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    Clinical Trial Results:
    Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo when administered to patients with stable chronic obstructive pulmonary disease

    Summary
    EudraCT number
    2011-001524-38
    Trial protocol
    GB   SE   SK   HU   CZ   ES   FI   BE   DE   AT   DK   PL   IT  
    Global end of trial date
    04 Jan 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Sep 2016
    First version publication date
    30 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M/40464/30
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01462942
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    2 Kingdom St, London, United Kingdom, W2 6BD
    Public contact
    Esther Garcia, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Esther Garcia, 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
    04 Jan 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the long-term bronchodilation of aclidinium bromide/formoterol fixed dose combinations compared to individual components and placebo, when administered BID via inhalation to COPD patients 2. To assess the benefits of aclidinium bromide/formoterol fixed dose combinations in COPD symptoms, disease-related health status and COPD exacerbations compared to individual components and placebo, when administered BID via inhalation to COPD patients 3. To evaluate the long-term safety and tolerability of aclidinium bromide/formoterol fixed dose combinations compared to individual components and placebo when administered BID via inhalation to COPD patients
    Protection of trial subjects
    This study was performed according to the local regulations of each country where the study was conducted, the directives of the Declaration of Helsinki for biomedical research in humans adopted by the 18th World Medical Assembly, Helsinki (1964), revised at Tokyo (1975), Venice (1983), Hong Kong (1989), Somerset West (1996) and Edinburgh (2000) including the Note of Clarification in paragraph 29, Washington (2002), Tokyo (2004) and Seoul (2008), as well as in compliance with the guidelines of the International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) Salbutamol pMDI (100 μg/puff) was allowed during the study as relief medication provided the 6 hours washout was maintained prior to any scheduled visit
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Oct 2011
    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
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Croatia: 13
    Country: Number of subjects enrolled
    Czech Republic: 134
    Country: Number of subjects enrolled
    Denmark: 30
    Country: Number of subjects enrolled
    Finland: 27
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 303
    Country: Number of subjects enrolled
    Hungary: 88
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    Poland: 244
    Country: Number of subjects enrolled
    Romania: 119
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    Slovakia: 36
    Country: Number of subjects enrolled
    South Africa: 141
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 34
    Country: Number of subjects enrolled
    Ukraine: 210
    Country: Number of subjects enrolled
    United Kingdom: 120
    Worldwide total number of subjects
    1729
    EEA total number of subjects
    1289
    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)
    965
    From 65 to 84 years
    763
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 22 countries (Austria, Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, the Netherlands, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Ukraine and UK). The first patient was screened in October 2011 and the last patient visit was in January 2013

    Pre-assignment
    Screening details
    In total 2443 patients were screened, of whom, 1729 patients were considered eligible and were randomised into the study. In total, 714 (29.2%) patients were considered screen failures, the main reason being non-fulfilment of inclusion/exclusion criteria (88.9%)

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)
    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
    Administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Arm title
    Aclidinium/Formoterol 400/12 μg
    Arm description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide / Formoterol fumarate 400/12 μg fixed-dose combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aclidinium bromide / Formoterol fumarate 400/12 μg administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Arm title
    Aclidinium/Formoterol 400/6 μg
    Arm description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide / Formoterol fumarate 400/6 μg fixed-dose combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aclidinium bromide / Formoterol fumarate 400/6 μg administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Arm title
    Aclidinium 400 μg
    Arm description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)
    Arm type
    Active comparator

    Investigational medicinal product name
    Aclidinium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    400 μg administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Arm title
    Formoterol 12 μg
    Arm description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)
    Arm type
    Active comparator

    Investigational medicinal product name
    Formoterol fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    12 μg administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Number of subjects in period 1
    Placebo Aclidinium/Formoterol 400/12 μg Aclidinium/Formoterol 400/6 μg Aclidinium 400 μg Formoterol 12 μg
    Started
    194
    385
    381
    385
    384
    Completed
    160
    351
    341
    335
    339
    Not completed
    34
    34
    40
    50
    45
         Protocol deviation
    4
    6
    9
    9
    6
         Lack of efficacy
    6
    -
    4
    5
    3
         Adverse event, non-fatal
    7
    12
    10
    11
    11
         Consent withdrawn by subject
    14
    10
    14
    16
    19
         Lost to follow-up
    -
    1
    1
    1
    1
         Other, including COPD exacerbation
    3
    5
    2
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/6 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Formoterol 12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group values
    Placebo Aclidinium/Formoterol 400/12 μg Aclidinium/Formoterol 400/6 μg Aclidinium 400 μg Formoterol 12 μg Total
    Number of subjects
    194 385 381 385 384 1729
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    94 230 222 208 211 965
        From 65-84 years
    100 155 158 177 173 763
        85 years and over
    0 0 1 0 0 1
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    64.2 ± 8 62.7 ± 8.1 62.9 ± 7.7 63.1 ± 8.2 63.4 ± 7.8 -
    Gender, Male/Female
    Units: Participants
        Female
    56 124 122 129 129 560
        Male
    138 261 259 256 255 1169

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/6 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Formoterol 12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Subject analysis set title
    Placebo (ITT population)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population defined as all randomised patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

    Subject analysis set title
    Aclidinium/Formoterol 400/12 μg (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population defined as all randomised patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

    Subject analysis set title
    Aclidinium/Formoterol 400/6 μg (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population defined as all randomised patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

    Subject analysis set title
    Aclidinium 400 μg (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population defined as all randomised patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

    Subject analysis set title
    Formoterol 12 μg (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population defined as all randomised patients who took at least one administration of study medication and had a baseline and at least one post-baseline FEV1 assessment

    Primary: Change from baseline in 1-hour morning post-dose forced expiratory volume in one second (FEV1)

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    End point title
    Change from baseline in 1-hour morning post-dose forced expiratory volume in one second (FEV1)
    End point description
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    Placebo (ITT population) Aclidinium/Formoterol 400/12 μg (ITT) Aclidinium/Formoterol 400/6 μg (ITT) Aclidinium 400 μg (ITT) Formoterol 12 μg (ITT)
    Number of subjects analysed
    157
    347
    339
    327
    335
    Units: Liters
        least squares mean (standard error)
    -0.03 ± 0.018
    0.269 ± 0.013
    0.213 ± 0.013
    0.144 ± 0.013
    0.129 ± 0.013
    Statistical analysis title
    Aclidinium/Formoterol 400/12 µg v Aclidinium
    Comparison groups
    Aclidinium/Formoterol 400/12 μg (ITT) v Aclidinium 400 μg (ITT)
    Number of subjects included in analysis
    674
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.16
    Statistical analysis title
    Aclidinium/Formoterol 400/6 µg v Aclidinium
    Comparison groups
    Aclidinium/Formoterol 400/6 μg (ITT) v Aclidinium 400 μg (ITT)
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.069
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.034
         upper limit
    0.105

    Primary: Change from baseline in morning pre-dose (trough) forced expiratory volume in one second (FEV1)

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    End point title
    Change from baseline in morning pre-dose (trough) forced expiratory volume in one second (FEV1)
    End point description
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    Placebo (ITT population) Aclidinium/Formoterol 400/12 μg (ITT) Aclidinium/Formoterol 400/6 μg (ITT) Aclidinium 400 μg (ITT) Formoterol 12 μg (ITT)
    Number of subjects analysed
    159
    349
    340
    332
    337
    Units: Liters
        least squares mean (standard error)
    -0.061 ± 0.018
    0.083 ± 0.012
    0.05 ± 0.012
    0.056 ± 0.012
    -0.002 ± 0.012
    Statistical analysis title
    Aclidinium/Formoterol 400/12 μg v Formoterol 12 μg
    Comparison groups
    Aclidinium/Formoterol 400/12 μg (ITT) v Formoterol 12 μg (ITT)
    Number of subjects included in analysis
    686
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.119
    Statistical analysis title
    Aclidinium/Formoterol 400/6 μg v Formoterol 12 μg
    Comparison groups
    Aclidinium/Formoterol 400/6 μg (ITT) v Formoterol 12 μg (ITT)
    Number of subjects included in analysis
    677
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.019
         upper limit
    0.087

    Secondary: Improvement in Transition Dyspnoea Index (TDI) focal score

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    End point title
    Improvement in Transition Dyspnoea Index (TDI) focal score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (ITT population) Aclidinium/Formoterol 400/12 μg (ITT) Aclidinium/Formoterol 400/6 μg (ITT) Aclidinium 400 μg (ITT) Formoterol 12 μg (ITT)
    Number of subjects analysed
    156
    344
    333
    331
    333
    Units: Total score
        least squares mean (standard error)
    1.215 ± 0.241
    2.508 ± 0.162
    2.377 ± 0.165
    2.112 ± 0.165
    2.062 ± 0.164
    Statistical analysis title
    Aclidinium/Formoterol 400/12 μg v Placebo
    Comparison groups
    Placebo (ITT population) v Aclidinium/Formoterol 400/12 μg (ITT)
    Number of subjects included in analysis
    500
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.293
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.728
         upper limit
    1.859
    Statistical analysis title
    Aclidinium/Formoterol 400/6 μg v Placebo
    Comparison groups
    Placebo (ITT population) v Aclidinium/Formoterol 400/6 μg (ITT)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Least Squares Mean Difference
    Point estimate
    1.162
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.593
         upper limit
    1.73

    Secondary: Change from baseline in St. George´s Respiratory Questionnaire (SGRQ) total score

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    End point title
    Change from baseline in St. George´s Respiratory Questionnaire (SGRQ) total score
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Placebo (ITT population) Aclidinium/Formoterol 400/12 μg (ITT) Aclidinium/Formoterol 400/6 μg (ITT) Aclidinium 400 μg (ITT) Formoterol 12 μg (ITT)
    Number of subjects analysed
    154
    338
    332
    327
    332
    Units: Total score
        least squares mean (standard error)
    -6.511 ± 1.029
    -7.164 ± 0.703
    -8.339 ± 0.706
    -5.801 ± 0.71
    -5.579 ± 0.706
    Statistical analysis title
    Aclidinium/Formoterol 400/12 μg v Placebo
    Comparison groups
    Placebo (ITT population) v Aclidinium/Formoterol 400/12 μg (ITT)
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.598
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -0.653
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.082
         upper limit
    1.776
    Statistical analysis title
    Aclidinium/Formoterol 400/6 μg v Placebo
    Comparison groups
    Placebo (ITT population) v Aclidinium/Formoterol 400/6 μg (ITT)
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1406
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -1.828
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.259
         upper limit
    0.604

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    26 Weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium/Formoterol 400/6 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Aclidinium 400 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Reporting group title
    Formoterol 12 μg
    Reporting group description
    Safety population defined as all randomised patients who took at least one administration of study medication - medication administered BID by inhalation, in the mornings and evenings using a multi-dose dry powder inhaler (Genuair®)

    Serious adverse events
    Placebo Aclidinium/Formoterol 400/12 μg Aclidinium/Formoterol 400/6 μg Aclidinium 400 μg Formoterol 12 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 194 (6.19%)
    24 / 385 (6.23%)
    20 / 381 (5.25%)
    16 / 385 (4.16%)
    15 / 384 (3.91%)
         number of deaths (all causes)
    0
    1
    2
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemi
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage unspecified
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal cancer stage unspecified
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer stage unspecified
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic oedema
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal injury
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic shock
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    1 / 385 (0.26%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 194 (0.00%)
    2 / 385 (0.52%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Diverticulum Meckel's
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary diseas
         subjects affected / exposed
    5 / 194 (2.58%)
    4 / 385 (1.04%)
    4 / 381 (1.05%)
    7 / 385 (1.82%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 4
    1 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Episcleritis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer hemorrhage
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer hemorrhage
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Breast abscess
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious peritonitis
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 194 (0.52%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    1 / 381 (0.26%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 194 (0.52%)
    3 / 385 (0.78%)
    4 / 381 (1.05%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    1 / 385 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    0 / 385 (0.00%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 194 (0.00%)
    1 / 385 (0.26%)
    0 / 381 (0.00%)
    0 / 385 (0.00%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Aclidinium/Formoterol 400/12 μg Aclidinium/Formoterol 400/6 μg Aclidinium 400 μg Formoterol 12 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 194 (21.65%)
    82 / 385 (21.30%)
    84 / 381 (22.05%)
    94 / 385 (24.42%)
    105 / 384 (27.34%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    23 / 194 (11.86%)
    33 / 385 (8.57%)
    36 / 381 (9.45%)
    39 / 385 (10.13%)
    59 / 384 (15.36%)
         occurrences all number
    24
    38
    45
    45
    71
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 194 (8.25%)
    29 / 385 (7.53%)
    27 / 381 (7.09%)
    35 / 385 (9.09%)
    43 / 384 (11.20%)
         occurrences all number
    22
    50
    48
    67
    114
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 194 (4.64%)
    18 / 385 (4.68%)
    13 / 381 (3.41%)
    20 / 385 (5.19%)
    19 / 384 (4.95%)
         occurrences all number
    12
    21
    15
    32
    27
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 194 (7.22%)
    30 / 385 (7.79%)
    30 / 381 (7.87%)
    22 / 385 (5.71%)
    26 / 384 (6.77%)
         occurrences all number
    15
    32
    43
    67
    114

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2012
    Amendments included: MACE adjudication was to be assessed during the study; Statistical analyses updated according to the CHMP scientific advice; COPD exacerbations according to Health Resource Utilisation updated; An additional analysis population added, ITT-Exacerbations; Pooled analysis adjusted for EU and US filing purposes; Sensitivity analysis to assess the robustness of the MMRM model was updated.

    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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