clinical Practice and applicable regulatory requirements and the AstraZeneca policy on Bioethics Before enrolment into the study, all patients were comprehensively informed by the investigator (or the personnel identified as designated staff) orally and by means of the patient information sheet about the characteristics of the investigational medicinal products to be administered, the nature of the clinical investigation, the risks and the discomfort that could reasonably be expected as a result of their participation and about their right to withdraw at any time from the study, without prejudice and without any need to specify the reasons Patients documented their willingness to participate in the study by giving their written consent by signing the Informed Consent Form before the start of any study procedure Salbutamol pMDI (100 μg/puff) was allowed as relief medication
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Mar 2015
    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: 115
    Country: Number of subjects enrolled
    Hungary: 88
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    United Kingdom: 36
    Worldwide total number of subjects
    269
    EEA total number of subjects
    269
    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)
    163
    From 65 to 84 years
    105
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were randomized in 30 study sites in 5 countries Germany (10 sites), Hungary (6), Italy (2), Spain (9) and the United Kingdom (3) First patient was enrolled in March 2015 and last patient last visit was in November 2015

    Pre-assignment
    Screening details
    		 300 patients were screened; 269 were assessed as eligible and were randomized into the study Thirty-one patients failed screening, with the main reason for screening failure being non-fulfilment of the inclusion or exclusion criteria (24 patients)

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Aclidinium 400 μg
    Arm description
    		 Aclidinium bromide 400 μg BID administered by Genuair® multidose dry powder inhaler
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aclidinium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 puff of 400 μg in the morning (09:00±1 hour) and in the evening (21:00±1 hour)

    Arm title
    		 Placebo
    Arm description
    		 Placebo BID administered by Genuair® multidose dry powder inhaler
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 puff of 400 μg in the morning (09:00±1 hour) and in the evening (21:00±1 hour)

    Number of subjects in period 1
    		Aclidinium 400 μg Placebo
    Started
    135
    134
    Completed
    129
    128
    Not completed
    6
    6
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    2
    4
         Lost to follow-up
    1
    -
         Lack of efficacy
    1
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    		 Aclidinium bromide 400 μg BID administered by Genuair® multidose dry powder inhaler

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BID administered by Genuair® multidose dry powder inhaler

    Reporting group values
    		 Aclidinium 400 μg Placebo Total
    Number of subjects
    		 135 134 269
    Age categorical
    Units: Subjects
        Adults (18-65 years)
    		 89 81 170
        From 66-84 years
    		 45 53 98
        85 years and over
    		 1 0 1
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 62 ( 8.4 ) 62 ( 9.1 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 57 50 107
        Male
    		 78 84 162

    End points

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    End points reporting groups
    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    		 Aclidinium bromide 400 μg BID administered by Genuair® multidose dry powder inhaler

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BID administered by Genuair® multidose dry powder inhaler

    Primary: Change from baseline in overall Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS) total score

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    End point title
    		 Change from baseline in overall Exacerbations of Chronic Pulmonary Disease Tool-Respiratory Symptoms (E-RS) total score
    End point description
    The EXACT-Respiratory Symptoms (E-RS) questionnaire was completed every evening The E-RS scale is an instrument comprising a subset of EXACT items to test the effect of treatment on the severity of respiratory symptoms in stable COPD Eleven of the 14-items of the EXACT questionnaire provides information about COPD symptoms: The E-RS Total Score is an aggregate of three domains: chest symptoms (derived sum of 3 items), cough and sputum (derived sum of 3 items) and RS-breathlessness (derived sum of 4 items) Individual scores are rated from 0 to 4
    End point type
    Primary
    End point timeframe
    Week 8
    End point values
    		 Aclidinium 400 μg Placebo
    Number of subjects analysed
    131
    133
    Units: Score
        least squares mean (standard error)
    -1.75 ( 0.342 )
    -0.73 ( 0.342 )
    Statistical analysis title
    		 Aclidinium v Placebo
    Comparison groups
    Aclidinium 400 μg v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0306
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 -0.1

    Secondary: Change from baseline in overall E-RS cough and sputum domain score

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    End point title
    		 Change from baseline in overall E-RS cough and sputum domain score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Aclidinium 400 μg Placebo
    Number of subjects analysed
    131
    133
    Units: Score
        least squares mean (standard error)
    -0.54 ( 0.09 )
    -0.33 ( 0.09 )
    Statistical analysis title
    		 Aclidinium v Placebo
    Comparison groups
    Aclidinium 400 μg v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0793
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.03

    Secondary: Change from baseline in the Leicester Cough Questionnaire (LCQ) total score

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    End point title
    		 Change from baseline in the Leicester Cough Questionnaire (LCQ) total score
    End point description
    The LCQ is a self-administered questionnaire that assesses cough related quality of life The LCQ comprises 19 items and 3 domains (physical, psychological and social) The total score ranges from 3 to 21 and each domain scores range from 1 to 7; a higher score indicates a better quality of life
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Aclidinium 400 μg Placebo
    Number of subjects analysed
    126
    128
    Units: Score
        least squares mean (standard error)
    1.18 ( 0.214 )
    1.24 ( 0.214 )
    Statistical analysis title
    		 Aclidinium v Placebo
    Comparison groups
    Aclidinium 400 μg v Placebo
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.844
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 0.52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 70±3
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo BID administered by Genuair® multidose dry powder inhaler

    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    		 Aclidinium bromide 400 μg BID administered by Genuair® multidose dry powder inhaler

    Serious adverse events
    		 Placebo Aclidinium 400 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 134 (1.49%)
    2 / 135 (1.48%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Cartilage injury
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Aclidinium 400 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 134 (14.93%)
    11 / 135 (8.15%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 134 (9.70%)
    7 / 135 (5.19%)
         occurrences all number
    25
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 134 (6.72%)
    4 / 135 (2.96%)
         occurrences all number
    10
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2014
    Correction included, as the Investigator Brochure was not provided along with the protocol and was available on request; Modification of the clarification note of inclusion criteria 1, as a serum pregnancy test was not performed in the study, but a urine pregnancy test was performed; Correction on the number of digits for site identification, as the first 5 digits representing the investigator identifier was replaced by the first 4 digits representing the site identifier

    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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